Dear All Answer the following question with a justification of your answer (not more than 50 words):Late acute rejection
A. Usually associated with poor graft outcome
B. The prognosis may be better if due to non-compliance
C. Commonly antibody-mediated
D. Usually responds well to steroid pulses
E. May be caused by de novo DSA
LAR differ from EAR in risk factors, management & prognosis. While the incidence of EAR is decreasing due to using of MMF & CNI, the incidence of LAR is not changed markedly. It had poorer graft survival as most patients will losses their graft after one year of follow-up. Most cases of LAR are due to ABMR that mainly caused by de novo DSA & TCMR occurs only in minority of cases.
There are no standard treatment for LAR, but IVIG, rituximab & bortezumab had been used with no significant benefit.
Cases of LAR that show no or little chronic histopathological changes on renal biopsy had good response to IV methyl-prednisolone or high oral prednisolone, with maintenance MMF, CNI & low dose steroids.
References:
Eid L., Tuchman S. and Moudgil A. Late acute rejection: Incidence, risk factors, and effect on graft survival and function. Pediatric Transplantation. 2013; (18): 155-162.
Kunchala R., Gudipati A., Guditi S., et al. Late Acute Rejection in Renal Allografts: Clinical, and Follow-up Data from a Single Tertiary Care Center. Indian Journal of Transplantation. 2018; 12.
Nair R., Agrawal N., and Lebaeau M., et al. Late Acute Kidney Transplantation Rejection: Clinicaopathological Correlates and Response to Corticosteroid Therapy. Transplantation Proceedings. 2009, (41): 4150-4153.
the correct answer A, C&E
late acute rejection type is more due to ABMR, immunsuppressive non-adhereance can play role in late acute rejection in addition to the prsence of denovo DSAs-AB usually diagnosed late due to less frequent clinical monitroing so patinet might present with some chronicity index in tissue biopsy at time of diagnosis also difficult to treat , not responding to steriods need more aggressive treatment and can progress to chronic allograft rejection with poor graft survival.
A and c :
Late acute rejection is usually associated with poor graft survival more than EAR which incidence has decreased now due to advances on immunosuppressive
One study of 687 transplant recipients at one U.K. center in 1984 to 1996 defined “early” AR as occurring within 90 days of transplantation and “later” AR as any AR event from 91 days out to a maximum of 14 years Five-year graft survival rates were 87% in patients without AR, 63% in those with “early” AR, and 45% in those with “late” AR
C: increased graft loss risk associated with late AR is likely mediated by multiple factors
late AR is more of AB mediated and carry poor prognosis as clinical monitoring is less intense in the later period , patient follow up every 2-3 months so late AR can be diagnosed late with more sever and chronic graft damage and less treatable at time of diagnosis.
E: among significant risk factors for LAR IS denovo DSA
Philip A. Clayton, Stephen P. McDonald.
Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis.JASN September 2019, 30 (9) 1697-1707;
A. Usually associated with poor graft outcome T B. Commonly antibody-mediated T
Episodes of LAR was reported by several studies to be more aggressive than episodes of EAR this may be explained by the higher incidence and severity of ABMR which is associated with lower graft survival, Moreover frequency of attacks of TCMR usually decline with time but if occur late it is usually associated with ABMR (pure TCMR > 1 year is not common) and is not sensitive to corticosteroid when compared to attacks < 1 year post transplant (1, 2)
C. The prognosis may be better if due to non-compliance F
Noncompliance leads to development of DSA with subsequent ABMR and also leads to increase in the risk of TCMR so mixed rejection is common which is associated with poor graft outcome
Moreover noncompliance is associated with increase in the probability of recurrence of rejection with more poor prognosis
C. D. Usually responds well to steroid pulses F
ABMR is not steroid sensitive and need aggressive therapy including IVIG, plasmapheresis, Rituximab in addition to pulse steroids, Moreover TCMR occurring late usually is not steroid sensitive and this may be explained by the associated with ABMR.
A. May be caused by de novo DSA T
Denovo DSA is strongly linked to ABMR
REFERANCES
1. Bertrand D, Gatault P, Jauréguy M, Garrouste C, Sayegh J, Bouvier N, et al. Protocol Biopsies in Patients With Subclinical De Novo Donor-specific Antibodies After Kidney Transplantation: A Multicentric Study. Transplantation. 2020;104(8): 1726–1737.
2. Wan SS, Chadban SJ, Watson N, Wyburn K. Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients. Am J Transplant. 2020;20(5): 1351–1364
Late acute rejection
A. Usually associated with poor graft outcome….T
1)Late rejection mostly sever ABMR or steroids resistant TCMR
2)late discover
3) patient usually underimmune suppressed
B. The prognosis may be better if due to non-compliance…F
Non compliance associated with sever both ABMR ,TCMR with poor graft survival
C. Commonly antibody-mediated….T
Pure TCMR is lower after 1st year post transplant
D. Usually responds well to steroid pulses…F
Usually discovered late and of class 2,3 and show steroids resistant
E. May be caused by de novo DSA…T
Donovo DSA occurs in 11% of non sensitized patients and associated with both late acute ABMR and chronic ABMR
Late acute rejection is commonly ABMR and may be due to the development of de novo DSA.
Non-compliance is a major problem as it may lead to the development of DSA and specialized memory cells against the donor antigens which are associated with a poor long term outcome (that is also aggravated by the under immune suppression secondary to non-compliance).
Late acute rejection
A. Usually associated with poor graft outcome
B. The prognosis may be better if due to non-compliance
C. Commonly antibody-mediated
D. Usually responds well to steroid pulses
E. May be caused by de novo DSA
True: A, C, E False: B, D
A: True: Late acute rejection is usually due to under-immunosuppression and de-novo DSA, antibody mediated and hence usually has poor graft outcomes.
B: False: Non-compliance leads to under-immunosuppression, and hence increased DSA formation, with poor prognosis.
C: True: Late acute rejection is usually antibody-mediated due to de novo DSA
D: False: Steroid pulses have a role in treatment of late acute rejection as a component of T cell mediated rejection is usually present, but Steroid ALONE will not be effective, unless it is pure T cell mediated rejection.
E: True: Late acute rejection is usually due to under-immunosuppression and de-novo DSA.
it is usually associated with poor graft outcome as it affects an already impaired and exhauseted graft. then both proper diagnosis and treatment are usually done late in the course of diseae.
compliance to ttt is critical for managing transplantation, even it can let some patients to be not transplanted if they have poor compliance to any offerred treatment.
it is commonly due to de novo DSA and responds poorly to steroids.
B. Late acute rejection is associated with worsened graft survival than early but the reason for the bad prognosis could be because of immunologic activity and triggering factors such as infection or no adherence to immunosuppressive medication. Hence prognosis could be better if the issue is due to non compliance.
Ref:
Eun Hee Koo, Jang et al. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney research and clinical practice. Vol 34, issue 3, 2015 Sep, pp. 160-164. https://doi.org/10.1016/j.krcp.2015.06.003
Several studies had shown that Late AR (LAR) has a worse prognosis than early acute rejection with inferior graft survival. Development of de novo DSA, non-adherence or suboptimal immunosuppression, and recurrent acute rejection episodes are important risk factors for LAR. Hence, Patients with de novo DSA and DGF should be considered at risk of LAR.
Acute cellular rejection is the most common form of rejection. Most acute rejection episodes improve with steroid boluses or with an escalation of immunosuppression.
Usually associated with poor graft out come? T Many studies have been conducted to explore whether the timing of AR affects graft survival. The majority of these studies reported that LAR was correlated with poor long-term graft survival . ]Joseph JT, Kingsmore DB, Junor BJ, Briggs JD, Mun Woo Y, JaquesBC, Hamilton DN, Jardine AG, Jindal RM: The impact of late acuterejection after cadaveric kidney transplantation.Clin Transplant15:221–227, 2001[2 The prognosis may better if due to none-compliance ? F
Nonadherence was more frequent in patients who progressed to failure versus those who survived . ] [5]Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B,Hidalgo LG, Famulski K, Matas A, Halloran PF: Understanding thecauses of kidney transplant failure: the dominant role ofantibody-mediated rejection and nonadherence.Am J Transplant.
.
Commonly antibody mediated ? T
ABMR became common in biopsy specimens obtained 1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time.
Am Soc Nephrol 26: ccc–ccc, 2014. doi: 10.1681/ASN.201406058
Usually respond well to steroid pulses ? F
There is significant advantage for pulse therapy in patients who sought treatment early . Pulse therapy also appeared beneficial in preventing subsequent rejection episodes. John C.HillFRCS1RichardMaskeFCS(SA)1PeterWatsonFRCS2
May be caused by de novo DSA? T
Late ABMR is commonly associated with de novo DSA
Aubert O, Loupy A, Hidalgo L, et al. Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients. J Am Soc Nephrol 2017; 28: 1912.
A _true ACR associated with poor graft function and survival
B_ false non compliance cause DSA and AMR
C_ true most commonly is AMR
D_ false respondent well to steroid in cases of ACR but some patients need to give ATG
E_true
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome
• True – majority of studies reported that LAR was correlated with poor long- term graft survival
B. The prognosis may be better if due to non-compliance
• False – the LAR probably either pure ABMR or mixed because by the time of failure, every nonadherent patient failing with rejection had DSA, have such a poor prognosis and response to therapy
C. Commonly antibody-mediated
• True- its probably pure ABMR or mixed type. Rarely T cell mediated.
D. Usually responds well to steroid pulses
• False- LAR usually antibody mediated rejection and it need IVIG , PLEX with or without Rituximab. It may respond to steroid but not as
E. May be caused by de novo DSA
• True- LAR may be caused by DnDSA
References
1-Kunchala R., Gudipati A., Guditi S., Taduri G., et al. Late Acute Rejection in Renal Allografts: Clinical, Pathologic, and Follow‑up Data from a Single Tertiary Care Center. Indian Journal of Transplantation.2018;January-March. Volume 12,Issue 1.
2-Krisl J.C., Alloway R.R.,Shield A.R.,Govil A., et al. Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival. Transplantation.October 2015,Volume 99, Number 10.
3-Cooper J.E. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN. 2020; March,15: 430–438.
Renal transplant recipients who develop a de novo DSA after transplantation can present with late-onset ABMR. ABMR in patients with a de novo DSA has been associated with poorer outcomes compared with ABMR in patients with preexisting DSA
A,C,E
Commonly AMR as de novo DSA performed causing TG that affect the survival of the graft
& also it difficult to treated as mentioned above ( using steroid, plasma ex, Rituximab, IVIG ) and they also try toclizomab
Late acute rejection
A. Usually associated with poor graft outcome. True
-LAR has a serious impact on long-term graft survival.
B. The prognosis may be better if due to non-compliance. False
-Non-adherence to immunosuppressive therapy lead to de novo DSA which can lead to SAMR and graft deterioration and long-term graft dysfunction
C. Commonly antibody-mediated.True
-LAR in most cases is AMR while pure TCMR accounts for only a minority of LAR cases.
D. Usually responds well to steroid pulses. False
-Response to steroid according to the type of rejection (AMR or TCMR)
E. May be caused by de novo DSA. True
-It due to de novo DSA References :
1.Rajamahesh Kunchala1, Archana Gudipati1, Swarnalatha Guditi2, Gangadhar Taduri2, Sree Bhushan Raju2, Megha S Uppin1 .Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center .Indian journal of transplant.Year : 2018 | Volume : 12 | Issue : 1 | Page : 48-52.
A. Usually associated with poor graft outcome True
LAR associated with poor long -term graft survival
B. The prognosis may be better if due to non-compliance False
Non adherence to treatment is a strong
risk factor for LAR with poor graft survival outcome
C. Commonly antibody-mediated True
Mainly AMR with small percentage CMR
D. Usually responds well to steroid pulses True
subset of C4d+ patients with acute rejection who do not have severe chronic changes might respond to corticosteroid therapy alone.
The majority of C4d+ patients with late acute rejection who were treated with corticosteroids alone responded to treatment.
E. May be caused by de novo DSA True
formation of de novo DSA after kidney transplantation is associated with antibody-mediated graft injury that may lead to graft failure
de novo production of DSA, of any specificity, was found to be associated with acute mediated rejection (AMR) and transplant glomerulopathy. Only HLA- Cw DSA were found not to be significantly associated with allograft failure
LAR mostly duet o to ABMR is associated with poor graft outcome especially if repeated. de-novo antibodies may be difficult to treat more than non-compliance that may respond better with dose adjustment if detected early before chronic atrophic changes. the steroid is the first-line treatment but the response is not always excellent to steroid-only treatment all time.
In sum A, B,C and D are logical D is not accurate (response is not always well)
Late acute rejection is usually associated with poor graft outcome. Development of de novo DSA increases the risk of ABMR and could also leads to increase in development of mixed rejection which is associated with poor graft outcome. Late acute rejection may respond to steroids but most of cases do not, and frequently need more aggressive treatment.
A. Usually associated with poor graft outcome.
True
Late ARE showed a strong adverse effect on long-term graft survival
B. The prognosis may be better if due to non-compliance. false
The association of young recipient age and LAR could be partly explained by noncompliance .
Non compliance lead to formation of denovo antibodies
C. Commonly antibody-mediated. true
Late onset of chronic AMR due to denovo DSA has been strongly associated with graft loss and effective therapies are currently lacking.
D. Usually responds well to steroid pulses. false
Poor response to steroid therapy
E. May be caused by de novo DSA. true
Because of non compliance the patient will develop denovo DSA which lead to rejection
Reference
1-YVO W. J. SIJPKENS. EARLY VERSUS LATE ACUTE REJECTION EPISODES IN RENAL TRANSPLANTATION. Vol. 75, 204–208, No. 2, January 27, 2003
Printed in U.S.A.
2-Philip A. Clayton,1,2,3 Stephen P. McDonald,1,2,3 Graeme R. Russ,1,2,3 and Steven J. Chadban1,4,5. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis. JASN 30: 1697–1707, 2019
3-Eun Hee Koo 1, Hye Ryoun Jang 1, The impact of early and late acute rejection on graft survival in renal transplantation. 2015. The Korean Society of Nephrology. Published by Elsevier.
LATE ACUTE GRAFT RJECTION
A. TRUE : compared to early acute rejection due to severe ABMR.
B.FALSE .non compliance to medications can cause DSA and ABMR with increased risk of TCMR and recurrent rejection
C.T due to de novo DSA.
D. FALSE usually resistant to steroid as monotherapy.
E.TRUE de novo DSA are closely related to ABMHR.
REFERENCES:
Danovitch, GM: Handbook of kidney transplantation ,6th edition,2018
KOO,EH, et al The impact of early and late acute rejection on graft survival in renal transplantation, Kid Res and Clin Pract ,vol 34,issue 3,2015,Sept.pp:160-164.
●. Usually associated with poor graft outcome
T . Due to developing ab Mr. And denovo Dsa .
●The prognosis may be better if due to non-compliance
F.
NON COMPLIANCE TO Medication leads to ab mediated rejection
● Commonly antibody-mediated
T . As it is late .. it is rare to be TC mR after 6 months .
●Usually responds well to steroid pulses
F .
However pulse steroid is one role for management it doent respond well
It need ivig /plasma pheresis and iv rituximab.
●May be caused by de novo DSA
T.
Dear All Answer the following question with a justification of your answer (not more than 50 words):Late acute rejection A. Usually associated with poor graft outcome– true
Late-onset AR (occurring beyond the first 6 months after transplantation) has long been known to be associated with increased risk of graft loss. Late onset of chronic AMR in particular has been strongly associated with graft loss
B. The prognosis may be better if due to non-compliance — false non compliance which is more common in young patients is associated DSA formation and AMR WITH POOR POTCOME
C. Commonly antibody-mediated — TRUE
D. Usually responds well to steroid pulses — FALSE
it is usually non steroid responsive antd it is difficult to treat.
E. May be caused by de novo DSA — true yes it is
reffrences
— Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, et al.: Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients. J Am Soc Nephrol26: 1711–1720, 2015pmid:25377077
A-True.
It is sever ABMR , not respond to steroid.
B-False.
As non-compliance related sever ABMR ,TCMR and poor graft survival.
C-True.
D- it discovered late with resistance to steroid.
E-True.
Rehab Fahmy
3 years ago
Late acute rejection can be ABMR or CMR ,it has poor outcome of graft function
management :IVIG ,plasmapheresis ,rejection ituximab ,or bortezomib
it could be due to non compliance
Ben Lomatayo
3 years ago
A. True ;In early rejection, the immune system became more prime than in late rejection where you have more of APCs presenting donor’s particles to recipient lymphoid organs. This activate CD4 T cells which in turn stimulate the humoral arm of the immune system.
B. True ; non-adherence is bad because it is usually chronic and associated with chronic graft loss. Once patient became non-adherent is very difficult to convince them about taking the treatment
C. True ; early acute rejection is commonly T cell mediated while late acute is AMR or it can mixed
D. False ; it may not respond to corticosteroid alone
E. True ; Class II DSA usually develop after some time following transplantation although it can be detected in the pre-transplants period.
Ben Lomatayo
3 years ago
Late acute rejection is defined by a sudden rise in Cr usually after the first year following kidney transplantation. It is seen in < 10% of the recipients. A single event of rejection decreases 5-year allograft survival by < 10%.
Late acute rejection is mostly AMR and may be mixed.
The most important risk factor is non-adherent to immunosuppressive therapy.
The evidence for management is not robust, although acute AMR rejection may be better than chronic AMR.
The best is to prevent rejection to occur at first place.
It involved; IV Corticosteroids, plasmapheresis, IVIG.
Optimise maintenance therapy
Counselling about adherence to drugs.
Wessam Moustafa
3 years ago
Late AR have worse graft and patient survival compared to early acute rejection .
The clinical and pathological features of late acute kidney allograft rejection are not fully understood.
Risk factors are de novo DSA, non compliance , improper prescription and recurrent acute rejection
Management includes:
Close monitoring of at risk patiens to pick them early
Some studies suggested that intensive treatment of LAR may help improve graft survival and long term outcome.
Other studies suggested that it there was no high chronicity index , treatment with steroids may be enough for such patients
1-Esra Baskin, Asli Kantar, Kaan Gulleroglu, Esra Ozmen, Handan Ozdemir, Mahir Kirnap, Gokhan Moray, Mehmet Haberal, SP873 EFFECTS OF LATE ACUTE REJECTION ON GRAFT SURVIVAL AND OUTCOME IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS, Nephrology Dialysis Transplantation, Volume 30, Issue suppl_3, May 2015, Page iii665, https://doi.org/10.1093/ndt/gfv203.11
2-Nair, R., Agrawal, N., Lebaeau, M., Tuteja, S., Chandran, P. K. G., & Suneja, M. (2009). Late Acute Kidney Transplant Rejection: Clinicopathological Correlates and Response to Corticosteroid Therapy. Transplantation Proceedings, 41(10), 4150–4153. doi:10.1016/j.transproceed.2009.
3-Eid L, Tuchman S, Moudgil A. Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant. 2014 Mar;18(2):155-62. doi: 10.1111/petr.12203. Epub 2013 Dec 28. PMID:
Balaji Kirushnan
3 years ago
Late acute rejection
A. Usually associated with poor graft outcome
B. The prognosis may be better if due to non-compliance
C. Commonly antibody-mediated
D. Usually responds well to steroid pulses
E. May be caused by de novo DSA
A: True: Various studies have reported late acute rejections and the outcomes with poor graft survival. Late acute rejections are due to de-novo DSA and they causing late ABMR. Cellular rejections are usually steroid resistant if they occur very late. B: False; Non Compliance of drugs may lead to under immunosuppressed state. This leads to the production of de novo DSA productions and lead on to graft injury C: True: Late acute rejections are due to Class II HLA antibodies and are due to them getting produced de novo after transplant D: False: Partial improvement is known with steroid pulses, but chronic ABMR usually is resistant to any form of treatment including plasmapheresis, IVIG or bortezomib. E: True Late acute rejections are usually due to de Novo DSA which are formed in the post transplant period
Ahmed Omran
3 years ago
Renal biopsy with C4d staining and determination of DSA are required for AR classification.
Acute TCMR
needs to be treated with more aggressive IS ;Tac trough level 5-7 ,and proper MMF dose ,pulse steroid followed by oral steroid .ATG is given according to Banff grading: total max dose of 6 mg in Banff grade IB and 9 mg in Banff grade II&III.. Alemtuzumab could be used if ATG is contraindicated .Additionally, prophylactic antimicrobial therapy is given
Acute ABMR
needs aggressive IS ;Tac trough level 5-7 ,and proper MMF dose, high dose methylprednisolone 3-5 mg/kg daily max 500 mg with rapid tapering.
IVIG to decease AB production. Rituximab to deplete B cells after i week of full IVIG therapy in case of active microvascular inflammation.6 sessions of plasmapheresis to remove DSA ,together with prophylactic antimicrobials of or 3 months.
Mixed TCMR&ABMR
Aggressive IS; high dose steroids, IVIG, plasmapheresis .Single rituximab dose one week after IVIG if there is active microvascular inflammation .
REFERENCES: Uptodate,2021.
Fatima AlTaher
3 years ago
Acute rejection is a major risk factor for graft loss depending on
· timing of occurrence (Late acute rejection has more negative impact on graft survival). LAT is mostly AMR due to donovo DSA , rarely its caused by pure TCMR.
For treatment of AMR , the commonly used medications include : pulse methylprednisolone, plasmapheresis, rituximab, and/or bortezomib and IVIG. For trewatment of TCMR : Pulse methylprednisolone and IVIG.
1- Ragheb A , Kora M , HassanY, KasemH. Study of the effect of early and late acute rejection episodes on renal graft survival.Journal of The Egyptian society of Nephrology and Transplantation. Volume : 21, Issue : 2 , Page : 98-105 2- Kunchala, Rajamahesh & Gudipati, Archana & Guditi, Swarnalatha & Taduri, Gangadhar & Raju, Sree & Uppin, Megha. (2018). Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian Journal of Transplantation. 12. 48. 10.4103/ijot.ijot_65_17.
AMAL Anan
3 years ago
Management of late acute rejection after 6 months must be diagnostic by biopsy.
Late acute rejection associated with:
– poor graft survival.
– discovered late and patient discharged from TX Center and came only for routine follow up.
-patients on tapering or low doses of immunosuppression .
* Management according to type of severity:
~ Borderline:
Manipulation of immunosuppression with higher target level of tacrolimus and oral steroid.
~ Class Ia/Ib : pulse steroid therapy 500 mg for 3-5 days.
~ Class 2-3 : pulse steroid + ATG ( 5-10mg/kg) according to response.
With given 3 month prophylaxis for CMV & pcj.
Acute ABMR:
Pulse steroid 500 mg 3-5 days
If rejection at 1 year post transplant:
– monitor DSA .
– 5 session of plasamaphareresis day after day , each one followed by IVIG 100 mg/kg and last one followed by high dose of IVIG 200 mg/kg divided in four doses daily and followed by ruitixmab 375 mg /m2 and similar doses of IVIG 2g/kg repeated after 1 month.
-After 1 year post-transplantation:
IVIG 2g/kg without plasmapheresis and single dose of rutiximab 500 mg after 1week
Nasrin Esfandiar
3 years ago
Late acute rejection (after 6 month) are usually antibody mediated rejection associated with identification of de Novo DSA Novo and may have worse effect on graft survival. Treatment in first year after transplantation consists of removal of antibodies by plasmapheresis and prevention of new antibody formation by IVIG with or without rituximab administration and if plasma cells are involved using bortizumab may be indicated.
Hamdy Hegazy
3 years ago
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome (True) B. The prognosis may be better if due to non-compliance (False) C. Commonly antibody-mediated (True) D. Usually responds well to steroid pulses (False) E. May be caused by de novo DSA (True)
Justification: A- True. B- Non-compliance is usually associated with poor outcome because of ABMR, de novo DSAs, mixed rejection. C- True. D- Usually steroid resistant and require second lines of treatment like IVIG, Rituximab, Plasma exchange, Bortezomib. E- True.
Hinda Hassan
3 years ago
A. True
B. False .non compliance end with DSA and AMR which are known to harm the kidney
C. True Commonly antibody-mediated
D. True.The majority of C4d+ patients with late acute rejection who were treated with corticosteroids alone responded to treatment
E. True
Esmat MD
3 years ago
Answer the following question with a justification of your answer (not more than 50 words):Late acute rejection A. Usually associated with poor graft outcome true B. The prognosis may be better if due to non-compliance true C. Commonly antibody-mediated True D. Usually responds well to steroid pulses false E. Can be caused by de novo DSA true
ABMR of renal allografts occurs in the following 2 forms:
Type 1, resulting from persistence and/or a rebound of preexisting DSA in sensitized patients, and type 2, associated with de novo DS. It is generally accepted that type 1 ABMR usually occurs early after transplantation, whereas type 2 ABMR most often occurs at least 1 year after transplantation and not infrequently much later.
Type 1 ABMR is usually “pure” ABMR without concurrent cell-mediated rejection (CMR), acute/active (without TG), and associated with DSA against either HLA class I or class II.
By contrast, type 2 ABMR is more frequently mixed ABMR/CMR and chronic, active, and mainly associated with anti-class II DSA. There is a strong association between anti-class II DSA and TG.
In type 2 ABMR, high fraction of C4d-negative, and a worse outcome for C4d-positive ABMR has been reported.
Late posttransplant ABMR progresses slowly and is commonly identified on a surveillance biopsy or a for-cause biopsy for minor allograft dysfunction.
Late or recurrent acute rejection, commonly occurs as a result of nonadherence to immunosuppressive medications or underimmunosuppression.
Depending on the timing of the biopsy, subclinical, active, or chronic active ABMR is diagnosed.
The allograft biopsy shows subclinical ABMR, it can proceed to transplant glomerulopathy (TG) or allograft failure.
ABMR with dnDSA usually occurs 3 months or later after transplantation and the majority is associated with anti-HLA class II. In a study by Aubert et al., ABMR with dnDSA was diagnosed at a median of 1,437 (range, 437–3,127) days after transplantation, whereas ABMR with the preexisting DSA was diagnosed at a median of 85 (range 17–369) days. 69% had class II dnDSA, 17% had both class I and class II dnDSA, and 14% had class I dnDSA. De novo DSA is a significan risk factor for TG and allograft failure.
Immunoglobulin G (IgG) subclasses are also related to the phenotypes of ABMR.
Subclass IgG4 is associated with a slower progression to graft failure and a lower incidence of C4d deposition. But IgG4 is associated with transplant glomerulopathy and interstitial fibrosis/tubular atrophy. T cell-mediated rejection may be more often encountered in ABMR with dnDSA than ABMR with preformed DSA.
Acute rejection due to non-compliance has better prognosis than acute rejection in the context of appropriate immunosuppressive therapy.
The cellular acute rejection more commonly occurs earlier after kidney transplantation and usually in the first post-transplant.
Optimizing baseline immunosuppression and evaluation and managing nonadherence are standard care.
Mahmud Islam
3 years ago
rejection classified as either acute or chronic can be differentiated histologically based on biopsy findings. in acute rejection which is mostly anybody mediated. In early rejection mostly performed DSA while in late acute rejection mostly due to denovo DSA or delayed graft function. In acute rejection, we will see glomerulitis, capillaritis, arteritis, etc. Although the definition of LAR (late acute rejection) is obscure with no consensus, most papers define it as ejection after 6 months. As it is antibody-mediated we treat it with steroids, plasmapheresis, sometimes bortezomib. also we adjust the dose of maintenance immune suppression
Asmaa Khudhur
3 years ago
Late acute rejection (LAR), which is defined as acute rejection 6 months after transplant, is associated with a worse prognosis than early acute rejection.
It is important to determine the type of acute rejection because treatment for cell-mediated rejection (ACR) and antibody-mediated rejection (AMR) are different. Acute AMR has a poor prognosis and represents 20% to 30% of acute rejection cases in recipients of kidney transplants. It is typically labeled as steroid resistant, and is usually treated aggressively with plasmaphoresis and intravenous immunoglobulin (IVIG).
C4d used as a marker to distinguish late AMR from late ACR.
significant proportion of C4d+rejections also have a cellular component
both C4d+and C4d-groups responded to therapy with corticosteroids alone.
This finding may be explained by the fact that the patients with positive C4d staining who responded to steroid therapy alone had a mixed cellular component as well.
Another explanation for the good response to steroids of C4d+patients may be the fact that severe chronic changes and transplant glomerulopathy were absent, as both of these latter findings have been associated with a poor graft outcome.
Therefore in selected patients with C4d+ LAR without severe chronic interstitial changes or transplant glomerulopathy, treatment with plasmapheresis, IVIG, and other immunomodulation agents may be unnecessary. In these patients a strategy of initial treatment with pulse corticosteroids and continued maintenance with MMF and calcineurin inhibitors may prove sufficient to treat late AMR just as with late ACR.
MICHAEL Farag
3 years ago
Late acute rejection associated with poor outcome in the graft function
Treatment first by prevention of it’s occurrence by frequent monitoring of high risk group DSA monitoring and protocol biopsy.
There are no standard treatment for LAR, but IVIG, rituximab & bortezumab can be used
Tahani Hadi
3 years ago
Late acute rejection LAR is known as decreasing in graft function with poor outcome than early AR most common cause is AMR and there are alot of risk factors causing LAR and also affecting on graft survival like denovo DSA which is the common cause ,viral and bacterial infection,drug toxicity ,previous rejection ,non compliance patient to the medication .
Treatment first by prevention of it’s occurrence by frequent monitoring of high risk group patients with prophylaxis antibiotics and antiviral ,DSA monitoring and protocol biopsy.
For ACR using pulses methylprednisolone is usually effective but ATG need to be added in some patients.
AMR need aggressive management with PLEX ,IVIG and Bortezomib or rituximab .
In all types immunosuppressants adjustment and monitoring and adding prednisolone in cases with steroid free regimen.
Reference
_ OSH renal transplantation, (2011),oxford university:Nicholas Torpey ,Nadeem Moghal , Evylen Waston ,David Tolbat.
_Shawar SH ,Naik Rh(2020).pathophysiology. (Renal transplant rejection. Treasure island:Statpearls(internet) p.25).
Abdulrahman Ishag
3 years ago
Usually associated with poor graft out come? T Many studies have been conducted to explore whether the timing of AR affects graft survival. The majority of these studies reported that LAR was correlated with poor long-term graft survival . ]Joseph JT, Kingsmore DB, Junor BJ, Briggs JD, Mun Woo Y, JaquesBC, Hamilton DN, Jardine AG, Jindal RM: The impact of late acuterejection after cadaveric kidney transplantation.Clin Transplant15:221–227, 2001[2 The prognosis may better if due to none-compliance ? F
Nonadherence was more frequent in patients who progressed to failure versus those who survived . ] [5]Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B,Hidalgo LG, Famulski K, Matas A, Halloran PF: Understanding thecauses of kidney transplant failure: the dominant role ofantibody-mediated rejection and nonadherence.Am J Transplant.
.
Commonly antibody mediated ? T
ABMR became common in biopsy specimens obtained 1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time.
Am Soc Nephrol 26: ccc–ccc, 2014. doi: 10.1681/ASN.201406058 Usually respond well to steroid pulses ? F
There is significant advantage for pulse therapy in patients who sought treatment early . Pulse therapy also appeared beneficial in preventing subsequent rejection episodes. John C.HillFRCS1RichardMaskeFCS(SA)1PeterWatsonFRCS2 May be caused by de novo DSA? T
Late ABMR is commonly associated with de novo DSA
Aubert O, Loupy A, Hidalgo L, et al. Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients. J Am Soc Nephrol 2017; 28: 1912.
fakhriya Alalawi
3 years ago
Both early and late acute (antibody-mediated and T cell-mediated) rejections are major causes of renal allograft dysfunction. Late acute rejection (LAR) is defined as the first rejection episode occurring after the first six months of transplantation. LAR has a worse prognosis than early acute rejection. Baskin E et al, in a study of 34 pediatric patients with acute rejections, found that late acute rejections are associated with worse prognosis and inferior graft survival. Development of de novo DSA, non-adherence or suboptimal immunosuppression, and recurrent acute rejection episodes are important risk factors for LAR. Similarly, Jalalzadeh M et al, in 2015, found that late acute rejection (LAR) had a negative impact on long-term renal allograft survival (lower 5-year graft survival rate) compared to early AR, and the risk of chronic graft dysfunction increased in patients with a history of LAR.
References:
1. Baskin E, Kantar A, Gulleroglu K, Ozmen E, Ozdemir H, Kirnap M, Moray G, Haberal M. Sp873effects of late acute rejection on graft survival and outcome in pediatric renal transplant recipients. Nephrology dialysis transplantation. 2015;30(suppl_3):iii665-.
2. Jalalzadeh M, Mousavinasab N, Peyrovi S, Ghadiani MH. The impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. Nephrourol Mon. 2015 Jan 20;7(1):e24439. doi: 10.5812/numonthly.24439.
Nandita Sugumar
3 years ago
Management of late acute rejection involves aggressive therapy with plasmapheresis and IVIG. This is done with or without rituximab. C4d staining of peritubular capillaries is a valuable tool to identify antibody mediated rejection.
Newer treatment like Bortezomib, C1 esterase inhibitors are not consistent with findings.
Ref:
Nair R, Agrawal N, Lebaeau M, Tuteja S, Chandran PK, Suneja M. Late acute kidney transplant rejection: clinicopathological correlates and response to corticosteroid therapy. Transplant Proc. 2009 Dec;41(10):4150-3. doi: 10.1016/j.transproceed.2009.09.074. Erratum in: Transplant Proc. 2010 Mar;42(2):673. PMID: 20005357.
Cooper, J. Evaluation and treatment of acute rejection in kidney allografts. CJASN March 2020, 15(3) pp 430-438. DOI: https://doi.org/10.2215/CJN.11991019
Theepa Mariamutu
3 years ago
Late acute graft rejection
• De-novo (class 1) has been associated for LAR
• mostly AMR but small percentages is T cell mediated
• Has a poorer effect on long term graft survival than EAR
• More likely to be PRA positive, younger than no AR group
• 5 year graft survival is 85 % compared with no AR, 97% and EAR, 89%
o LAR and EAR showed lower graft survival rates than no AR
• LAR has HR 5.10 for graft failure
• Management of LAR depends on histological findings, DSA and severity of the rejection
o Mostly need preventive measures such as maintaining good level of Immunosuppressants, reassurance of adherence to meds
o ABMR -need PLEX and IVIG with without rituximab, eculizima and CI esterase inhibitors
o TCMR- methylprednisolone and rATG with optimisation of IS
References
1-Kunchala R., Gudipati A., Guditi S., Taduri G., et al. Late Acute Rejection in Renal Allografts: Clinical, Pathologic, and Follow‑up Data from a Single Tertiary Care Center. Indian Journal of Transplantation.2018;January-March. Volume 12,Issue 1.
2-Krisl J.C., Alloway R.R.,Shield A.R.,Govil A., et al. Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival. Transplantation.October 2015,Volume 99, Number 10.
3-Cooper J.E. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN. 2020; March,15: 430–438.
Ibrahim Omar
3 years ago
late acute rejection usually results from development of de novo DSA or under treatment with immunosuppression.
it will adversely affect graft function if not adequately treated at earlier stages.
management include the following :
1- frequent monitoring of renal functions, CNI trough levels and DSA …..
2- protocol biopsy has some beneficial roles in management.
3- early and proper treatment of acute rejection.
4- local policies for monitoring and management of de novo DSA
Amit Sharma
3 years ago
What is the effect of late acute rejection (after 6 months of transplantation) on graft survival? Post renal transplant acute rejection episodes have been shown to reduce long-term graft survival. (1)
Late acute rejections are a consequence of underimmunosuppression, non-adherence, infections and formation of de-novo DSAs. These, as compared to early acute rejections have been shown to have poorer graft outcomes and are associated with class I MHC incompatibility. (2)
Opelz et al, in their study, showed that the risk of graft loss in a patient with acute rejection within 6-12 months post transplant is 174% more as compared to someone who did not face any acute rejection episode. (3)
Jalazadeh et al also showed that acute rejection episodes are associated with poorer graft survival, but more so in patients with late acute rejection. (4)
How do manage it?
Substantiate your answer please!
Management of Late acute rejection: Management of a late acute rejection will be essentially the management of acute rejection as late acute rejection is rejection occurring after first 6 months of transplantation. A kidney biopsy is a must for the diagnosis.
Augmentation of immunosuppression is important, with triple drug immunosuppression (CNI, MMF, steroids).
The treatment depends on the histological diagnosis: (5)
Antibody mediated rejection: 5 sessions of Plasma exchange followed by IVIG (100-200mg/kg). Injection Rituximab 375 mg/m2 following last treatment.
Acute T cell mediated rejection: Banff Ia: IV methylprednisolone 500 mg/d x 3-5 days Banff Ib: If mild graft dysfunction: IV methylprednisolone 500 mg/d x 3-5 days Banff Ib: If severe graft dysfunction: rATG 1.5mg/kg/day x 5-7 days or until recovery Banff IIa, IIb or III: rATG 1.5mg/kg/day x 5-7 days or until recovery
In mixed rejection: A combination of therapy to cover both aspects of the rejection.
In addition:
Pneumocystis prophylaxis, CMV prophylaxis needs to be given.
References:
1) Clayton PA, McDonald SP, Russ GR, et al. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis. JASN 2019;30:1697-1707. 2) Sijpkens YW, Doxiadis IIN, Mallat MJK, et al. Early versus late acute rejection episodes in renal transplantation. Transplantation 2003;75:204-208.3) Opelz G, Dohler B. Influence of Time of Rejection on Long-Term Graft Survival in Renal Transplantation. Transplantation 2008;85:661-666. 4) Jalazadeh M, Mousavinasab N, Peyrovi S, et al. The Impact of Acute Rejection in Kidney Transplantation on Long-Term Allograft and Patient Outcome. Nephro Urol Mon 2015;7:e24439. 5) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN 2020;15: 430–438.
Mohammed Sobair
3 years ago
A- Usually associated with poor graft outcome, True rejection has worse prognosis than
early ABMR.
B-The prognosis may be better if due to non-compliance . False as noncompliance is risk
factor to develop DSA LAR. in addition to donor-recipient HLA mismatches, recipient race,
donor age and delayed graft function have been shown to be associated with rejection
episodes.
C-Commonly antibody-mediated. True .
D- Usually responds well to steroid pulses. False most need Plasmapheresis
Intravenous immunoglobulin
E-May be caused by do NoVo DSA .True ,DSA in late AMR episodes were almost
exclusively Class II in general, with the vast majority being DQ specific
Weam Elnazer
3 years ago
Answer A, C, E
A-Late acute rejection usually associated with poor graft outcome is true. because it is usually related to non-compliance and formation of alloantibodies.
b-the prognosis may be better if non-compliance is wrong because once the graft is exposed to the antibodies,this will lead to recurrent formation of alloantibodies
c-commonly antibody-mediated true
d-Usually responds well to steroid pulses is false, because it is usually antibody-mediated e-may be caused by de novo DSA is true.
Doaa Elwasly
3 years ago
Late acute rejection
A. Usually associated with poor graft outcome —True
B. The prognosis may be better if due to non-compliance—– False
C. Commonly antibody-mediated—True
D. Usually responds well to steroid pulses—False
E. May be caused by de novo DSA— True
Late acute rejection in most of the cases is antibody mediated. Pure Tcell mediated rejection represents only small number of cases. De novo appearing donor-specific antibodies (DSAs) are responsible for antibody mediated rejection.
Late acute rejection has also been reported to have an adverse effect on the long-term graft survival with documented graft loss in most of the cases
Reference
Kunchala R etal.Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center.Indian journal of trasnplanation 2018 , 12,1 ( 48-52).
Doaa Elwasly
3 years ago
Late acute rejection episodes are difficult to diagnose and treat
It’s common risk factors are non-adherence , viral infections including CMV and EBV, immunosuppression weaning and steroid withdrawal , and HLA mismatches at class II.
Delayed graft function negatively affects patient survival as well as short- and long-term graft survival . However, its role in Late acute rejection has not been defined. Intensifying induction therapy during delayed graft function might have protected from Early acute rejection, but not from Late as the effect of induction therapy had faded.
Protocols reducing Delayed graft function and adjusting immunosuppression may help improve long-term graft survival and function.
De novo DSA indicating non adherence to immunosuppression was found in patients at the time of Late acute rejection compared to those without Late acute rejection
It’s management
intravenous Methyl prednisolone 10 mg/kg/dose (maximum 1000 mg/dose) for three consecutive days followed by oral prednisone 2 mg/kg/day to be tapered to baseline dose over2 weeks in steroid-based protocol.
In steroid resistant cases
thymoglobulin 1.5 mg/kg/dose once a day for 5–7 days.
Patients with low positive DSA can be treated with IVIG 2 g/kg to a maximum dose of 140 gm/dose. Dose can be repeated 4 weeks later.
Those with strong positive DSA were additionally treated with a single dose of rituximab 375 mg/m2 /dose.
additional treatments with IVIG and rituximab can be added if needed , this will be decided according to renal biopsy and DSA titers obtained 6-8 weeks after first therapy
Reference
Eid L et al. Late acute rejection: Incidence, risk factors, and effect on graft survival and function. Pediatr Transplantation 2014: 18: 155–162
Mahmoud Rabie
3 years ago
Acute rejection is defined as acute deterioration of graft function . The effect of acute rejection on graft survival vary according to time of rejection and whether graft fuction returned to base line or not. Late acute rejection episodes may be attributed to the non compliance to immunosuppressive drugs or the overhasty weaning of the IS drugs. The late acute rejection may be also attributed to HLA class l incompatibility.
LAT effect on graft survival is poorer than the effect of EAR. Most late acute rejection is due to AMR due to the formation of de novo DSA. treatment of LAR need aggressive intervention using plasmapheresis , IVIG, RITUXIMAB , Bortezomib, and eculizumab and usually does not respond to pulse steroid alone.
So my answer is A,C, E
What is the effect of late acute rejection (after 6 months of transplantation) on graft survival?
How do manage it?
Substantiate your answer please!
acute rejection refer to acute clinical deterioration of graft function with biopsy proven acute rejection as per Banff criteria, Both the survival rates of renal allograft in the EAR and LAR groups were significantly lower than that in the NAR group (P = 0.025) (1)
The graft survival rates were not different between the EAR group and LAR group (P=0.22 by log-rank test).(1) EAR, as well as LAR, had negative effects on long-term graft survival(2).
LAR more in young recipient age, and this can be explained by noncompliance with subtherapeutic drug level or increased immune responsiveness,with denovo DSAs especially in previously sensitized patients with low DSA s level, in addition the type of Acute late rejection is more with ABMR (4). so, education for noncompliant patients is important in the prevention of AMR. Also monitoring with SAB Luminex for the presence of DSAs AB would be necessary for early detection and intervention.it’s not only the time of AR will impact the graft survival the most important than time is the response to the treatment (3). Both EAR and LAR if completely responsive to therapeutic intervention with no chronic histological changes so likely the long-term graft survival will be not significantly different from those without acute rejection (2).
HLA mismatch type: HLA mismatch in HLA -A-B, DR, also-HLA DQ In one study shows the 5-yr graft survival for those who had LAR was 45% and 10-yr survival was 28%.
class I mismatches have been associated with late AR, suggest the role of indirect allorecognition pathways in the pathophysiology late AR (4).
How do manage it?
Management plan will depened on many factors including the histological finding considering the type and severity rejection TCMR vs AMR, mixed TYPE, and according to the Banff scoring will decide the therapeutic agents, patient immunological status, DSAs type ,level andsub -class,also non-immunological factors that should be considered before treating the rejection like BKV status, CMV , CVD risk ,previous history of AR ,DGF
for late mild ACR-usualy steriod responsive for 3-5 days with modification of maintenance IS, in sever type with vascular lesions will give ATG , however AMR is more common type of LAR with C4D+ve-PTC will start with Plasma pheresis not less than 5-6 sessions followed by IVIG 1-2gm/kg( total dose)followed by rituximab 375mg/m2 of one or two doses a week after with modification of the maintenance IS like shifting from cyclosporine to tacrolimus with target trough level 5-7 ng and azathioprine to MMF, plus steroid ifno steroid before with DSAs intensity monitoring for the response to treatment and the recurrence of AMR by SAB DSAs MFI value , and RFT with proteinuria,CMV ,PJP prophylaxis and BKV screening should be considered also entecavir prophylaxis for HBV status with rituximab, In general short term graft survival is good in compelete responsive AMR but in general the long-term graft survival after 5, 8, 10 years will be poor especially in case of AMR with chronic tissue injury in the presence of DSAs, De novo DSAs, DD transplant or second transplantation.
Innovation of the molecular genetic assay like immune – cell assays ,complement mediated biomarkers, cell based genetic transcription assay and the use of molecular microscopic system like endothelial associated transcripts (ENDATs) in biopsies of DSA-positive patients can reveal ABMR even in the absence of C4d positivity and early detection of AR prior to histological changes which allows preemptive diagnosis and treatment of AMR , such molecular assay still in subclinical cohorts studies hold promise for better future non invasive tools for early diagnosis and prompt therapeutic intervention before even clinical and histological damage (5).
The correct answers for the question:
A, C, E
References :
1-The impact of early and late acute rejection on graft survival in renal transplantation
Eun Hee Koo,1 Hye Ryoun Jang,1 Jung Eun Lee,1 Jae Berm Park,2 Sung-Joo Kim,2 Dae Joong Kim,1 Yoon-Goo Kim,1 Ha Young Oh,1 and Wooseong Huh1, Kidney Res Clin Pract. 2015 Sep; 34(3): 160–164.
2-impact of acute rejection episodes on long-term renal allograft survival
Jianyong Wu 1, Jianghua Chen, Yimin Wang, Jianguo Zhang, Zong Zhu, Zhangfei Shou, Suya Wang, Ping Zhang, Hongfeng Huang, Qiang He
Chin Med J (Engl). 2003 Nov;116(11):1741-5.
3-Arvizu-Hernandez M, Morales-Buenrostro LE, Vilatoba-Chapa M,
et al. Time of occurrence of kidney acute antibody-mediated allograft
rejection/acute cellular rejection and cell senescence: implications for
function outcome. Transplant Proc 2010; 42: 2486.
4-The impact of late acute rejection after cadaveric kidney transplantation
J T Joseph 1, D B Kingsmore, B J Junor, J D Briggs, Y Mun Woo, B C Jaques, D N Hamilton, A G Jardine, R M Jindal, Clin Transplant. 2001 Aug;15(4):221-7.
6-Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction
by Marco Quaglia 1,Guido Merlotti 1ORCID,Gabriele Guglielmetti 1ORCID,Giuseppe Castellano 2 andVincenzo Cantaluppi 1,
5-Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction
by Marco Quaglia 1,Guido Merlotti 1ORCID,Gabriele Guglielmetti 1ORCID,Giuseppe Castellano 2 andVincenzo Cantaluppi 1
Last edited 3 years ago by saja Mohammed
Ramy Elshahat
3 years ago
What is the effect of late acute rejection (after 6 months of transplantation) on graft survival?
Late acute rejection is associated with poor graft survival due to multiple aspects
1)Mostly sever ABMR or TCMR
2)Usually discovered late as patient is already discharged to home and on just routine follow up
3) immune suppression medications usually at lower side and damage is sever
How do manage it?
According to type and degree of severity
acute TCMR
Borderline rejection….tailoring immune suppression medications targeting higher levels of tac (5-7) and oral steroids
Class1a/1b…. pulse steroids usually 500mg 3-5 days will be sufficient
Class 2-3…. pulse steroids plus ATG 5-10mg/kg according to response
With 3m CMV,PCJ prophylaxis
Acute ABMR
Pulse steroids 500mg for 3-5days then if rejection
1)At 1st year post transplant…. withdraw baseline DSA
plasma exchange 1-1.5 plasma volume on every other day base followed by IVIG 0.5-1gm/kg with the last session or divided 200mg/kg after each session followed by rutiximab 500mg after one week.beside augmentation of the conventional triple immunosuppressive medications
Monitoring of dsa, stabilization of kidney function, decrease of proteinuria will be of great prognostic and therapeutic value.
2)After 1st year post transplant
DSA baseline then
Role of plasma exchange decrease.IVIG 2gm/kg without plasma exchange and single dose of rutiximab 500mg after 1w can be given.
Reference
Up-to-date
Mahmoud Hamada
3 years ago
Late acute rejection A. Usually associated with poor graft outcome True LAR is associated with negative outcomes on allograft survival (1) B. The prognosis may be better if due to non-compliance False De novo DSA, ABO incompatibility, African Americans all are associated with poor prognoses. C. Commonly antibody-mediated true although also TCMR may cause late acute graft rejection. In one study, TCMR was present in about 25% of graft rejection assumed initially to be AMR. (2) D. Usually responds well to steroid pulses True However, management may include pulse steroid, plasmapheresis, and IV Ig. E. May be caused by de novo DSA true De novo DSA is commonly associated with LAR. References:
1- Jalalzadeh, M., Mousavinasab, N., Peyrovi, S., & Ghadiani, M. H. (2015). The impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. Nephro-urology monthly, 7(1), e24439. https://doi.org/10.5812/numonthly.24439
2- Mauiyyedi S, Crespo M, Collins AB, Schneeberger EE, Pascual MA, Saidman SL, Tolkoff-Rubin NE, Williams WW, Delmonico FL, Cosimi AB, Colvin RB. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol. 2002 Mar;13(3):779-787. doi: 10.1681/ASN.V133779. PMID: 11856785.
Reem Younis
3 years ago
-Late acute rejection (LAR) in most cases is antibody-mediated (AMR) while pure T cell-mediated rejection accounts for an only minority of LAR cases.
– LAR -AMR is due to de novo DSA.
-Risk factors for LAR: infections, non complain to the immunosuppressive drugs, earlier rejection episode,low dose of immunosuppressive drugs.
-LAR has a worse prognosis and poor graft survival than early acute rejection.
-Renal allograft biopsy is essential to confirm and classify LAR.. adequat biopsy must contain 10 glomeruli and 2 arteries. Management of LAR :
– There are no stander treatments for LAR but treatment according to types rejection.
antibody-mediated rejection (AMR): Plasma exchange , IVIG ,Rituximab, Bortezomib.
T cell-mediated rejection:IV Methyl prednisone and IV ATG .
-Optimization of maintenance immunosuppressive drugs and their level is the cornerstone in preventing LAR.
-Monitor DSA level. Referrences
1.Rajamahesh Kunchala1, Archana Gudipati1, Swarnalatha Guditi2, Gangadhar Taduri2, Sree Bhushan Raju2, Megha S Uppin1 .Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center .Indian journal of transplant.Year : 2018 | Volume : 12 | Issue : 1 | Page : 48-52
2.Ruchi H. Naik; Saed H. Shawar. Renal Transplantation Rejection. Statpearls.July 25, 2021.
Jamila Elamouri
3 years ago
Late acute rejection
A. Usually associated with poor graft outcome. (T)
B. The prognosis may be better if due to non-compliance (F)
C. Commonly antibody-mediated. (T)
D. Usually responds well to steroid pulses. (F)
E. May be caused by de novo DSA. (T)
Nonadherence to immunosuppressive regimens plays a role in most late acute rejections. Inadequate dosing of medications or tendency of providers to wean medications in the late post-transplant period. It is a sensitive and difficult task to determine the minimum dose required to prevent rejection, and maintain optimal graft outcomes.
Current methods for immune monitoring cannot reliably inform whether a given immunosuppression regimen is adequate. Therefore, although immunosuppression reduction may be considered in some patients in the late post-transplant period, patients who reduce doses of immunosuppression should be monitored carefully for signs of graft dysfunction. Periodic screening for the development of donor-specific antibodies may be considered for those on reduced immunosuppression and may be a marker for inadequate immunosuppression.
Shereen Yousef
3 years ago
Late acute rejection ≥6 months post-Tx may contribute to lack of improvement
And it has long been known to be associated with increased risk of graft loss.
significant risk factors for LAR included DGF, de novo DSA ,mean COV% of TAC and non-adherence 1.
DGF and DSA remained statistically significant COV% TAC had borderline significance and non-adherence was not significant on multivariate regression analysis.
Patients with LAR had inferior graft survival and function, whereas graft function was stable in the no LAR group over a mean follow-up of 31.2 months.
Patients with de novo DSA and DGF should be considered at risk of LAR; an early diagnosis and treatment of LAR may improve graft survival and function 1.
LAR was shown to adversely impact graft survival and function. This may be in part due to delayed diagnosis as many of the recipients are followed less frequently after the first year of transplantation and in part due to recurrent episodes of LAR.
The treatment plan determination uses multiple factors, including the type of rejection, the severity of the histological lesion, the chronicity score, and the recipient comorbidity. tailoring medical treatment of individual characteristics is needed 2.
Differential Diagnosis 3.
1Volume depletion
2. Acute tubular necrosis
3. Calcineurin inhibitor nephrotoxicity –
4. Urinary obstruction
5. Infections (Bacterial pyelonephritis,Viral infections – BK polyomavirus and CMV)
6. Acute and chronic interstitial nephritis
7. Recurrent primary glomerular diseases (Focal segmental glomerulosclerosis (FSGS),Primary membranous nephropathy,Diabetic nephropathy,Ig A nephropathy,C3 Glomerulonephritis (C3 GN)
8. De novo glomerular disease
9. Thrombotic microangiopathy.
10. Transplant renal artery stenosis
11.PTLD. 3.
Management; 3.
Antibody-Mediated Rejection:
depends on the level of the antibody levels. Higher antibody levels need plasma exchange The following are the different modalities used for AMR:
plasma exchange: 3 to 5 sessions daily on every other day is used followed by IVIG and rituximab
iVIG: IV immunoglobulin (100 to 200 mg/kg) is used followed by the last session of plasma exchange when used in combination with plasmapheresis or a higher dose of 2g/kg after the final session of plasmapheresis.
Rituximab Anti CD20 cell antibody rituximab (375 mg/m^2) is used in combination with IVIG followed by plasma exchange
Bortezomib: Plasma cell inhibitor bortezomib (1.3 mg/m^2) is also used in combination with plasma exchange and IVIG
splenectomy: A splenectomy is very rarely an option,
Optimize the dose and the level of the maintenance immunosuppressive drugs.
T Cell-Mediated rejection:
Methyl prednisone IV (250 to 1000 mg daily) targeting T cells, B cells, and macrophages; given for 3 to 5 days.
rATG – rabbit anti-thymocyte globulin IV (1 to 1.5 mg/kg) targeting T cell receptors. for 7 to 14 doses based on the response and Cd3 level.
Optimize the dose and the level of the maintenance immunosuppressive drugs.
Chronic rejection: Since the antibody-mediated rejection mechanism is a major cause of chronic rejection, the same therapy as ABMR has been used, but generally, these measures are ineffective when serum creatinine is over 3 mg/dl and/or heavy proteinuria is present.
Prognosis
The acute rejections predispose to chronic graft dysfunction.
T Cell-Mediated rejections have better graft survival, especially when they respond to therapy, and the serum creatinine reaches near to the previous baseline after the treatment.
Acute rejections occurring after three months, vascular rejections, and the rejections not responding to therapy (serum creatinine not reaching 75% of baseline value) are associated with poor graft survival.
The appearance of de novo DSAs at any time post-transplant is associated with 5% poor graft outcome per year as compared to recipients without these antibodies.
Reference;
1Philip A. Clayton, Stephen PMcDonald, Graeme R. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis.JASN September 2019,30 (9) 1697-1707.
2Sharif A, Shabir S, Chand S, Cockwell P, Ball S, Borrows R. Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation. J Am Soc Nephrol. 2011 Nov;22(11):2107-18.
3 Naik RH, Shawar SH. Renal Transplantation Rejection. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.
Effect of late acute rejection:
Acute rejection is a major risk factor for graft loss, severity of rejection, timing (early or late) and recovery to baseline or not affect the long term graft outcome.
Studies suggested that late acute rejection was correlated with poorer long term graft survival.
A study showed that new onset graft dysfunction and acute rejection after 90 days post transplant was followed by marked increase in the risk of death censored graft failure.
Management of late acute rejection:
treatment of acute rejection depends on accurate diagnosis, type of rejection and severity of rejection.
There is no standard treatment protocols for treatment of late acute rejection
Most cases of acute late rejection are antibody mediated. Antibody mediated rejection (ABMR):
late acute ABMR should be differentiated from chronic ABMR, diagnostic criteria include peritubular capillaritis, arteritis and glomerulitits with positive C4d and DSA
treatment directed at removing antibody producing B cells, DSA and/or inhibiting subsequent complement regulated graft damage.
Plasma exchange, IVIG with or without Rituximab are the most commonly used (3)
several studies are evaluating other agents for treatment of AMR refractory to standard treatment include:
Bortezomib: induce apoptosis of plasma cells through proteosome inhibition
Eculizumab: inhibit terminal complement C5
C1 esterase inhibitor: inhibit classical complement pathway T cell mediated rejection:
Banff Ia and Ib treated with methylprednisolone
Banff Ib, IIa, IIb and III treated with rATG for T cell depletion
Koo, E.H., Jang, H.R., Lee, J.E., Park, J.B., Kim, S.J., Kim, D.J., Kim, Y.G., Oh, H.Y. and Huh, W., 2015. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney research and clinical practice, 34(3), pp.160-164.
Gaston, R.S., Fieberg, A., Hunsicker, L., Kasiske, B.L., Leduc, R., Cosio, F.G., Gourishankar, S., Grande, J., Mannon, R.B., Rush, D. and Cecka, J.M., 2018. Late graft failure after kidney transplantation as the consequence of late versus early events. American Journal of Transplantation, 18(5), pp.1158-1167.
Webster AC,Wu S, Tallapragada K, Park MY, Chapman JR, Carr SJ:
Polyclonal andmonoclonal antibodiesfortreating acute rejection
episodes in kidney transplant recipients. Cochrane Database Syst
Rev 7: CD004756, 2017
Cooper, J.E., 2020. Evaluation and treatment of acute rejection in kidney allografts. Clinical Journal of the American Society of Nephrology, 15(3), pp.430-438.
Haas M. The revised (2013) Banff classification for antibody‑mediated
rejection of renal allografts: Update, difficulties, and future
considerations. Am J Transplant 2016;16:1352‑7.
Kunchala, R., Gudipati, A., Guditi, S., Taduri, G., Raju, S.B. and Uppin, M.S., 2018. Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian Journal of Transplantation, 12(1), p.48.
Dalia Eltahir
3 years ago
LAR had a negative impact on long-term renal allograft survival and increase the risk of chronic graft dysfunction . LAR was more commonly associated with males Late acute rejection has a worse prognosis than early acute rejection. It is important to distinguish between cellular and antibody-mediated rejection to guide the treatment strategy so biopsy is standard for diagnosis . The management of acute antibody-mediated rejection includes aggressive therapy with plasmapheresis and intravenous immunoglobulin and Rituximab . Acute cellular rejection Intensification of maintenance immunosuppression Pulse methylprednisolone followed by oral prednisolone .If no response we add ATG . Aggressive treatment was associated with better graft outcome. However, higher incidence of posttreatment viral (cytomegalovirus and BK virus) and bacterial infections that necessitated more hospitalization Appropriate prophylactic antibiotics and antiviral are recommended for aggressive treatment patients.
2008;22:316-23. 21. O’Grady JG, Alexander GJ, Sutherland S, et al … by R Nair · 2009 · Cited by 13 — The management of acute antibody-mediated rejection includes aggressive therapy with plasmapheresis and intravenous immunoglobulin. C4d staining of peritubular …
Hinda Hassan
3 years ago
Late AR have more chances to develop DSA 42% than early 13% . It leads to worse graft survival 3. Risk factors are de novo DSA, non compliance , improper prescription and recurrent acute rejection Management includes: Close monitoring of at risk patiens to pick them early intensive treatment of LAR may help improve graft survival and long term outcome. 1 However, in a retrospective analysis of LAR in small transplant population, followed after 8 years, ,both c4d positive and c4d negative patients respond to steroid without plasmapheresis or IVIG. The latter were not provided because at that time the c4d was not considered and the biopsies were stained later during the study. The response to steroid could be due to presence of acute cellular rejection or it could be due to the absence of severe chronic changes and transplant glomerulopathy in patients under the study. So in such patients pulse corticosteroids and continued maintenance with MMF and calcineurin inhibitors may be just enough.
1-Esra Baskin, Asli Kantar, Kaan Gulleroglu, Esra Ozmen, Handan Ozdemir, Mahir Kirnap, Gokhan Moray, Mehmet Haberal, SP873 EFFECTS OF LATE ACUTE REJECTION ON GRAFT SURVIVAL AND OUTCOME IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS, Nephrology Dialysis Transplantation, Volume 30, Issue suppl_3, May 2015, Page iii665, https://doi.org/10.1093/ndt/gfv203.11 2-Nair, R., Agrawal, N., Lebaeau, M., Tuteja, S., Chandran, P. K. G., & Suneja, M. (2009). Late Acute Kidney Transplant Rejection: Clinicopathological Correlates and Response to Corticosteroid Therapy. Transplantation Proceedings, 41(10), 4150–4153. doi:10.1016/j.transproceed.2009.
3-Eid L, Tuchman S, Moudgil A. Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant. 2014 Mar;18(2):155-62. doi: 10.1111/petr.12203. Epub 2013 Dec 28. PMID: 24372967.
Professor Ahmed Halawa
Admin
3 years ago
Dear All You hit a fly with a cannonball. An extensive answer to an easy question. I want you to focus your answer, please.
Mohamed Fouad
3 years ago
-Basically the gold standard to diagnose rejection is the renal biopsy and examine the graft tissue samples with LM,IF,IHC and special stain and EM to give comprehensive pathological picture.
-Acute rejection means an acute deterioration in allograft function with increase of serum creatinine by 20% from the baseline.
–Late acute rejection(LAR) is defined as first rejection episode occurring after the first six months of transplantation.
-Development of de novo DSA, non adherence or suboptimal immunosuppression and recurrent acute rejection episodes are important risk factors for LAR. Close monitoring of these patients , making an early diagnosis and intensive treatment of LAR may help improve graft survival and long term outcome.
DD for LAR:
-Recurrence of glomerulonephritis and den novo GN
-BK nephropathy
-CMV nephropathy
-CNI nephrotoxicity
-Graft renal A. stenosis
-Obstructive uropathy
*Management of acute graft dysfunction will include good history taking, lab. investigations including virology screening (CMV PCR,BK PCR), CNI levels, proteinuria level, Renal graft duplex and graft US
*Acute rejection proved with tissue diagnosis: 1-Acute TCMR: Acute TCMR occurs most commonly within the first year after transplantation and rarely occurs after five years posttransplant.
According to Banff classification of TCMR:
Borderline rejection: Nospecific treatment for rejection but augment maintenance immunosuppression by targeting higher Tacrolimus levels ( 5 to 7 ng/mL) and optimized MMF dose.
Banff gradeIA or IB: Pulse steroids then oral glucocorticoids are tapered immediately to the maintenance dose of oral prednisolone which was taken before AR.Some centres treat Banff grade IB if present less than one year posttransplant with adding ATG.
Banff grade II or III rejection: Pulse steroids 3-5 days+ ATG at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg according to severity of Banff classification.
A decrease in serum creatinine to within 10 percent of the baseline level is considered to be successful reversal of rejection.
2-Acute ABMR:
-Pulse steroids 500-1000 mg 3-5 days -Low dose IV IG (total cumulative dose of 1gm/kg) with plasmapheresis 5-7 sessions one-and-one-half-volume exchange with albumin in alternating days. -High dose IV IG (total cumulative dose of 2gm/kg) without PP. -One dose Rituximab375 mg/sqm after PP sessions.
Rescue therapy including Bortezomib, Eculizumab, Tocilizumab that can be used in selected cases.
*All patients have to receive CMV prophylaxis Valganciclovir for 3 months ,PCP prophylaxis using Atovaquone 1500 mg daily if they have high serum creatinine in addition to bone protection with calcium and vitamin D and gastric protection for high dose steroids.
In case of allograft dysfunction we should do renal biopsy with C4d staining and DSA and according to the finding we diagnose AR and categorize rejection into:
Pure acute TCMR
Pure acute (active) ABMR
Mixed acute ABMR, TCMR
Acute TCMR
Intensification of maintenance immunosuppression targeting tacrolimus level trough between 5-7, optimize MMF dose
Pulse methylprednisolone followed by oral prednisolone tapering to maintenance dose used in patients with Banff grade Banff grade I, II or III rejection
rATG is given in patients with Banff grade IB rejection if < 1 year or in patients with Banff grade II or III rejection, the dose is 1.5-3 mg per kg /d for a maximum total cumulative dose of 6mg (in Banff grade IB) or 9 mg (in Banff grade II, III), if ATG is contraindicated alemtuzumab can be given instead.
All patients who received ATG, or Alemtuzumab and high dose corticosteroids should receive antiviral and Pneumocystis pneumonia (PCP) prophylaxis for 3 months
Acute ABMR
Intensification of maintenance immunosuppression targeting tacrolimus level trough between 5-7, optimize MMF dose
Decreasing inflammation produced by rejection : high dose methylprednisolone 3 to 5 mg/kg daily 3-5 doses (maximum 500 mg), followed by rapid oral prednisone taper till reaching previous maintenance dose
Decreasing production of antibodies (IVIG in a dose 200 mg/kg every 2 weeks for 3 doses if used alone or 100 mg/kg after each plasmapheresis session and 500 mg/kg after the last session)
Depleting B cells (one dose of rituximab 375mg/m2) only if there is biopsy evidence of active microvascular inflammation and given 1 week after completion of IVIG
Removing DSA (6 sessions of plasmapheresis daily or every other day) only if ABMR occur < 1 year after renal transplantation
All patients with ABMR should receive antiviral and Pneumocystis pneumonia (PCP) prophylaxis for 3 months
Mixed TCMR, ABMR
Intensification of maintenance immunosuppression, high dose CS, IVIG, plasmapheresis, (if indicated), ATG (if indicated) , antiviral and Pneumocystis pneumonia (PCP) prophylaxis
If plasmapheresis and ATG are to be given together they can be given on alternating days.
Single dose of Rituximab can be given if there is biopsy evidence of active microvascular inflammation and given 1 week after completion of IVIG.
The question was about Late Acute Rejection, NOT treatment of rejection. Thanks for the efforts
Mohamad Habli
3 years ago
Introduction
Acute renal rejection should be suspected in patients with 1 or > of the following:
Increase in Cr of ≥25 percent from baseline or creatinine higher than expected/Proteinuria >1 g/day/worsening hypertension/ dd-cfDNA >1 percent.
The standard for the diagnosis of renal allograft rejection is a renal allograft biopsy, which is used to accurately grade the severity of rejection, differentiate between T cell-mediated rejection (TCMR) and ABMR, and determine the degree of irreversible kidney damage (interstitial fibrosis/tubular atrophy).
AR, regardless of its timing, significantly worsened graft survival. Treatments to reduce the incidence of AR and improve prognosis are needed. There is no standardized definition for early and late acute allograft rejection and the cutoff of 6 months varies between studies. EAR and LAR were defined as rejection before 1 year and after 1 year in most of studies.
In one study evaluated the impact of early and late acute rejection on graft survival in renal transplantation showed that out of 198 biopsy proven rejection , 21% had EAR, 7% had LAR, and 72% had no rejection episode.
Patients with EAR were more likely to be male, and had short dialysis duration. Patients with LAR were more likely to be PRA positive and younger. The no AR group had more HLA-A,-B, and -DR matches.
However, in terms of graft survival, the patients with EAR or LAR showed lower graft survival rates than those with no AR but no significant difference between the EAR group and LAR group.
Better and precise definitions of early and late rejections, protocol biopsies and standardized risk stratification and therapies could lead to better prediction of outcomes based on rejection timing.
How to manage it?
Because of the poor outcomes of acute rejection, regardless if clinical or subclinical, early or late, rejection should be treated to avoid long term deleterious effects on graft survival.
In patients with biopsy proven late active ABMR, treatment is combination of glucocorticoids, intravenous IVIG, and, in some patients, rituximab if there is evidence of active microvascular inflammation on kidney biopsy.
-IV methylprednisolone 300 500 mg daily for 3-5 days, followed by oral prednisone taper.
-IVIG at a dose of 100 mg/kg after each session of plasmapheresis. Followed by 500 mg/kg per day for one to two days after the final session of plasmapheresis, with a total cumulative target dose of at least 1000 mg/kg of IVIG.
– Rituximab as a single dose of 200 to 375 mg/m2 after completion of IVIG
– plasmapheresis is not performed because of the lack of evidence.
Second-line agents in patients who have failed initial therapy
Bortezomib and Eculizumab can be considered as rescue therapy, but treatment is usually individualized based on the etiology and ABMR and histological findings.
For T cell mediated rejection, the treatment varies between centers. In patients with borderline TCMR based on Banff criteria, there is no consensus regarding optimal management. Some transplant centers adjust maintenance immunosuppression by increasing tacrolimus and/or by MMF dosing. Some centers treat borderline rejection as acute TCMR.
Treatment of Banff grade I rejection with administration of IV pulse glucocorticoids, followed by an oral glucocorticoid taper, in addition, to adjustment of t maintenance immunosuppression doses.
In patients with Banff grade IB rejection and few or no chronic histologic lesions who present less than one year posttransplant including 6-12 months, give r-ATG + pulse glucocorticoids.
In patients with Banff grade II or III rejection, administer high dose pulse IV glucocorticoids, followed by an oral glucocorticoid taper + rATG-Thymoglobulin + augment maintenance immunosuppression. If there is contraindication to r-ATG give Alemtezumab.
References
1-Uptodate(Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection of the renal allograft, Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the renal allograft)
2-Eun Hee Koo, Hye Ryoun Jang, Jung Eun Lee, Jae Berm Park, Sung-Joo Kim. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney Research and Clinical Practice. Volume 34, Issue 3, September 2015, Pages 160-164
Assafi Mohammed
3 years ago
The effect of late acute rejection (after 6 months of transplantation) on graft survival:
Results are similar to that shown by Eun Hee Koo et al Study as mentioned in Scenario 2 in this week.
Another important study similar to Eun Hee Koo et al Study is An ANZDATA Analysis (Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients):An ANZDATA AnalysisPhilip A. Clayton, Stephen P. McDonald, Graeme R. Russ and Steven J. Chadban JASN September 2019, 30 (9) 1697-1707; DOI: https://doi.org/10.1681/ASN.2018111101.
An ANZDATA Analysis Method:To understand the long-term effect of AR on outcomes, they analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics. Results:AR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results. Conclusions AR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials. An ANZDATA Analysis:
This study adds to the literature by demonstrating robust associations between AR and long-term graft loss, mediated by increased risks of both death with function and death-censored graft failure.
Those with AR incurred an excess of death attributed to cardiovascular disease and cancer. Both appear to be biologically plausible.
Lower eGFR and albuminuria are recognized as independent risk factors for all-cause and cardiovascular mortality in the generaland kidney transplant populations and both may occur consequent to AR.
The intensity of immunosuppression may affect both cardiovascular risk, through mechanisms including development of new-onset diabetes, hypertension, dyslipidemia, renal impairment and proteinuria, and cancer risk.
Somewhat surprisingly, AR treated with lymphocyte depleting antibodies was not significantly associated with death due to cancer. This may reflect a lack of statistical power, or potentially loss caused by competing outcomes, including infection, cardiovascular disease, and CAN.
Late-onset AR (occurring beyond the first 6 months after transplantation) has long been known to be associated with increased risk of graft loss.
Late onset of chronic AMR in particular has been strongly associated with graft lossand effective therapies are currently lacking.
Late AR causing graft loss was significantly more frequent among those with than without AR in this study. This is not surprising but may be important in considering the management of patients after an episode of AR.
The study data has demonstrated excess risks of death due to cardiovascular disease and cancer after AR and the greater burden of immunosuppression administered to such patients may have a causal role. However, any reduction in immunosuppression to curb death risk may incur increased risk of late AR.
Understanding the potential contribution of nonadherenceand variability in drug exposure in this context may be critical, as both may contribute to the development of AR both early and late after transplantation.
Previously documented associations between nonadherence and AMR in particular are noteworthy,given that AMR was associated with the highest risk of graft failure due to recurrent AR in this study.
Limitations to ANZDATA Analysis:
As a registry analysis, several limitations should be borne in mind when interpreting the results of this study. Although ANZDATA uses rigorous internal quality control procedures, as with any registry data there is risk of misclassification and underreporting.
Risks of misclassification exist for causes of graft loss and death. Over 90% of episodes of AR reported to the registry are biopsy proven.
However, as the coding of AR used by the registry has not been assessed for interobserver consistency, risk of misclassification is also relevant here.
Detailed biopsy data (e.g., Banff scores) is not consistently reported.
Coding for antibody mediated AR was added to the registry only from 2005 and before that time we coded any biopsy that showed glomerulitis as indicating AMR, after excluding all patients with GN as their cause of ESKD. This may also have led to attribution errors.
The Registry also does not currently collect donor-specific antibody status.
Furthermore we were not able to separate acute from chronic AMR; however, as our focus was on AR diagnosed during the first 6 months after transplantation, the bulk of AMR episodes were likely to have been acute. The reason for choice of particular treatments of AR is not collected, and the response to treatment data have not been validated.
Registry data are by nature observational, and associations reported should not be interpreted as causal.
Our analyses were subjected to multiple sensitivity analyses and although these confirmed the primary analyses, the variables included in our models were restricted to those captured by the registry, and as such, we cannot exclude the possibility of unmeasured confounders.
Finally, the study was restricted to Australia and New Zealand where the majority of patients are white and do not receive lymphocyte-depleting induction therapy, but do receive a calcineurin inhibitor, an antiproliferative drug, and low-dose steroids throughout maintenance phase,and such features may differ from other regions of the world.
In conclusionANZDATA Analysis
this study has revealed the adverse long-term consequences associated with AR that occurs within the first 6 months after kidney transplantation.
AR was associated with significant increases in risk of both death with function and graft loss due to CAN, the leading causes of transplant failure in the current era.
The associations noted were strongest for those with AMR and for those where initial therapy failed to enable return to baseline serum creatinine.
Despite the decline in both the incidence of AR and the incidence of early graft loss directly caused by AR, these data highlight the importance of AR as a pivotal early event after transplantation with long-lasting consequences.
Prevention of AR should therefore remain a priority in patient management and an important outcome to be captured in clinical trials.
How to be managed: According to KDIGO GUIDELINES 2009.
6.1: We recommend biopsy before treating acute rejection, unless the biopsy will substantially delay treatment. (1C)
6.2: We suggest treating subclinical and borderline acute rejection. (2D)
6.3: We recommend corticosteroids for the initial treatment of acute cellular rejection. (1D)
6.3.1: We suggest adding or restoring maintenance prednisone in patients not on steroids who have a rejection
episode. (2D)
6.3.2: We suggest using lymphocyte-depleting antibodies or OKT3 for acute cellular rejections that do not respond to
corticosteroids, and for recurrent acute cellular rejections. (2C) (OKT3, muromonab (anti–T-cell antibody).
6.4: We suggest treating antibody-mediated acute rejection with one or more of the following alternatives, with or without
corticosteroids (2C):
• plasma exchange;
• intravenous immunoglobulin;
• anti-CD20 antibody;
• lymphocyte-depleting antibody.
6.5: For patients who have a rejection episode, we suggest adding mycophenolate if the patient is not receiving
mycophenolate or azathioprine, or switching azathioprine to mycophenolate. (2D)
Huda Al-Taee
3 years ago
Late acute rejection has been shown to be associated with poor allograft survival.
De novo DSA( class I) appears to be responsible for late acute rejection. Infection, non compliance to medications, de escalation of immunosuppressive medications and earlier rejection episodes are responsible for their formation.
Late acute rejection is antibody mediated in most cases, pure cellular rejection accounts for minority of the cases.
Previous studies showed that late acute rejection associated with lower graft survival rate as compared to early acute rejection, One study evaluated the effect of timing of rejection and the type of rejection on allograft survival and found that death censored graft survival was worse in all late acute rejection types, and there was a hierarchical relationship in both early and late acute rejection with death censored graft loss highest in ABMR followed by mixed rejection and then cellular rejection.
Management consist of preventive measures such as monitoring of immunosuppressant drug level to ensure adequate immunosuppression, monitoring of patient adherence to the drugs, proper diagnosis and management of infection,monitoring of DSA level and if rejection occur, the treatment will be according to the type and severity of rejection, if it is ABMR then PE & IVIG should be started, another IS medications can be used based on the severity and response such as Rituximab, Bortezomib, Eculizumab, and C1 esterase inhibitor, and if is ACR pulse MP for 3 days and if no response, ATG added, with optimization of immunosuppression.
References:
Kunchala R., Gudipati A., Guditi S., Taduri G., et al. Late Acute Rejection in Renal Allografts: Clinical, Pathologic, and Follow‑up Data from a Single Tertiary Care Center. Indian Journal of Transplantation.2018;January-March. Volume 12,Issue 1.
Krisl J.C., Alloway R.R.,Shield A.R.,Govil A., et al. Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival. Transplantation.October 2015,Volume 99, Number 10.
Cooper J.E. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN. 2020; March,15: 430–438.
Acute rejection either early or late will affect graft survival.
Definitions:
Acute rejection is defined as acute deterioration of graft function and proved with tissue diagnosis (diagnostic biopsy).
Graft failure defined as graft nephrectomy or retransplantation or return back to chronic dialysis.
DGF is defined as need of dialysis in the 1st week posttransplant.
Graft survival is lower in the patient with acute rejection either early or late than those with the patients with no rejection. Some studies suggested that there is no difference between early and late rejection on graft survival.
There are some factors may be related to early acute rejection (EAR) like HLA mismatch, male sex , living donor, old donor age , short ischemic time. Other factors may be related to late acute rejection (LAR) like young age, and positive PRA.
Both EAR and LAR affect negatively graft survival but no significant difference between both of them.
Some studies found significant impact of EAR on graft survival than LAR, some studies found the contrast.
So, both have a negative impact on survival either early or late.
Management:
LAR in most of the cases is AMR , TCR is happened in minor cases late, appearance of de novo DSA is the responsible factor to initiate AMR , which may be related to non compliance or dose reduction of ISD (immunosuppressive drugs), or infection.
Diagnosis of late acute AMR should be differentiated from chronic AMR , the presence of DSA and tissue difference between both acute and chronic is observed, presence of tubular atrophy and interstitial fibrosis is the key of chronicity , and c4d stain and noted inflammatory process are the key of acute type.
CMV which may be asymptomatic and treatment with ganciclovir will results in stable graft function and improve the picture.
treatment if TCR by iv methylprednisolone with or without ATG
if AMR, will proceed for plasmapharesis and ivig
and treat the underlying cause in all cases
The majority of the studies report that Late Acute Rejection was correlated with poor long-term graft survival.
Predisposing factors for late acute rejection-
Development of de novo DSA
Non adherence or suboptimal immunosuppression
Recurrent acute rejection episodes .
Close monitoring of these patients, making an early diagnosis and intensive treatment of LAR may help improve graft survival and long term outcome.
1. Joseph JT, Kingsmore DB, Junor BJ, Briggs JD, Mun Woo Y, Jaques BC, Hamilton DN, Jardine AG, Jindal RM. The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant 15:2001;221-227.
2. Opelz G, Dohler B. Influence of time of rejection on long-term graft survival in renal transplantation. Transplantation 85:2008;661-666.
3. Sijpkens YW, Doxiadis II, Mallat MJ, de Fijter JW, Bruijn JA, Claas FH, Paul LC. Early versus late acute rejection episodes in renal transplantation. Transplantation 75:2003;204-208.
Late TCR
methylprednisolone 1gm x 3 and increase maintenance prednisolone to 1mg/kg
if steroid resistant then ATG
Late AMR
methyl prednisolone 1gm x 3 invariably gone till biopsy report comes
plasmapharesis f/b low dose ivig
one of the following may be used-
rituximab
ATG
bortezomib
Dear All
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome
B. The prognosis may be better if due to non-compliance
C. Commonly antibody-mediated
D. Usually responds well to steroid pulses
E. May be caused by de novo DSA
There is a reward for the correct answer.
LAR differ from EAR in risk factors, management & prognosis. While the incidence of EAR is decreasing due to using of MMF & CNI, the incidence of LAR is not changed markedly. It had poorer graft survival as most patients will losses their graft after one year of follow-up. Most cases of LAR are due to ABMR that mainly caused by de novo DSA & TCMR occurs only in minority of cases.
There are no standard treatment for LAR, but IVIG, rituximab & bortezumab had been used with no significant benefit.
Cases of LAR that show no or little chronic histopathological changes on renal biopsy had good response to IV methyl-prednisolone or high oral prednisolone, with maintenance MMF, CNI & low dose steroids.
References:
It may respond to steroid pulses. Usually is the first line of treatment.
the correct answer A, C&E
late acute rejection type is more due to ABMR, immunsuppressive non-adhereance can play role in late acute rejection in addition to the prsence of denovo DSAs-AB usually diagnosed late due to less frequent clinical monitroing so patinet might present with some chronicity index in tissue biopsy at time of diagnosis also difficult to treat , not responding to steriods need more aggressive treatment and can progress to chronic allograft rejection with poor graft survival.
A and c :
Late acute rejection is usually associated with poor graft survival more than EAR which incidence has decreased now due to advances on immunosuppressive
One study of 687 transplant recipients at one U.K. center in 1984 to 1996 defined “early” AR as occurring within 90 days of transplantation and “later” AR as any AR event from 91 days out to a maximum of 14 years Five-year graft survival rates were 87% in patients without AR, 63% in those with “early” AR, and 45% in those with “late” AR
C: increased graft loss risk associated with late AR is likely mediated by multiple factors
late AR is more of AB mediated and carry poor prognosis as clinical monitoring is less intense in the later period , patient follow up every 2-3 months so late AR can be diagnosed late with more sever and chronic graft damage and less treatable at time of diagnosis.
E: among significant risk factors for LAR IS denovo DSA
Philip A. Clayton, Stephen P. McDonald.
Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis.JASN September 2019, 30 (9) 1697-1707;
A. True: Due to Development of de novo DSA and predominance of ABMR in late rejections
B. False: Non compliance or reduction of immunosuppressions can generate de nofo DSA and ABMR
C.True
D.False: Usually need more aggressive immunosuppressions and PP to remove DSAs
E.True Usually due to non compliance or sub optimal immunosuppressions
A. Usually associated with poor graft outcome T
B. Commonly antibody-mediated T
C. The prognosis may be better if due to non-compliance F
C. D. Usually responds well to steroid pulses F
A. May be caused by de novo DSA T
REFERANCES
1. Bertrand D, Gatault P, Jauréguy M, Garrouste C, Sayegh J, Bouvier N, et al. Protocol Biopsies in Patients With Subclinical De Novo Donor-specific Antibodies After Kidney Transplantation: A Multicentric Study. Transplantation. 2020;104(8): 1726–1737.
2. Wan SS, Chadban SJ, Watson N, Wyburn K. Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients. Am J Transplant. 2020;20(5): 1351–1364
Thank you, Professor, for such a critical question!
Late acute rejection
A. Usually associated with poor graft outcome….T
1)Late rejection mostly sever ABMR or steroids resistant TCMR
2)late discover
3) patient usually underimmune suppressed
B. The prognosis may be better if due to non-compliance…F
Non compliance associated with sever both ABMR ,TCMR with poor graft survival
C. Commonly antibody-mediated….T
Pure TCMR is lower after 1st year post transplant
D. Usually responds well to steroid pulses…F
Usually discovered late and of class 2,3 and show steroids resistant
E. May be caused by de novo DSA…T
Donovo DSA occurs in 11% of non sensitized patients and associated with both late acute ABMR and chronic ABMR
Dear Dr Ahmed,
I think the right answers will be A, C, and E.
Late acute rejection is commonly ABMR and may be due to the development of de novo DSA.
Non-compliance is a major problem as it may lead to the development of DSA and specialized memory cells against the donor antigens which are associated with a poor long term outcome (that is also aggravated by the under immune suppression secondary to non-compliance).
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Late acute rejection
A. Usually associated with poor graft outcome
B. The prognosis may be better if due to non-compliance
C. Commonly antibody-mediated
D. Usually responds well to steroid pulses
E. May be caused by de novo DSA
True: A, C, E
False: B, D
A: True: Late acute rejection is usually due to under-immunosuppression and de-novo DSA, antibody mediated and hence usually has poor graft outcomes.
B: False: Non-compliance leads to under-immunosuppression, and hence increased DSA formation, with poor prognosis.
C: True: Late acute rejection is usually antibody-mediated due to de novo DSA
D: False: Steroid pulses have a role in treatment of late acute rejection as a component of T cell mediated rejection is usually present, but Steroid ALONE will not be effective, unless it is pure T cell mediated rejection.
E: True: Late acute rejection is usually due to under-immunosuppression and de-novo DSA.
Late acute rejection
A, C, E
B. Late acute rejection is associated with worsened graft survival than early but the reason for the bad prognosis could be because of immunologic activity and triggering factors such as infection or no adherence to immunosuppressive medication. Hence prognosis could be better if the issue is due to non compliance.
Ref:
Eun Hee Koo, Jang et al. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney research and clinical practice. Vol 34, issue 3, 2015 Sep, pp. 160-164. https://doi.org/10.1016/j.krcp.2015.06.003
I would also like to add that A is also true. LAR is usually associated with poor graft outcome.
However, C is not true since AMR is less common than acute cellular rejection.
D is not true as well. This is because the patient may respond to steroid pulses, but this is not a common thing that is seen with every patient.
A, D, E
Several studies had shown that Late AR (LAR) has a worse prognosis than early acute rejection with inferior graft survival. Development of de novo DSA, non-adherence or suboptimal immunosuppression, and recurrent acute rejection episodes are important risk factors for LAR. Hence, Patients with de novo DSA and DGF should be considered at risk of LAR.
Acute cellular rejection is the most common form of rejection. Most acute rejection episodes improve with steroid boluses or with an escalation of immunosuppression.
Usually associated with poor graft out come? T
Many studies have been conducted to explore whether the timing of AR affects graft survival. The majority of these studies reported that LAR was correlated with poor long-term graft survival .
] Joseph JT, Kingsmore DB, Junor BJ, Briggs JD, Mun Woo Y, JaquesBC, Hamilton DN, Jardine AG, Jindal RM: The impact of late acuterejection after cadaveric kidney transplantation.Clin Transplant15:221–227, 2001[2
The prognosis may better if due to none-compliance ? F
Nonadherence was more frequent in patients who progressed to failure versus those who survived .
] [5]Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B,Hidalgo LG, Famulski K, Matas A, Halloran PF: Understanding thecauses of kidney transplant failure: the dominant role ofantibody-mediated rejection and nonadherence.Am J Transplant.
.
Commonly antibody mediated ? T
ABMR became common in biopsy specimens obtained 1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time.
Am Soc Nephrol 26: ccc–ccc, 2014. doi: 10.1681/ASN.201406058
Usually respond well to steroid pulses ? F
There is significant advantage for pulse therapy in patients who sought treatment early . Pulse therapy also appeared beneficial in preventing subsequent rejection episodes.
John C.HillFRCS1RichardMaskeFCS(SA)1PeterWatsonFRCS2
May be caused by de novo DSA? T
Late ABMR is commonly associated with de novo DSA
Aubert O, Loupy A, Hidalgo L, et al. Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients. J Am Soc Nephrol 2017; 28: 1912.
A _true ACR associated with poor graft function and survival
B_ false non compliance cause DSA and AMR
C_ true most commonly is AMR
D_ false respondent well to steroid in cases of ACR but some patients need to give ATG
E_true
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome
• True – majority of studies reported that LAR was correlated with poor long- term graft survival
B. The prognosis may be better if due to non-compliance
• False – the LAR probably either pure ABMR or mixed because by the time of failure, every nonadherent patient failing with rejection had DSA, have such a poor prognosis and response to therapy
C. Commonly antibody-mediated
• True- its probably pure ABMR or mixed type. Rarely T cell mediated.
D. Usually responds well to steroid pulses
• False- LAR usually antibody mediated rejection and it need IVIG , PLEX with or without Rituximab. It may respond to steroid but not as
E. May be caused by de novo DSA
• True- LAR may be caused by DnDSA
References
1-Kunchala R., Gudipati A., Guditi S., Taduri G., et al. Late Acute Rejection in Renal Allografts: Clinical, Pathologic, and Follow‑up Data from a Single Tertiary Care Center. Indian Journal of Transplantation.2018;January-March. Volume 12,Issue 1.
2-Krisl J.C., Alloway R.R.,Shield A.R.,Govil A., et al. Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival. Transplantation.October 2015,Volume 99, Number 10.
3-Cooper J.E. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN. 2020; March,15: 430–438.
the answer is E
Renal transplant recipients who develop a de novo DSA after transplantation can present with late-onset ABMR. ABMR in patients with a de novo DSA has been associated with poorer outcomes compared with ABMR in patients with preexisting DSA
https://teksmedik.com/uptodate20/d/topic.htm?path=c4d-staining-in-renal-allografts-and-treatment-of-antibody-mediated-rejection#H64238091 at 17/12/2021
A,C,E
Commonly AMR as de novo DSA performed causing TG that affect the survival of the graft
& also it difficult to treated as mentioned above ( using steroid, plasma ex, Rituximab, IVIG ) and they also try toclizomab
Late acute rejection
A. Usually associated with poor graft outcome. True
-LAR has a serious impact on long-term graft survival.
B. The prognosis may be better if due to non-compliance. False
-Non-adherence to immunosuppressive therapy lead to de novo DSA which can lead to SAMR and graft deterioration and long-term graft dysfunction
C. Commonly antibody-mediated.True
-LAR in most cases is AMR while pure TCMR accounts for only a minority of LAR cases.
D. Usually responds well to steroid pulses. False
-Response to steroid according to the type of rejection (AMR or TCMR)
E. May be caused by de novo DSA. True
-It due to de novo DSA
References :
1.Rajamahesh Kunchala1, Archana Gudipati1, Swarnalatha Guditi2, Gangadhar Taduri2, Sree Bhushan Raju2, Megha S Uppin1 .Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center .Indian journal of transplant.Year : 2018 | Volume : 12 | Issue : 1 | Page : 48-52.
A. Usually associated with poor graft outcome True
LAR associated with poor long -term graft survival
B. The prognosis may be better if due to non-compliance False
Non adherence to treatment is a strong
risk factor for LAR with poor graft survival outcome
C. Commonly antibody-mediated True
Mainly AMR with small percentage CMR
D. Usually responds well to steroid pulses True
subset of C4d+ patients with acute rejection who do not have severe chronic changes might respond to corticosteroid therapy alone.
The majority of C4d+ patients with late acute rejection who were treated with corticosteroids alone responded to treatment.
E. May be caused by de novo DSA True
formation of de novo DSA after kidney transplantation is associated with antibody-mediated graft injury that may lead to graft failure
de novo production of DSA, of any specificity, was found to be associated with acute mediated rejection (AMR) and transplant glomerulopathy. Only HLA- Cw DSA were found not to be significantly associated with allograft failure
LAR mostly duet o to ABMR is associated with poor graft outcome especially if repeated. de-novo antibodies may be difficult to treat more than non-compliance that may respond better with dose adjustment if detected early before chronic atrophic changes. the steroid is the first-line treatment but the response is not always excellent to steroid-only treatment all time.
In sum A, B,C and D are logical D is not accurate (response is not always well)
Correct answers: A,C,E
Late acute rejection is usually associated with poor graft outcome. Development of de novo DSA increases the risk of ABMR and could also leads to increase in development of mixed rejection which is associated with poor graft outcome. Late acute rejection may respond to steroids but most of cases do not, and frequently need more aggressive treatment.
A. Usually associated with poor graft outcome.
True
Late ARE showed a strong adverse effect on long-term graft survival
B. The prognosis may be better if due to non-compliance. false
The association of young recipient age and LAR could be partly explained by noncompliance .
Non compliance lead to formation of denovo antibodies
C. Commonly antibody-mediated. true
Late onset of chronic AMR due to denovo DSA has been strongly associated with graft loss and effective therapies are currently lacking.
D. Usually responds well to steroid pulses. false
Poor response to steroid therapy
E. May be caused by de novo DSA. true
Because of non compliance the patient will develop denovo DSA which lead to rejection
Reference
1-YVO W. J. SIJPKENS. EARLY VERSUS LATE ACUTE REJECTION EPISODES IN RENAL TRANSPLANTATION. Vol. 75, 204–208, No. 2, January 27, 2003
Printed in U.S.A.
2-Philip A. Clayton,1,2,3 Stephen P. McDonald,1,2,3 Graeme R. Russ,1,2,3 and Steven J. Chadban1,4,5. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis. JASN 30: 1697–1707, 2019
3-Eun Hee Koo 1, Hye Ryoun Jang 1, The impact of early and late acute rejection on graft survival in renal transplantation. 2015. The Korean Society of Nephrology. Published by Elsevier.
LATE ACUTE GRAFT RJECTION
A. TRUE : compared to early acute rejection due to severe ABMR.
B.FALSE .non compliance to medications can cause DSA and ABMR with increased risk of TCMR and recurrent rejection
C.T due to de novo DSA.
D. FALSE usually resistant to steroid as monotherapy.
E.TRUE de novo DSA are closely related to ABMHR.
REFERENCES:
Danovitch, GM: Handbook of kidney transplantation ,6th edition,2018
KOO,EH, et al The impact of early and late acute rejection on graft survival in renal transplantation, Kid Res and Clin Pract ,vol 34,issue 3,2015,Sept.pp:160-164.
●. Usually associated with poor graft outcome
T . Due to developing ab Mr. And denovo Dsa .
●The prognosis may be better if due to non-compliance
F.
NON COMPLIANCE TO Medication leads to ab mediated rejection
● Commonly antibody-mediated
T . As it is late .. it is rare to be TC mR after 6 months .
●Usually responds well to steroid pulses
F .
However pulse steroid is one role for management it doent respond well
It need ivig /plasma pheresis and iv rituximab.
●May be caused by de novo DSA
T.
Dear All
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome– true
Late-onset AR (occurring beyond the first 6 months after transplantation) has long been known to be associated with increased risk of graft loss. Late onset of chronic AMR in particular has been strongly associated with graft loss
B. The prognosis may be better if due to non-compliance — false
non compliance which is more common in young patients is associated DSA formation and AMR WITH POOR POTCOME
C. Commonly antibody-mediated — TRUE
D. Usually responds well to steroid pulses — FALSE
it is usually non steroid responsive antd it is difficult to treat.
E. May be caused by de novo DSA — true
yes it is
reffrences
— Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, et al.: Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients. J Am Soc Nephrol 26: 1711–1720, 2015pmid:25377077
A-True.
It is sever ABMR , not respond to steroid.
B-False.
As non-compliance related sever ABMR ,TCMR and poor graft survival.
C-True.
D- it discovered late with resistance to steroid.
E-True.
Late acute rejection can be ABMR or CMR ,it has poor outcome of graft function
management :IVIG ,plasmapheresis ,rejection ituximab ,or bortezomib
it could be due to non compliance
A. True ;In early rejection, the immune system became more prime than in late rejection where you have more of APCs presenting donor’s particles to recipient lymphoid organs. This activate CD4 T cells which in turn stimulate the humoral arm of the immune system.
B. True ; non-adherence is bad because it is usually chronic and associated with chronic graft loss. Once patient became non-adherent is very difficult to convince them about taking the treatment
C. True ; early acute rejection is commonly T cell mediated while late acute is AMR or it can mixed
D. False ; it may not respond to corticosteroid alone
E. True ; Class II DSA usually develop after some time following transplantation although it can be detected in the pre-transplants period.
Late acute rejection is defined by a sudden rise in Cr usually after the first year following kidney transplantation. It is seen in < 10% of the recipients. A single event of rejection decreases 5-year allograft survival by < 10%.
Late acute rejection is mostly AMR and may be mixed.
The most important risk factor is non-adherent to immunosuppressive therapy.
The evidence for management is not robust, although acute AMR rejection may be better than chronic AMR.
The best is to prevent rejection to occur at first place.
It involved; IV Corticosteroids, plasmapheresis, IVIG.
Optimise maintenance therapy
Counselling about adherence to drugs.
Late AR have worse graft and patient survival compared to early acute rejection .
The clinical and pathological features of late acute kidney allograft rejection are not fully understood.
Risk factors are de novo DSA, non compliance , improper prescription and recurrent acute rejection
Management includes:
Close monitoring of at risk patiens to pick them early
Some studies suggested that intensive treatment of LAR may help improve graft survival and long term outcome.
Other studies suggested that it there was no high chronicity index , treatment with steroids may be enough for such patients
1-Esra Baskin, Asli Kantar, Kaan Gulleroglu, Esra Ozmen, Handan Ozdemir, Mahir Kirnap, Gokhan Moray, Mehmet Haberal, SP873 EFFECTS OF LATE ACUTE REJECTION ON GRAFT SURVIVAL AND OUTCOME IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS, Nephrology Dialysis Transplantation, Volume 30, Issue suppl_3, May 2015, Page iii665, https://doi.org/10.1093/ndt/gfv203.11
2-Nair, R., Agrawal, N., Lebaeau, M., Tuteja, S., Chandran, P. K. G., & Suneja, M. (2009). Late Acute Kidney Transplant Rejection: Clinicopathological Correlates and Response to Corticosteroid Therapy. Transplantation Proceedings, 41(10), 4150–4153. doi:10.1016/j.transproceed.2009.
3-Eid L, Tuchman S, Moudgil A. Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant. 2014 Mar;18(2):155-62. doi: 10.1111/petr.12203. Epub 2013 Dec 28. PMID:
Late acute rejection
A. Usually associated with poor graft outcome
B. The prognosis may be better if due to non-compliance
C. Commonly antibody-mediated
D. Usually responds well to steroid pulses
E. May be caused by de novo DSA
A: True: Various studies have reported late acute rejections and the outcomes with poor graft survival. Late acute rejections are due to de-novo DSA and they causing late ABMR. Cellular rejections are usually steroid resistant if they occur very late.
B: False; Non Compliance of drugs may lead to under immunosuppressed state. This leads to the production of de novo DSA productions and lead on to graft injury
C: True: Late acute rejections are due to Class II HLA antibodies and are due to them getting produced de novo after transplant
D: False: Partial improvement is known with steroid pulses, but chronic ABMR usually is resistant to any form of treatment including plasmapheresis, IVIG or bortezomib.
E: True Late acute rejections are usually due to de Novo DSA which are formed in the post transplant period
Renal biopsy with C4d staining and determination of DSA are required for AR classification.
Acute TCMR
needs to be treated with more aggressive IS ;Tac trough level 5-7 ,and proper MMF dose ,pulse steroid followed by oral steroid .ATG is given according to Banff grading: total max dose of 6 mg in Banff grade IB and 9 mg in Banff grade II&III.. Alemtuzumab could be used if ATG is contraindicated .Additionally, prophylactic antimicrobial therapy is given
Acute ABMR
needs aggressive IS ;Tac trough level 5-7 ,and proper MMF dose, high dose methylprednisolone 3-5 mg/kg daily max 500 mg with rapid tapering.
IVIG to decease AB production. Rituximab to deplete B cells after i week of full IVIG therapy in case of active microvascular inflammation.6 sessions of plasmapheresis to remove DSA ,together with prophylactic antimicrobials of or 3 months.
Mixed TCMR&ABMR
Aggressive IS; high dose steroids, IVIG, plasmapheresis .Single rituximab dose one week after IVIG if there is active microvascular inflammation .
REFERENCES: Uptodate,2021.
Acute rejection is a major risk factor for graft loss depending on
· timing of occurrence (Late acute rejection has more negative impact on graft survival). LAT is mostly AMR due to donovo DSA , rarely its caused by pure TCMR.
For treatment of AMR , the commonly used medications include : pulse methylprednisolone, plasmapheresis, rituximab, and/or bortezomib and IVIG.
For trewatment of TCMR : Pulse methylprednisolone and IVIG.
1- Ragheb A , Kora M , Hassan Y, Kasem H. Study of the effect of early and late acute rejection episodes on renal graft survival.Journal of The Egyptian society of Nephrology and Transplantation. Volume : 21, Issue : 2 , Page : 98-105
2- Kunchala, Rajamahesh & Gudipati, Archana & Guditi, Swarnalatha & Taduri, Gangadhar & Raju, Sree & Uppin, Megha. (2018). Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian Journal of Transplantation. 12. 48. 10.4103/ijot.ijot_65_17.
Management of late acute rejection after 6 months must be diagnostic by biopsy.
Late acute rejection associated with:
– poor graft survival.
– discovered late and patient discharged from TX Center and came only for routine follow up.
-patients on tapering or low doses of immunosuppression .
* Management according to type of severity:
~ Borderline:
Manipulation of immunosuppression with higher target level of tacrolimus and oral steroid.
~ Class Ia/Ib : pulse steroid therapy 500 mg for 3-5 days.
~ Class 2-3 : pulse steroid + ATG ( 5-10mg/kg) according to response.
With given 3 month prophylaxis for CMV & pcj.
Acute ABMR:
Pulse steroid 500 mg 3-5 days
If rejection at 1 year post transplant:
– monitor DSA .
– 5 session of plasamaphareresis day after day , each one followed by IVIG 100 mg/kg and last one followed by high dose of IVIG 200 mg/kg divided in four doses daily and followed by ruitixmab 375 mg /m2 and similar doses of IVIG 2g/kg repeated after 1 month.
-After 1 year post-transplantation:
IVIG 2g/kg without plasmapheresis and single dose of rutiximab 500 mg after 1week
Late acute rejection (after 6 month) are usually antibody mediated rejection associated with identification of de Novo DSA Novo and may have worse effect on graft survival.
Treatment in first year after transplantation consists of removal of antibodies by plasmapheresis and prevention of new antibody formation by IVIG with or without rituximab administration and if plasma cells are involved using bortizumab may be indicated.
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome (True)
B. The prognosis may be better if due to non-compliance (False)
C. Commonly antibody-mediated (True)
D. Usually responds well to steroid pulses (False)
E. May be caused by de novo DSA (True)
Justification:
A- True.
B- Non-compliance is usually associated with poor outcome because of ABMR, de novo DSAs, mixed rejection.
C- True.
D- Usually steroid resistant and require second lines of treatment like IVIG, Rituximab, Plasma exchange, Bortezomib.
E- True.
A. True
B. False .non compliance end with DSA and AMR which are known to harm the kidney
C. True Commonly antibody-mediated
D. True.The majority of C4d+ patients with late acute rejection who were treated with corticosteroids alone responded to treatment
E. True
Answer the following question with a justification of your answer (not more than 50 words): Late acute rejection
A. Usually associated with poor graft outcome true
B. The prognosis may be better if due to non-compliance true
C. Commonly antibody-mediated True
D. Usually responds well to steroid pulses false
E. Can be caused by de novo DSA true
ABMR of renal allografts occurs in the following 2 forms:
Type 1, resulting from persistence and/or a rebound of preexisting DSA in sensitized patients, and type 2, associated with de novo DS. It is generally accepted that type 1 ABMR usually occurs early after transplantation, whereas type 2 ABMR most often occurs at least 1 year after transplantation and not infrequently much later.
Type 1 ABMR is usually “pure” ABMR without concurrent cell-mediated rejection (CMR), acute/active (without TG), and associated with DSA against either HLA class I or class II.
By contrast, type 2 ABMR is more frequently mixed ABMR/CMR and chronic, active, and mainly associated with anti-class II DSA. There is a strong association between anti-class II DSA and TG.
In type 2 ABMR, high fraction of C4d-negative, and a worse outcome for C4d-positive ABMR has been reported.
Late posttransplant ABMR progresses slowly and is commonly identified on a surveillance biopsy or a for-cause biopsy for minor allograft dysfunction.
Late or recurrent acute rejection, commonly occurs as a result of nonadherence to immunosuppressive medications or underimmunosuppression.
Depending on the timing of the biopsy, subclinical, active, or chronic active ABMR is diagnosed.
The allograft biopsy shows subclinical ABMR, it can proceed to transplant glomerulopathy (TG) or allograft failure.
ABMR with dnDSA usually occurs 3 months or later after transplantation and the majority is associated with anti-HLA class II. In a study by Aubert et al., ABMR with dnDSA was diagnosed at a median of 1,437 (range, 437–3,127) days after transplantation, whereas ABMR with the preexisting DSA was diagnosed at a median of 85 (range 17–369) days. 69% had class II dnDSA, 17% had both class I and class II dnDSA, and 14% had class I dnDSA. De novo DSA is a significan risk factor for TG and allograft failure.
Immunoglobulin G (IgG) subclasses are also related to the phenotypes of ABMR.
Subclass IgG4 is associated with a slower progression to graft failure and a lower incidence of C4d deposition. But IgG4 is associated with transplant glomerulopathy and interstitial fibrosis/tubular atrophy. T cell-mediated rejection may be more often encountered in ABMR with dnDSA than ABMR with preformed DSA.
Acute rejection due to non-compliance has better prognosis than acute rejection in the context of appropriate immunosuppressive therapy.
The cellular acute rejection more commonly occurs earlier after kidney transplantation and usually in the first post-transplant.
Optimizing baseline immunosuppression and evaluation and managing nonadherence are standard care.
rejection classified as either acute or chronic can be differentiated histologically based on biopsy findings. in acute rejection which is mostly anybody mediated. In early rejection mostly performed DSA while in late acute rejection mostly due to denovo DSA or delayed graft function. In acute rejection, we will see glomerulitis, capillaritis, arteritis, etc. Although the definition of LAR (late acute rejection) is obscure with no consensus, most papers define it as ejection after 6 months. As it is antibody-mediated we treat it with steroids, plasmapheresis, sometimes bortezomib. also we adjust the dose of maintenance immune suppression
Late acute rejection (LAR), which is defined as acute rejection 6 months after transplant, is associated with a worse prognosis than early acute rejection.
It is important to determine the type of acute rejection because treatment for cell-mediated rejection (ACR) and antibody-mediated rejection (AMR) are different. Acute AMR has a poor prognosis and represents 20% to 30% of acute rejection cases in recipients of kidney transplants. It is typically labeled as steroid resistant, and is usually treated aggressively with plasmaphoresis and intravenous immunoglobulin (IVIG).
C4d used as a marker to distinguish late AMR from late ACR.
significant proportion of C4d+rejections also have a cellular component
both C4d+and C4d-groups responded to therapy with corticosteroids alone.
This finding may be explained by the fact that the patients with positive C4d staining who responded to steroid therapy alone had a mixed cellular component as well.
Another explanation for the good response to steroids of C4d+patients may be the fact that severe chronic changes and transplant glomerulopathy were absent, as both of these latter findings have been associated with a poor graft outcome.
Therefore in selected patients with C4d+ LAR without severe chronic interstitial changes or transplant glomerulopathy, treatment with plasmapheresis, IVIG, and other immunomodulation agents may be unnecessary. In these patients a strategy of initial treatment with pulse corticosteroids and continued maintenance with MMF and calcineurin inhibitors may prove sufficient to treat late AMR just as with late ACR.
Late acute rejection associated with poor outcome in the graft function
Treatment first by prevention of it’s occurrence by frequent monitoring of high risk group DSA monitoring and protocol biopsy.
There are no standard treatment for LAR, but IVIG, rituximab & bortezumab can be used
Late acute rejection LAR is known as decreasing in graft function with poor outcome than early AR most common cause is AMR and there are alot of risk factors causing LAR and also affecting on graft survival like denovo DSA which is the common cause ,viral and bacterial infection,drug toxicity ,previous rejection ,non compliance patient to the medication .
Treatment first by prevention of it’s occurrence by frequent monitoring of high risk group patients with prophylaxis antibiotics and antiviral ,DSA monitoring and protocol biopsy.
For ACR using pulses methylprednisolone is usually effective but ATG need to be added in some patients.
AMR need aggressive management with PLEX ,IVIG and Bortezomib or rituximab .
In all types immunosuppressants adjustment and monitoring and adding prednisolone in cases with steroid free regimen.
Reference
_ OSH renal transplantation, (2011),oxford university:Nicholas Torpey ,Nadeem Moghal , Evylen Waston ,David Tolbat.
_Shawar SH ,Naik Rh(2020).pathophysiology. (Renal transplant rejection. Treasure island:Statpearls(internet) p.25).
Usually associated with poor graft out come? T
Many studies have been conducted to explore whether the timing of AR affects graft survival. The majority of these studies reported that LAR was correlated with poor long-term graft survival .
] Joseph JT, Kingsmore DB, Junor BJ, Briggs JD, Mun Woo Y, JaquesBC, Hamilton DN, Jardine AG, Jindal RM: The impact of late acuterejection after cadaveric kidney transplantation.Clin Transplant15:221–227, 2001[2
The prognosis may better if due to none-compliance ? F
Nonadherence was more frequent in patients who progressed to failure versus those who survived .
] [5]Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B,Hidalgo LG, Famulski K, Matas A, Halloran PF: Understanding thecauses of kidney transplant failure: the dominant role ofantibody-mediated rejection and nonadherence.Am J Transplant.
.
Commonly antibody mediated ? T
ABMR became common in biopsy specimens obtained 1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time.
Am Soc Nephrol 26: ccc–ccc, 2014. doi: 10.1681/ASN.201406058
Usually respond well to steroid pulses ? F
There is significant advantage for pulse therapy in patients who sought treatment early . Pulse therapy also appeared beneficial in preventing subsequent rejection episodes.
John C.HillFRCS1RichardMaskeFCS(SA)1PeterWatsonFRCS2
May be caused by de novo DSA? T
Late ABMR is commonly associated with de novo DSA
Aubert O, Loupy A, Hidalgo L, et al. Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients. J Am Soc Nephrol 2017; 28: 1912.
Both early and late acute (antibody-mediated and T cell-mediated) rejections are major causes of renal allograft dysfunction. Late acute rejection (LAR) is defined as the first rejection episode occurring after the first six months of transplantation. LAR has a worse prognosis than early acute rejection. Baskin E et al, in a study of 34 pediatric patients with acute rejections, found that late acute rejections are associated with worse prognosis and inferior graft survival. Development of de novo DSA, non-adherence or suboptimal immunosuppression, and recurrent acute rejection episodes are important risk factors for LAR. Similarly, Jalalzadeh M et al, in 2015, found that late acute rejection (LAR) had a negative impact on long-term renal allograft survival (lower 5-year graft survival rate) compared to early AR, and the risk of chronic graft dysfunction increased in patients with a history of LAR.
References:
1. Baskin E, Kantar A, Gulleroglu K, Ozmen E, Ozdemir H, Kirnap M, Moray G, Haberal M. Sp873effects of late acute rejection on graft survival and outcome in pediatric renal transplant recipients. Nephrology dialysis transplantation. 2015;30(suppl_3):iii665-.
2. Jalalzadeh M, Mousavinasab N, Peyrovi S, Ghadiani MH. The impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. Nephrourol Mon. 2015 Jan 20;7(1):e24439. doi: 10.5812/numonthly.24439.
Management of late acute rejection involves aggressive therapy with plasmapheresis and IVIG. This is done with or without rituximab. C4d staining of peritubular capillaries is a valuable tool to identify antibody mediated rejection.
Newer treatment like Bortezomib, C1 esterase inhibitors are not consistent with findings.
Ref:
Nair R, Agrawal N, Lebaeau M, Tuteja S, Chandran PK, Suneja M. Late acute kidney transplant rejection: clinicopathological correlates and response to corticosteroid therapy. Transplant Proc. 2009 Dec;41(10):4150-3. doi: 10.1016/j.transproceed.2009.09.074. Erratum in: Transplant Proc. 2010 Mar;42(2):673. PMID: 20005357.
Cooper, J. Evaluation and treatment of acute rejection in kidney allografts. CJASN March 2020, 15(3) pp 430-438.
DOI: https://doi.org/10.2215/CJN.11991019
Late acute graft rejection
• De-novo (class 1) has been associated for LAR
• mostly AMR but small percentages is T cell mediated
• Has a poorer effect on long term graft survival than EAR
• More likely to be PRA positive, younger than no AR group
• 5 year graft survival is 85 % compared with no AR, 97% and EAR, 89%
o LAR and EAR showed lower graft survival rates than no AR
• LAR has HR 5.10 for graft failure
• Management of LAR depends on histological findings, DSA and severity of the rejection
o Mostly need preventive measures such as maintaining good level of Immunosuppressants, reassurance of adherence to meds
o ABMR -need PLEX and IVIG with without rituximab, eculizima and CI esterase inhibitors
o TCMR- methylprednisolone and rATG with optimisation of IS
References
1-Kunchala R., Gudipati A., Guditi S., Taduri G., et al. Late Acute Rejection in Renal Allografts: Clinical, Pathologic, and Follow‑up Data from a Single Tertiary Care Center. Indian Journal of Transplantation.2018;January-March. Volume 12,Issue 1.
2-Krisl J.C., Alloway R.R.,Shield A.R.,Govil A., et al. Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival. Transplantation.October 2015,Volume 99, Number 10.
3-Cooper J.E. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN. 2020; March,15: 430–438.
1- frequent monitoring of renal functions, CNI trough levels and DSA …..
2- protocol biopsy has some beneficial roles in management.
3- early and proper treatment of acute rejection.
4- local policies for monitoring and management of de novo DSA
What is the effect of late acute rejection (after 6 months of transplantation) on graft survival?
Post renal transplant acute rejection episodes have been shown to reduce long-term graft survival. (1)
Late acute rejections are a consequence of underimmunosuppression, non-adherence, infections and formation of de-novo DSAs. These, as compared to early acute rejections have been shown to have poorer graft outcomes and are associated with class I MHC incompatibility. (2)
Opelz et al, in their study, showed that the risk of graft loss in a patient with acute rejection within 6-12 months post transplant is 174% more as compared to someone who did not face any acute rejection episode. (3)
Jalazadeh et al also showed that acute rejection episodes are associated with poorer graft survival, but more so in patients with late acute rejection. (4)
Management of Late acute rejection: Management of a late acute rejection will be essentially the management of acute rejection as late acute rejection is rejection occurring after first 6 months of transplantation. A kidney biopsy is a must for the diagnosis.
Augmentation of immunosuppression is important, with triple drug immunosuppression (CNI, MMF, steroids).
The treatment depends on the histological diagnosis: (5)
Antibody mediated rejection: 5 sessions of Plasma exchange followed by IVIG (100-200mg/kg). Injection Rituximab 375 mg/m2 following last treatment.
Acute T cell mediated rejection:
Banff Ia: IV methylprednisolone 500 mg/d x 3-5 days
Banff Ib: If mild graft dysfunction: IV methylprednisolone 500 mg/d x 3-5 days
Banff Ib: If severe graft dysfunction: rATG 1.5mg/kg/day x 5-7 days or until recovery
Banff IIa, IIb or III: rATG 1.5mg/kg/day x 5-7 days or until recovery
In mixed rejection: A combination of therapy to cover both aspects of the rejection.
In addition:
Pneumocystis prophylaxis, CMV prophylaxis needs to be given.
References:
1) Clayton PA, McDonald SP, Russ GR, et al. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis. JASN 2019;30:1697-1707.
2) Sijpkens YW, Doxiadis IIN, Mallat MJK, et al. Early versus late acute rejection episodes in renal transplantation. Transplantation 2003;75:204-208.3) Opelz G, Dohler B. Influence of Time of Rejection on Long-Term Graft Survival in Renal Transplantation. Transplantation 2008;85:661-666.
4) Jalazadeh M, Mousavinasab N, Peyrovi S, et al. The Impact of Acute Rejection in Kidney Transplantation on Long-Term Allograft and Patient Outcome. Nephro Urol Mon 2015;7:e24439.
5) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN 2020;15: 430–438.
A- Usually associated with poor graft outcome, True rejection has worse prognosis than
early ABMR.
B-The prognosis may be better if due to non-compliance . False as noncompliance is risk
factor to develop DSA LAR. in addition to donor-recipient HLA mismatches, recipient race,
donor age and delayed graft function have been shown to be associated with rejection
episodes.
C-Commonly antibody-mediated. True .
D- Usually responds well to steroid pulses. False most need Plasmapheresis
Intravenous immunoglobulin
E-May be caused by do NoVo DSA .True ,DSA in late AMR episodes were almost
exclusively Class II in general, with the vast majority being DQ specific
Answer A, C, E
A-Late acute rejection usually associated with poor graft outcome is true. because it is usually related to non-compliance and formation of alloantibodies.
b-the prognosis may be better if non-compliance is wrong because once the graft is exposed to the antibodies,this will lead to recurrent formation of alloantibodies
c-commonly antibody-mediated true
d-Usually responds well to steroid pulses is false, because it is usually antibody-mediated
e-may be caused by de novo DSA is true.
Late acute rejection
A. Usually associated with poor graft outcome —True
B. The prognosis may be better if due to non-compliance—– False
C. Commonly antibody-mediated—True
D. Usually responds well to steroid pulses—False
E. May be caused by de novo DSA— True
Late acute rejection in most of the cases is antibody mediated. Pure Tcell mediated rejection represents only small number of cases. De novo appearing donor-specific antibodies (DSAs) are responsible for antibody mediated rejection.
Late acute rejection has also been reported to have an adverse effect on the long-term graft survival with documented graft loss in most of the cases
Reference
Kunchala R etal. Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center.Indian journal of trasnplanation 2018 , 12,1 ( 48-52).
Late acute rejection episodes are difficult to diagnose and treat
It’s common risk factors are non-adherence , viral infections including CMV and EBV, immunosuppression weaning and steroid withdrawal , and HLA mismatches at class II.
Delayed graft function negatively affects patient survival as well as short- and long-term graft survival . However, its role in Late acute rejection has not been defined. Intensifying induction therapy during delayed graft function might have protected from Early acute rejection, but not from Late as the effect of induction therapy had faded.
Protocols reducing Delayed graft function and adjusting immunosuppression may help improve long-term graft survival and function.
De novo DSA indicating non adherence to immunosuppression was found in patients at the time of Late acute rejection compared to those without Late acute rejection
It’s management
intravenous Methyl prednisolone 10 mg/kg/dose (maximum 1000 mg/dose) for three consecutive days followed by oral prednisone 2 mg/kg/day to be tapered to baseline dose over2 weeks in steroid-based protocol.
In steroid resistant cases
thymoglobulin 1.5 mg/kg/dose once a day for 5–7 days.
Patients with low positive DSA can be treated with IVIG 2 g/kg to a maximum dose of 140 gm/dose. Dose can be repeated 4 weeks later.
Those with strong positive DSA were additionally treated with a single dose of rituximab 375 mg/m2 /dose.
additional treatments with IVIG and rituximab can be added if needed , this will be decided according to renal biopsy and DSA titers obtained 6-8 weeks after first therapy
Reference
Eid L et al. Late acute rejection: Incidence, risk factors, and effect on graft survival and function. Pediatr Transplantation 2014: 18: 155–162
Acute rejection is defined as acute deterioration of graft function . The effect of acute rejection on graft survival vary according to time of rejection and whether graft fuction returned to base line or not. Late acute rejection episodes may be attributed to the non compliance to immunosuppressive drugs or the overhasty weaning of the IS drugs. The late acute rejection may be also attributed to HLA class l incompatibility.
LAT effect on graft survival is poorer than the effect of EAR. Most late acute rejection is due to AMR due to the formation of de novo DSA. treatment of LAR need aggressive intervention using plasmapheresis , IVIG, RITUXIMAB , Bortezomib, and eculizumab and usually does not respond to pulse steroid alone.
So my answer is A,C, E
https://doi.org/10.1016/j.transproceed.2005.03.017
The impact of early and late acute rejection on graft survival in renal transplantation – ScienceDirect
Early versus late acute rejection episodes in renal transplantation – PubMed (nih.gov)
Late acute kidney transplant rejection: clinicopathological correlates and response to corticosteroid therapy – PubMed (nih.gov)
What is the effect of late acute rejection (after 6 months of transplantation) on graft survival?
acute rejection refer to acute clinical deterioration of graft function with biopsy proven acute rejection as per Banff criteria, Both the survival rates of renal allograft in the EAR and LAR groups were significantly lower than that in the NAR group (P = 0.025) (1)
The graft survival rates were not different between the EAR group and LAR group (P=0.22 by log-rank test).(1) EAR, as well as LAR, had negative effects on long-term graft survival(2).
LAR more in young recipient age, and this can be explained by noncompliance with subtherapeutic drug level or increased immune responsiveness,with denovo DSAs especially in previously sensitized patients with low DSA s level, in addition the type of Acute late rejection is more with ABMR (4). so, education for noncompliant patients is important in the prevention of AMR. Also monitoring with SAB Luminex for the presence of DSAs AB would be necessary for early detection and intervention.it’s not only the time of AR will impact the graft survival the most important than time is the response to the treatment (3). Both EAR and LAR if completely responsive to therapeutic intervention with no chronic histological changes so likely the long-term graft survival will be not significantly different from those without acute rejection (2).
HLA mismatch type: HLA mismatch in HLA -A-B, DR, also-HLA DQ In one study shows the 5-yr graft survival for those who had LAR was 45% and 10-yr survival was 28%.
class I mismatches have been associated with late AR, suggest the role of indirect allorecognition pathways in the pathophysiology late AR (4).
How do manage it?
Management plan will depened on many factors including the histological finding considering the type and severity rejection TCMR vs AMR, mixed TYPE, and according to the Banff scoring will decide the therapeutic agents, patient immunological status, DSAs type ,level andsub -class,also non-immunological factors that should be considered before treating the rejection like BKV status, CMV , CVD risk ,previous history of AR ,DGF
for late mild ACR-usualy steriod responsive for 3-5 days with modification of maintenance IS, in sever type with vascular lesions will give ATG , however AMR is more common type of LAR with C4D+ve-PTC will start with Plasma pheresis not less than 5-6 sessions followed by IVIG 1-2gm/kg( total dose)followed by rituximab 375mg/m2 of one or two doses a week after with modification of the maintenance IS like shifting from cyclosporine to tacrolimus with target trough level 5-7 ng and azathioprine to MMF, plus steroid ifno steroid before with DSAs intensity monitoring for the response to treatment and the recurrence of AMR by SAB DSAs MFI value , and RFT with proteinuria,CMV ,PJP prophylaxis and BKV screening should be considered also entecavir prophylaxis for HBV status with rituximab, In general short term graft survival is good in compelete responsive AMR but in general the long-term graft survival after 5, 8, 10 years will be poor especially in case of AMR with chronic tissue injury in the presence of DSAs, De novo DSAs, DD transplant or second transplantation.
Innovation of the molecular genetic assay like immune – cell assays ,complement mediated biomarkers, cell based genetic transcription assay and the use of molecular microscopic system like endothelial associated transcripts (ENDATs) in biopsies of DSA-positive patients can reveal ABMR even in the absence of C4d positivity and early detection of AR prior to histological changes which allows preemptive diagnosis and treatment of AMR , such molecular assay still in subclinical cohorts studies hold promise for better future non invasive tools for early diagnosis and prompt therapeutic intervention before even clinical and histological damage (5).
The correct answers for the question:
A, C, E
References :
1-The impact of early and late acute rejection on graft survival in renal transplantation
Eun Hee Koo,1 Hye Ryoun Jang,1 Jung Eun Lee,1 Jae Berm Park,2 Sung-Joo Kim,2 Dae Joong Kim,1 Yoon-Goo Kim,1 Ha Young Oh,1 and Wooseong Huh1, Kidney Res Clin Pract. 2015 Sep; 34(3): 160–164.
2-impact of acute rejection episodes on long-term renal allograft survival
Jianyong Wu 1, Jianghua Chen, Yimin Wang, Jianguo Zhang, Zong Zhu, Zhangfei Shou, Suya Wang, Ping Zhang, Hongfeng Huang, Qiang He
Chin Med J (Engl). 2003 Nov;116(11):1741-5.
3-Arvizu-Hernandez M, Morales-Buenrostro LE, Vilatoba-Chapa M,
et al. Time of occurrence of kidney acute antibody-mediated allograft
rejection/acute cellular rejection and cell senescence: implications for
function outcome. Transplant Proc 2010; 42: 2486.
4-The impact of late acute rejection after cadaveric kidney transplantation
J T Joseph 1, D B Kingsmore, B J Junor, J D Briggs, Y Mun Woo, B C Jaques, D N Hamilton, A G Jardine, R M Jindal, Clin Transplant. 2001 Aug;15(4):221-7.
6-Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction
by Marco Quaglia 1,Guido Merlotti 1ORCID,Gabriele Guglielmetti 1ORCID,Giuseppe Castellano 2 andVincenzo Cantaluppi 1,
5-Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction
by Marco Quaglia 1,Guido Merlotti 1ORCID,Gabriele Guglielmetti 1ORCID,Giuseppe Castellano 2 andVincenzo Cantaluppi 1
What is the effect of late acute rejection (after 6 months of transplantation) on graft survival?
Late acute rejection is associated with poor graft survival due to multiple aspects
1)Mostly sever ABMR or TCMR
2)Usually discovered late as patient is already discharged to home and on just routine follow up
3) immune suppression medications usually at lower side and damage is sever
How do manage it?
According to type and degree of severity
acute TCMR
Borderline rejection….tailoring immune suppression medications targeting higher levels of tac (5-7) and oral steroids
Class1a/1b…. pulse steroids usually 500mg 3-5 days will be sufficient
Class 2-3…. pulse steroids plus ATG 5-10mg/kg according to response
With 3m CMV,PCJ prophylaxis
Acute ABMR
Pulse steroids 500mg for 3-5days then if rejection
1)At 1st year post transplant…. withdraw baseline DSA
plasma exchange 1-1.5 plasma volume on every other day base followed by IVIG 0.5-1gm/kg with the last session or divided 200mg/kg after each session followed by rutiximab 500mg after one week.beside augmentation of the conventional triple immunosuppressive medications
Monitoring of dsa, stabilization of kidney function, decrease of proteinuria will be of great prognostic and therapeutic value.
2)After 1st year post transplant
DSA baseline then
Role of plasma exchange decrease.IVIG 2gm/kg without plasma exchange and single dose of rutiximab 500mg after 1w can be given.
Reference
Up-to-date
Late acute rejection
A. Usually associated with poor graft outcome True
LAR is associated with negative outcomes on allograft survival (1)
B. The prognosis may be better if due to non-compliance False
De novo DSA, ABO incompatibility, African Americans all are associated with poor prognoses.
C. Commonly antibody-mediated true
although also TCMR may cause late acute graft rejection. In one study, TCMR was present in about 25% of graft rejection assumed initially to be AMR. (2)
D. Usually responds well to steroid pulses True
However, management may include pulse steroid, plasmapheresis, and IV Ig.
E. May be caused by de novo DSA true
De novo DSA is commonly associated with LAR.
References:
1- Jalalzadeh, M., Mousavinasab, N., Peyrovi, S., & Ghadiani, M. H. (2015). The impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. Nephro-urology monthly, 7(1), e24439. https://doi.org/10.5812/numonthly.24439
2- Mauiyyedi S, Crespo M, Collins AB, Schneeberger EE, Pascual MA, Saidman SL, Tolkoff-Rubin NE, Williams WW, Delmonico FL, Cosimi AB, Colvin RB. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol. 2002 Mar;13(3):779-787. doi: 10.1681/ASN.V133779. PMID: 11856785.
-Late acute rejection (LAR) in most cases is antibody-mediated (AMR) while pure T cell-mediated rejection accounts for an only minority of LAR cases.
– LAR -AMR is due to de novo DSA.
-Risk factors for LAR: infections, non complain to the immunosuppressive drugs, earlier rejection episode,low dose of immunosuppressive drugs.
-LAR has a worse prognosis and poor graft survival than early acute rejection.
-Renal allograft biopsy is essential to confirm and classify LAR.. adequat biopsy must contain 10 glomeruli and 2 arteries.
Management of LAR :
– There are no stander treatments for LAR but treatment according to types rejection.
antibody-mediated rejection (AMR): Plasma exchange , IVIG ,Rituximab, Bortezomib.
T cell-mediated rejection:IV Methyl prednisone and IV ATG .
-Optimization of maintenance immunosuppressive drugs and their level is the cornerstone in preventing LAR.
-Monitor DSA level.
Referrences
1.Rajamahesh Kunchala1, Archana Gudipati1, Swarnalatha Guditi2, Gangadhar Taduri2, Sree Bhushan Raju2, Megha S Uppin1 .Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center .Indian journal of transplant.Year : 2018 | Volume : 12 | Issue : 1 | Page : 48-52
2.Ruchi H. Naik; Saed H. Shawar. Renal Transplantation Rejection. Statpearls.July 25, 2021.
Late acute rejection
A. Usually associated with poor graft outcome. (T)
B. The prognosis may be better if due to non-compliance (F)
C. Commonly antibody-mediated. (T)
D. Usually responds well to steroid pulses. (F)
E. May be caused by de novo DSA. (T)
Nonadherence to immunosuppressive regimens plays a role in most late acute rejections. Inadequate dosing of medications or tendency of providers to wean medications in the late post-transplant period. It is a sensitive and difficult task to determine the minimum dose required to prevent rejection, and maintain optimal graft outcomes.
Current methods for immune monitoring cannot reliably inform whether a given immunosuppression regimen is adequate. Therefore, although immunosuppression reduction may be considered in some patients in the late post-transplant period, patients who reduce doses of immunosuppression should be monitored carefully for signs of graft dysfunction. Periodic screening for the development of donor-specific antibodies may be considered for those on reduced immunosuppression and may be a marker for inadequate immunosuppression.
Late acute rejection ≥6 months post-Tx may contribute to lack of improvement
And it has long been known to be associated with increased risk of graft loss.
significant risk factors for LAR included DGF, de novo DSA ,mean COV% of TAC and non-adherence 1.
DGF and DSA remained statistically significant COV% TAC had borderline significance and non-adherence was not significant on multivariate regression analysis.
Patients with LAR had inferior graft survival and function, whereas graft function was stable in the no LAR group over a mean follow-up of 31.2 months.
Patients with de novo DSA and DGF should be considered at risk of LAR; an early diagnosis and treatment of LAR may improve graft survival and function 1.
LAR was shown to adversely impact graft survival and function. This may be in part due to delayed diagnosis as many of the recipients are followed less frequently after the first year of transplantation and in part due to recurrent episodes of LAR.
The treatment plan determination uses multiple factors, including the type of rejection, the severity of the histological lesion, the chronicity score, and the recipient comorbidity. tailoring medical treatment of individual characteristics is needed 2.
Differential Diagnosis 3.
1Volume depletion
2. Acute tubular necrosis
3. Calcineurin inhibitor nephrotoxicity –
4. Urinary obstruction
5. Infections (Bacterial pyelonephritis,Viral infections – BK polyomavirus and CMV)
6. Acute and chronic interstitial nephritis
7. Recurrent primary glomerular diseases (Focal segmental glomerulosclerosis (FSGS),Primary membranous nephropathy,Diabetic nephropathy,Ig A nephropathy,C3 Glomerulonephritis (C3 GN)
8. De novo glomerular disease
9. Thrombotic microangiopathy.
10. Transplant renal artery stenosis
11.PTLD. 3.
Management; 3.
Antibody-Mediated Rejection:
depends on the level of the antibody levels. Higher antibody levels need plasma exchange The following are the different modalities used for AMR:
plasma exchange: 3 to 5 sessions daily on every other day is used followed by IVIG and rituximab
iVIG: IV immunoglobulin (100 to 200 mg/kg) is used followed by the last session of plasma exchange when used in combination with plasmapheresis or a higher dose of 2g/kg after the final session of plasmapheresis.
Rituximab Anti CD20 cell antibody rituximab (375 mg/m^2) is used in combination with IVIG followed by plasma exchange
Bortezomib: Plasma cell inhibitor bortezomib (1.3 mg/m^2) is also used in combination with plasma exchange and IVIG
splenectomy: A splenectomy is very rarely an option,
Optimize the dose and the level of the maintenance immunosuppressive drugs.
T Cell-Mediated rejection:
Methyl prednisone IV (250 to 1000 mg daily) targeting T cells, B cells, and macrophages; given for 3 to 5 days.
rATG – rabbit anti-thymocyte globulin IV (1 to 1.5 mg/kg) targeting T cell receptors. for 7 to 14 doses based on the response and Cd3 level.
Optimize the dose and the level of the maintenance immunosuppressive drugs.
Chronic rejection: Since the antibody-mediated rejection mechanism is a major cause of chronic rejection, the same therapy as ABMR has been used, but generally, these measures are ineffective when serum creatinine is over 3 mg/dl and/or heavy proteinuria is present.
Prognosis
The acute rejections predispose to chronic graft dysfunction.
T Cell-Mediated rejections have better graft survival, especially when they respond to therapy, and the serum creatinine reaches near to the previous baseline after the treatment.
Acute rejections occurring after three months, vascular rejections, and the rejections not responding to therapy (serum creatinine not reaching 75% of baseline value) are associated with poor graft survival.
The appearance of de novo DSAs at any time post-transplant is associated with 5% poor graft outcome per year as compared to recipients without these antibodies.
Reference;
1Philip A. Clayton, Stephen PMcDonald, Graeme R. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis.JASN September 2019,30 (9) 1697-1707.
2Sharif A, Shabir S, Chand S, Cockwell P, Ball S, Borrows R. Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation. J Am Soc Nephrol. 2011 Nov;22(11):2107-18.
3 Naik RH, Shawar SH. Renal Transplantation Rejection. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.
Would you please answer to the point?
Effect of late acute rejection:
Acute rejection is a major risk factor for graft loss, severity of rejection, timing (early or late) and recovery to baseline or not affect the long term graft outcome.
Studies suggested that late acute rejection was correlated with poorer long term graft survival.
A study showed that new onset graft dysfunction and acute rejection after 90 days post transplant was followed by marked increase in the risk of death censored graft failure.
Management of late acute rejection:
treatment of acute rejection depends on accurate diagnosis, type of rejection and severity of rejection.
There is no standard treatment protocols for treatment of late acute rejection
Most cases of acute late rejection are antibody mediated.
Antibody mediated rejection (ABMR):
late acute ABMR should be differentiated from chronic ABMR, diagnostic criteria include peritubular capillaritis, arteritis and glomerulitits with positive C4d and DSA
treatment directed at removing antibody producing B cells, DSA and/or inhibiting subsequent complement regulated graft damage.
Plasma exchange, IVIG with or without Rituximab are the most commonly used (3)
several studies are evaluating other agents for treatment of AMR refractory to standard treatment include:
Bortezomib: induce apoptosis of plasma cells through proteosome inhibition
Eculizumab: inhibit terminal complement C5
C1 esterase inhibitor: inhibit classical complement pathway
T cell mediated rejection:
Banff Ia and Ib treated with methylprednisolone
Banff Ib, IIa, IIb and III treated with rATG for T cell depletion
Koo, E.H., Jang, H.R., Lee, J.E., Park, J.B., Kim, S.J., Kim, D.J., Kim, Y.G., Oh, H.Y. and Huh, W., 2015. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney research and clinical practice, 34(3), pp.160-164.
Gaston, R.S., Fieberg, A., Hunsicker, L., Kasiske, B.L., Leduc, R., Cosio, F.G., Gourishankar, S., Grande, J., Mannon, R.B., Rush, D. and Cecka, J.M., 2018. Late graft failure after kidney transplantation as the consequence of late versus early events. American Journal of Transplantation, 18(5), pp.1158-1167.
Webster AC,Wu S, Tallapragada K, Park MY, Chapman JR, Carr SJ:
Polyclonal andmonoclonal antibodiesfortreating acute rejection
episodes in kidney transplant recipients. Cochrane Database Syst
Rev 7: CD004756, 2017
Cooper, J.E., 2020. Evaluation and treatment of acute rejection in kidney allografts. Clinical Journal of the American Society of Nephrology, 15(3), pp.430-438.
Haas M. The revised (2013) Banff classification for antibody‑mediated
rejection of renal allografts: Update, difficulties, and future
considerations. Am J Transplant 2016;16:1352‑7.
Kunchala, R., Gudipati, A., Guditi, S., Taduri, G., Raju, S.B. and Uppin, M.S., 2018. Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian Journal of Transplantation, 12(1), p.48.
LAR had a negative impact on long-term renal allograft survival and increase the risk of chronic graft dysfunction . LAR was more commonly associated with males Late acute rejection has a worse prognosis than early acute rejection. It is important to distinguish between cellular and antibody-mediated rejection to guide the treatment strategy so biopsy is standard for diagnosis . The management of acute antibody-mediated rejection includes aggressive therapy with plasmapheresis and intravenous immunoglobulin and Rituximab .
Acute cellular rejection Intensification of maintenance immunosuppression Pulse methylprednisolone followed by oral prednisolone .If no response we add ATG . Aggressive treatment was associated with better graft outcome. However, higher incidence of posttreatment viral (cytomegalovirus and BK virus) and bacterial infections that necessitated more hospitalization Appropriate prophylactic antibiotics and antiviral are recommended for aggressive treatment patients.
2008;22:316-23. 21. O’Grady JG, Alexander GJ, Sutherland S, et al …
by R Nair · 2009 · Cited by 13 — The management of acute antibody-mediated rejection includes aggressive therapy with plasmapheresis and intravenous immunoglobulin. C4d staining of peritubular …
Late AR have more chances to develop DSA 42% than early 13% . It leads to worse graft survival 3.
Risk factors are de novo DSA, non compliance , improper prescription and recurrent acute rejection
Management includes:
Close monitoring of at risk patiens to pick them early
intensive treatment of LAR may help improve graft survival and long term outcome. 1 However, in a retrospective analysis of LAR in small transplant population, followed after 8 years, ,both c4d positive and c4d negative patients respond to steroid without plasmapheresis or IVIG. The latter were not provided because at that time the c4d was not considered and the biopsies were stained later during the study. The response to steroid could be due to presence of acute cellular rejection or it could be due to the absence of severe chronic changes and transplant glomerulopathy in patients under the study. So in such patients pulse corticosteroids and continued maintenance with MMF and calcineurin inhibitors may be just enough.
1-Esra Baskin, Asli Kantar, Kaan Gulleroglu, Esra Ozmen, Handan Ozdemir, Mahir Kirnap, Gokhan Moray, Mehmet Haberal, SP873 EFFECTS OF LATE ACUTE REJECTION ON GRAFT SURVIVAL AND OUTCOME IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS, Nephrology Dialysis Transplantation, Volume 30, Issue suppl_3, May 2015, Page iii665, https://doi.org/10.1093/ndt/gfv203.11
2-Nair, R., Agrawal, N., Lebaeau, M., Tuteja, S., Chandran, P. K. G., & Suneja, M. (2009). Late Acute Kidney Transplant Rejection: Clinicopathological Correlates and Response to Corticosteroid Therapy. Transplantation Proceedings, 41(10), 4150–4153. doi:10.1016/j.transproceed.2009.
3-Eid L, Tuchman S, Moudgil A. Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant. 2014 Mar;18(2):155-62. doi: 10.1111/petr.12203. Epub 2013 Dec 28. PMID: 24372967.
Dear All
You hit a fly with a cannonball. An extensive answer to an easy question. I want you to focus your answer, please.
-Basically the gold standard to diagnose rejection is the renal biopsy and examine the graft tissue samples with LM,IF,IHC and special stain and EM to give comprehensive pathological picture.
-Acute rejection means an acute deterioration in allograft function with increase of serum creatinine by 20% from the baseline.
–Late acute rejection(LAR) is defined as first rejection episode occurring after the first six months of transplantation.
-Development of de novo DSA, non adherence or suboptimal immunosuppression and recurrent acute rejection episodes are important risk factors for LAR. Close monitoring of these patients , making an early diagnosis and intensive treatment of LAR may help improve graft survival and long term outcome.
DD for LAR:
-Recurrence of glomerulonephritis and den novo GN
-BK nephropathy
-CMV nephropathy
-CNI nephrotoxicity
-Graft renal A. stenosis
-Obstructive uropathy
*Management of acute graft dysfunction will include good history taking, lab. investigations including virology screening (CMV PCR,BK PCR), CNI levels, proteinuria level, Renal graft duplex and graft US
*Acute rejection proved with tissue diagnosis:
1-Acute TCMR: Acute TCMR occurs most commonly within the first year after transplantation and rarely occurs after five years posttransplant.
According to Banff classification of TCMR:
Borderline rejection: No specific treatment for rejection but augment maintenance immunosuppression by targeting higher Tacrolimus levels ( 5 to 7 ng/mL) and optimized MMF dose.
Banff grade IA or IB: Pulse steroids then oral glucocorticoids are tapered immediately to the maintenance dose of oral prednisolone which was taken before AR.Some centres treat Banff grade IB if present less than one year posttransplant with adding ATG.
Banff grade II or III rejection: Pulse steroids 3-5 days+ ATG at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg according to severity of Banff classification.
A decrease in serum creatinine to within 10 percent of the baseline level is considered to be successful reversal of rejection.
2-Acute ABMR:
-Pulse steroids 500-1000 mg 3-5 days
-Low dose IV IG (total cumulative dose of 1gm/kg) with plasmapheresis 5-7 sessions one-and-one-half-volume exchange with albumin in alternating days.
-High dose IV IG (total cumulative dose of 2gm/kg) without PP.
-One dose Rituximab 375 mg/sqm after PP sessions.
Rescue therapy including Bortezomib, Eculizumab, Tocilizumab that can be used in selected cases.
*All patients have to receive CMV prophylaxis Valganciclovir for 3 months ,PCP prophylaxis using Atovaquone 1500 mg daily if they have high serum creatinine in addition to bone protection with calcium and vitamin D and gastric protection for high dose steroids.
This is an extensive answer Mohamed
Management of acute rejection
In case of allograft dysfunction we should do renal biopsy with C4d staining and DSA and according to the finding we diagnose AR and categorize rejection into:
Acute TCMR
Acute ABMR
Mixed TCMR, ABMR
REFERANCES
Uptodate
Exellent
The question was about Late Acute Rejection, NOT treatment of rejection.
Thanks for the efforts
Introduction
Acute renal rejection should be suspected in patients with 1 or > of the following:
Increase in Cr of ≥25 percent from baseline or creatinine higher than expected/Proteinuria >1 g/day/worsening hypertension/ dd-cfDNA >1 percent.
The standard for the diagnosis of renal allograft rejection is a renal allograft biopsy, which is used to accurately grade the severity of rejection, differentiate between T cell-mediated rejection (TCMR) and ABMR, and determine the degree of irreversible kidney damage (interstitial fibrosis/tubular atrophy).
AR, regardless of its timing, significantly worsened graft survival. Treatments to reduce the incidence of AR and improve prognosis are needed. There is no standardized definition for early and late acute allograft rejection and the cutoff of 6 months varies between studies. EAR and LAR were defined as rejection before 1 year and after 1 year in most of studies.
In one study evaluated the impact of early and late acute rejection on graft survival in renal transplantation showed that out of 198 biopsy proven rejection , 21% had EAR, 7% had LAR, and 72% had no rejection episode.
Patients with EAR were more likely to be male, and had short dialysis duration. Patients with LAR were more likely to be PRA positive and younger. The no AR group had more HLA-A,-B, and -DR matches.
However, in terms of graft survival, the patients with EAR or LAR showed lower graft survival rates than those with no AR but no significant difference between the EAR group and LAR group.
Better and precise definitions of early and late rejections, protocol biopsies and standardized risk stratification and therapies could lead to better prediction of outcomes based on rejection timing.
How to manage it?
Because of the poor outcomes of acute rejection, regardless if clinical or subclinical, early or late, rejection should be treated to avoid long term deleterious effects on graft survival.
In patients with biopsy proven late active ABMR, treatment is combination of glucocorticoids, intravenous IVIG, and, in some patients, rituximab if there is evidence of active microvascular inflammation on kidney biopsy.
-IV methylprednisolone 300 500 mg daily for 3-5 days, followed by oral prednisone taper.
-IVIG at a dose of 100 mg/kg after each session of plasmapheresis. Followed by 500 mg/kg per day for one to two days after the final session of plasmapheresis, with a total cumulative target dose of at least 1000 mg/kg of IVIG.
– Rituximab as a single dose of 200 to 375 mg/m2 after completion of IVIG
– plasmapheresis is not performed because of the lack of evidence.
Second-line agents in patients who have failed initial therapy
Bortezomib and Eculizumab can be considered as rescue therapy, but treatment is usually individualized based on the etiology and ABMR and histological findings.
For T cell mediated rejection, the treatment varies between centers. In patients with borderline TCMR based on Banff criteria, there is no consensus regarding optimal management. Some transplant centers adjust maintenance immunosuppression by increasing tacrolimus and/or by MMF dosing. Some centers treat borderline rejection as acute TCMR.
Treatment of Banff grade I rejection with administration of IV pulse glucocorticoids, followed by an oral glucocorticoid taper, in addition, to adjustment of t maintenance immunosuppression doses.
In patients with Banff grade IB rejection and few or no chronic histologic lesions who present less than one year posttransplant including 6-12 months, give r-ATG + pulse glucocorticoids.
In patients with Banff grade II or III rejection, administer high dose pulse IV glucocorticoids, followed by an oral glucocorticoid taper + rATG-Thymoglobulin + augment maintenance immunosuppression. If there is contraindication to r-ATG give Alemtezumab.
References
1-Uptodate(Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection of the renal allograft, Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the renal allograft)
2-Eun Hee Koo, Hye Ryoun Jang, Jung Eun Lee, Jae Berm Park, Sung-Joo Kim. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney Research and Clinical Practice. Volume 34, Issue 3, September 2015, Pages 160-164
The effect of late acute rejection (after 6 months of transplantation) on graft survival:
Results are similar to that shown by Eun Hee Koo et al Study as mentioned in Scenario 2 in this week.
Another important study similar to Eun Hee Koo et al Study is An ANZDATA Analysis (Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients): An ANZDATA Analysis Philip A. Clayton, Stephen P. McDonald, Graeme R. Russ and Steven J. Chadban
JASN September 2019, 30 (9) 1697-1707; DOI: https://doi.org/10.1681/ASN.2018111101.
An ANZDATA Analysis
Method:To understand the long-term effect of AR on outcomes, they analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics.
Results:AR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results.
Conclusions AR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials.
An ANZDATA Analysis:
This study adds to the literature by demonstrating robust associations between AR and long-term graft loss, mediated by increased risks of both death with function and death-censored graft failure.
Late-onset AR (occurring beyond the first 6 months after transplantation) has long been known to be associated with increased risk of graft loss.
Limitations to ANZDATA Analysis:
As a registry analysis, several limitations should be borne in mind when interpreting the results of this study. Although ANZDATA uses rigorous internal quality control procedures, as with any registry data there is risk of misclassification and underreporting.
In conclusion ANZDATA Analysis
How to be managed:
According to KDIGO GUIDELINES 2009.
6.1: We recommend biopsy before treating acute rejection, unless the biopsy will substantially delay treatment. (1C)
6.2: We suggest treating subclinical and borderline acute rejection. (2D)
6.3: We recommend corticosteroids for the initial treatment of acute cellular rejection. (1D)
6.3.1: We suggest adding or restoring maintenance prednisone in patients not on steroids who have a rejection
episode. (2D)
6.3.2: We suggest using lymphocyte-depleting antibodies or OKT3 for acute cellular rejections that do not respond to
corticosteroids, and for recurrent acute cellular rejections. (2C) (OKT3, muromonab (anti–T-cell antibody).
6.4: We suggest treating antibody-mediated acute rejection with one or more of the following alternatives, with or without
corticosteroids (2C):
• plasma exchange;
• intravenous immunoglobulin;
• anti-CD20 antibody;
• lymphocyte-depleting antibody.
6.5: For patients who have a rejection episode, we suggest adding mycophenolate if the patient is not receiving
mycophenolate or azathioprine, or switching azathioprine to mycophenolate. (2D)
Late acute rejection has been shown to be associated with poor allograft survival.
De novo DSA( class I) appears to be responsible for late acute rejection. Infection, non compliance to medications, de escalation of immunosuppressive medications and earlier rejection episodes are responsible for their formation.
Late acute rejection is antibody mediated in most cases, pure cellular rejection accounts for minority of the cases.
Previous studies showed that late acute rejection associated with lower graft survival rate as compared to early acute rejection, One study evaluated the effect of timing of rejection and the type of rejection on allograft survival and found that death censored graft survival was worse in all late acute rejection types, and there was a hierarchical relationship in both early and late acute rejection with death censored graft loss highest in ABMR followed by mixed rejection and then cellular rejection.
Management consist of preventive measures such as monitoring of immunosuppressant drug level to ensure adequate immunosuppression, monitoring of patient adherence to the drugs, proper diagnosis and management of infection,monitoring of DSA level and if rejection occur, the treatment will be according to the type and severity of rejection, if it is ABMR then PE & IVIG should be started, another IS medications can be used based on the severity and response such as Rituximab, Bortezomib, Eculizumab, and C1 esterase inhibitor, and if is ACR pulse MP for 3 days and if no response, ATG added, with optimization of immunosuppression.
References:
Excellent response and Good referencing
thanks
Acute rejection either early or late will affect graft survival.
Definitions:
Acute rejection is defined as acute deterioration of graft function and proved with tissue diagnosis (diagnostic biopsy).
Graft failure defined as graft nephrectomy or retransplantation or return back to chronic dialysis.
DGF is defined as need of dialysis in the 1st week posttransplant.
Graft survival is lower in the patient with acute rejection either early or late than those with the patients with no rejection. Some studies suggested that there is no difference between early and late rejection on graft survival.
There are some factors may be related to early acute rejection (EAR) like HLA mismatch, male sex , living donor, old donor age , short ischemic time. Other factors may be related to late acute rejection (LAR) like young age, and positive PRA.
Both EAR and LAR affect negatively graft survival but no significant difference between both of them.
Some studies found significant impact of EAR on graft survival than LAR, some studies found the contrast.
So, both have a negative impact on survival either early or late.
Management:
LAR in most of the cases is AMR , TCR is happened in minor cases late, appearance of de novo DSA is the responsible factor to initiate AMR , which may be related to non compliance or dose reduction of ISD (immunosuppressive drugs), or infection.
Diagnosis of late acute AMR should be differentiated from chronic AMR , the presence of DSA and tissue difference between both acute and chronic is observed, presence of tubular atrophy and interstitial fibrosis is the key of chronicity , and c4d stain and noted inflammatory process are the key of acute type.
CMV which may be asymptomatic and treatment with ganciclovir will results in stable graft function and improve the picture.
references :
Rajamahesh Kunchala, Archana Gudipati, Swarnalatha Guditi, Gangadhar Taduri, Sree Bhushan Raju, Megha S Uppin. Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian Journal of Transplantation. 2018, Volume : 12, Page : 48-52.
P Reinke , E Fietze, S Ode-Hakim, S Prösch, J Lippert, R Ewert, H D Volk. Late-acute renal allograft rejection and symptomless cytomegalovirus infection. Lancet. 1994 Dec 24-31;344(8939-8940):1737-8.
Eun Hee Koo, Hye Ryoun Jang, Jung Eun Lee, Jae Berm Park, Sung-Joo Kim. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney Research and Clinical Practice. Volume 34, Issue 3, September 2015, Pages 160-164
treatment if TCR by iv methylprednisolone with or without ATG
if AMR, will proceed for plasmapharesis and ivig
and treat the underlying cause in all cases
The majority of the studies report that Late Acute Rejection was correlated with poor long-term graft survival.
Predisposing factors for late acute rejection-
Development of de novo DSA
Non adherence or suboptimal immunosuppression
Recurrent acute rejection episodes .
Close monitoring of these patients, making an early diagnosis and intensive treatment of LAR may help improve graft survival and long term outcome.
1. Joseph JT, Kingsmore DB, Junor BJ, Briggs JD, Mun Woo Y, Jaques BC, Hamilton DN, Jardine AG, Jindal RM. The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant 15:2001;221-227.
2. Opelz G, Dohler B. Influence of time of rejection on long-term graft survival in renal transplantation. Transplantation 85:2008;661-666.
3. Sijpkens YW, Doxiadis II, Mallat MJ, de Fijter JW, Bruijn JA, Claas FH, Paul LC. Early versus late acute rejection episodes in renal transplantation. Transplantation 75:2003;204-208.
Late TCR
methylprednisolone 1gm x 3 and increase maintenance prednisolone to 1mg/kg
if steroid resistant then ATG
Late AMR
methyl prednisolone 1gm x 3 invariably gone till biopsy report comes
plasmapharesis f/b low dose ivig
one of the following may be used-
rituximab
ATG
bortezomib