1. A CKD 5 43-year-old patient lost 2 previous kidneys due to aggressive T cell-mediated rejection. Both previous kidneys were well matched for DR locus. He received a kidney offer from 56 years old donor, 110 mismatches, no DSA, and negative FCXM.
- What is the induction immunosuppression you are going to use?
- What is your maintenance protocol?
- Substantiate your answer please!
This patient caries high immunological risk in the form of 2 previous transplantation
So induction therapy should be in the form of Thymoglobulin + Methylene prednisone and maintainance therapy should be :Tacrolimus+MF+steroids
No DSA ,so no need for desensitization
Good history should be taken and investigations for the cause of recurrent rejection before:CMV ,BK or incompliant to therapy
As this is a high risk patient due to history of previous 2 rejection so the induction therapy that I will use either ATG or alemtuzumab.for maintenance I will use the triple immunosuppressant agent (Tac ,MMF and steroid)
No need for desensitization as there is no DSA
Protocol biopsy for follow up.
The patient is at high risk for rejection due to failed previous graft so induction therapy with ATG .
Maintenance protocol is TAcrolimus, MMF& steroid
What is the induction immunosuppression you are going to use?
Young age will give Induction by ATG or alemtuzumab
Maintenance therapy
Steroid + MMF + tacrolimus
High risk patient with previous acute cellular rejection .
FCXM negative no DSAs no need for desensitisation.
This is high risk patient so he must have induction
ATG is The proper choice for induction with standard protocol
no DSAs so no need for desensitization.
Maintenance immunosuppression will be TAC,MMF,steroid
Newer protocol may be used as Blatacept,MTORi,steroid
Follow up biopsy must be done to detect early rejection
What is the induction immunosuppression you are going to use?
* This patient is young age , lost 2 previous grafts so he is high risk patient induction with depleting agent alemtuzumab or rATG
I will choose rATG with methylprednisolone.
* Cause of loss of the previous 2 grafs must be investigated
With high risk of non compliance in this patient to be considered
* FCXM and negative DSA SO NO need for desensitization
* Maintenance immunosuppression;
Triple immunosuppression with steroids ,MMF and tacrolimus ER to decrease missing doses in case of non adherence, trough level 8-10 in the first month
Follow up of de novo DSA after transplantation
And protocol biopsy is recommended
What is the induction immunosuppression you are going to use?
What is your maintenance protocol?
This patient with history of previous 2 acute cellular rejection and graft loss is classified as High risk transplant patient. This is the 3rd renal transplant for the patient. As patient is highly sensitized, one should be vigilant about the use of induction immunosuppression. Inj Anti thymocyte globulin 1.5mg/kg on day 0 and to extend it for few days after transplant should be used. ATG is the choice of induction agent as the immunologic risk is high. IL2 receptor blocker is not the drug of choice for high risk immunological transplantation.
The reason for acute cellular rejection in the 2 previous transplants should be explored. The presence of delayed graft function, the under dosing of immunosuppression, non adherence to treatment are the usual causes of an aggressive T cell rejection. It is important to find out the causes as these should not be repeated in the 3rd transplant to preserve the graft.
This patient has negative DSA, negative FCMX making antibody mediated rejections unlikely
The patient should be maintained on standard triple immunosuppression protocol namely steroids, MMF and Tacrolimus. Frequent monitoring of Tacrolimus level is needed as Tacrolimus has varying pharmacokinetics and pharmacodynamic properties. Tacrolimus Genotyping may help in titrating the dose with the tacrolimus level monitoring. During infections cautious reduction in the dose of the immunosuppression is needed as too much dose reduction may lead to rejections.
I would use thymoglobulin as induction therapy, and combination of tacrolimus MMF and sterois as maintainence.
I will consider him high risk based on his history being on his 3rd renal transplant.
No desensitization is needed since he has no DSAs or positive cross matching
1 -ATG as an induction agent, DSA are negative, no need for desenitization
2-Triple maintenance therapy; Tac( trough 8-10),MMF 2gm daily and steroid.
Monitoring of DSA and possible protocol biopsy; a high immunological risk recipient with 2 previous transplantations.
References: KDIGO GUIDELINES,2009
High risk patient based on previous transplantation; lost kidney twice with severe rejection .Aggressive induction by ATG intraoperatively with methylprednisolone 7 mg/kg ,to complete 3-5 days of ATG ;total dose 6-10 mg/kg ,maintenance with triple therapy ;tac, MMF and steroid with periodic DSA monitoring and biopsy program to predict early rejection.
Dabare D, Kassimatis Th, Hodson J, Khurram MA, Papadakis G, Rompianes G. et al. Outcomes in Third and Fourth Kidney Transplants Based on the Type of Donor.Transplantation. 2019 July;103(7):1494-1503.
What is the induction immunosuppression you are going to use?
ATG is better induction therapy.
Triple therapy include TAC (high trough), MMF(2gm) and CS .
Patient with history of failed renal transplant twice is high risk patient ATG is better
protocol, he’s FcxM AND DSA negative, no need for desensitization.
This patient had high immunological risk ( 2 previous renal transplanted lost due to TCMR), although negative DSA & FCXM he need to check for non HLA DSA. Induction with T cell depleting agents with maintenance CNI, MMF & low dose steroids with close monitoring of DSA & if the patient accept protocol biopsy for early detection & treatment of subclinical rejection
What is the induction immunosuppression you are going to use?
according to his immunological risk i will consider him moderate to high risk patient for depleting induction rATG or campath plus methylprednisolone pulse 500mg D-1 and D0. Also its better to to start both tacrolimus 0.1mg/kg day -2 and MMF 500 mg TID day -2.
What is your maintenance protocol?
Triple conventional immunosuppressant medications including tacrolimus targeting high trough level around 7-10ng/ml and MMF 1gm BID and steroids with follow up of DSA with or without protocol biopsy
Substantiate your answer please!
43y old male patient with history of 2 graft loss caused by TCMR which mostly related to non compliance
Good matching with 110 mismatch
Fcxm is negative so need for desensitization
Also no DSA but with his history of previous 2 grafts his cPRA mostly will be high so he is considered as moderate to high risk patient so both basilixmab and depleting induction can be used but According to his young age and his history of 2 graft lost its better to give him depleting induction therapy using either rATG or campath
References:
KDIGO clinical practice guidelines for the care of kidney transplant recipients. AJT. 2009;3: supp.9.
Dabare D, Kassimatis Th, Hodson J, Khurram MA, Papadakis G, Rompianes G. et al. Outcomes in Third and Fourth Kidney Transplants Based on the Type of Donor.Transplantation. 2019 July;103(7):1494-1503.
Benko T, Halfmann P, Ga¨ckler A, Radu¨ nz S, Treckmann JW, Kaiser GM, et al. Long-term outcome of third, fourth and fifth kidney transplantation: technical aspects and immunological challenges. Clinical Kidney Journal, 2019;12( 6):895–900.
The patient has history of two previous transplant with ACR which is indicate his active immune system while he is in immune suppression medication and the donor age is 56 (old) so he had high immunological risk so the induction would be by ATG and continue with TAC ,MMF and predinsilone
For this patient there are alot of risk factors making him immunological high risk patient like previous 2 transplantation, old age donor and 2 mismatch so T_cell depleting agent especially rATG is preferable for induction with maintenance medications on steroid,MMF and tacrolimus.
Because this patient with a history of two times graft loss and 2 HLA mismatch should be considered as high risk for rejection, induction therapy with rATG is suggested.
In addition, triple maintenance immunosuppressive therapy with tacrolimus, MMF and prednisolone is suggested. Tacrolimus is associated with a lower risk of acute rejection and is better tolerated by patients than cyclosporine.
Higher risks for acute rejection include increased number of HLA mismatch, younger recipient and older donor age, high PRA, presence of DSA, blood group incompatibility, DGF, long cold ischemia time, retransplant and African-American ethnicity.
This is high risk patient because
He had previous 2 rejection .and 2 Hla mismatches
So induction with rATG intraoperative 1.5mg/kg for
10 days and 1gm methlprednisolne intraoperative then 30 mg/day during atg infusion.
Then maintain triple therapy tacrolimus with higher trough level .
MMF higher dose
Corticosteroids oral prednisone
Reference
●Hand book of kideny transplantation 6th edition .
●
https://cjasn.asnjournals.org/content/10/6/923
What is the induction immunosuppression you are going to use?
a lymphocyte-depleting agent, as he is a high immunologic risk 2. The total rATG doses less than or equal to 7.5 mg/kg 3 .Alternatively we can use intravenous alemtuzumab 4
What is your maintenance protocol?
Substantiate your answer please!
1- I need to revise his history to assess why he had ACR. Risk factors for ACR included type of transplantation (combined heart-kidney and heart-liver compared to isolated heart, pre-formed DSA , HLA A-B-DR mismatches and the type of induction (basiliximab compared to ATG )1 .
I need to make sure he was compliant with his medication and what was his age when he had received the past grafts. If there was any psychological issues it need to be solved. Then I need to revise his regimen of maintenance and was he subjective to any reduction protocol and why. I need to look for any possibility of AMR through revising his biopsies and tests.
2- Check his PRA and look for any historical PRA
3- Tacrolimus-based immunosuppression 5 , with avoidance of High intra-patient variability of tacrolimus trough concentrations as it was an independent risk factor for graft failure in the high risk group 7
4- Higher mycophenolate mofetil( if applicable the level is kept more than or equal to 30 mg hr/L)6
5- detection of AMR or subclinical rejection through protocol biopsy in the first year post transplant 8 and post–transplant DSA monitoring by single-antigen Luminex9
1- Coutance, G., Racapé, M., Bonnet, G., Van Keer, J., Duong Van Huyen, J., Bruneval, P., … Loupy, A. (2019). Risk Factors for Cellular and Antibody-Mediated Rejections in the First-Year Post-Transplant: A Population-Based Study. The Journal of Heart and Lung Transplantation, 38(4), S386. doi:10.1016/j.healun.2019.01.983
2- Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
3- Gurk-Turner C, Airee R, Philosophe B, Kukuruga D, Drachenberg C, Haririan A. Thymoglobulin dose optimization for induction therapy in high risk kidney transplant recipients. Transplantation. 2008 May 27;85(10):1425-30. doi: 10.1097/TP.0b013e31816dd596. PMID: 18497682.
4- Lü TM, Yang SL, Wu WZ, Tan JM. Alemtuzumab induction therapy in highly sensitized kidney transplant recipients. Chin Med J (Engl). 2011 Mar;124(5):664-8. PMID: 21518554.
5- Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005 Oct 8;331(7520):810. doi: 10.1136/bmj.38569.471007.AE. Epub 2005 Sep 12. PMID: 16157605; PMCID: PMC1246079.
6- van Gelder T, Tedesco Silva H, de Fijter JW, Budde K, Kuypers D, Arns W, Soulillou JP, Kanellis J, Zelvys A, Ekberg H, Holzer H, Rostaing L, Mamelok RD. Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid. Transplantation. 2010 Mar 15;89(5):595-9. doi: 10.1097/TP.0b013e3181ca7d84. PMID: 20124953.
7- Kim, E.J., Kim, S.J., Huh, K.H. et al. Clinical significance of tacrolimus intra-patient variability on kidney transplant outcomes according to pre-transplant immunological risk. Sci Rep 11, 12114 (2021). https://doi.org/10.1038/s41598-021-91630-4
8- Schinstock CA, Cosio F, Cheungpasitporn W, Dadhania DM, Everly MJ, Samaniego-Picota MD, Cornell L, Stegall MD. The Value of Protocol Biopsies to Identify Patients With De Novo Donor-Specific Antibody at High Risk for Allograft Loss. Am J Transplant. 2017 Jun;17(6):1574-1584. doi: 10.1111/ajt.14161. Epub 2017 Jan 25. PMID: 27977905; PMCID: PMC5445019.
9- Denis Viglietti, Alexandre Loupy, Dewi Vernerey, Carol Bentlejewski, Clément Gosset, Olivier Aubert, Jean-Paul Duong van Huyen, Xavier Jouven, Christophe Legendre, Denis Glotz, Adriana Zeevi, Carmen Lefaucheur, Value of Donor–Specific Anti–HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss,JASN Feb 2017, 28 (2) 702-715; DOI: 10.1681/ASN.2016030368
Excellent for mention of possible causes of aggressive 2 ACR
Thanks Hinda
Well done
What is the induction immunosuppression you are going to use?
This patient is immunologically high risk due
-2 previous kidney transplant (previous T-cell mediated rejection )
-old age donor
Although previous kidney were well matched for DR locus and the current HLA showed well matched DR locus with negative FCXM and no DSA , induction is needed with lymphocyte depleting agent ( ATG )
The important question why this patient lost 2 previous kidneys due to T-cell mediated rejection? It must be answered before transplantation .
What is your maintenance protocol?
Triple TAC showed be the maintenance protocol .
DSA monitoring and protocol biopsy
References:
1) John Vella, and Daniel C Brennan. Kidney transplantation in adults: Induction immunosuppressive therapy. © 2021 UpToDate. (Accessed on 3 January 2022).
2) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
V.good question any suggestions
To rank him as high risk is correct.
was it under IS
Or wrong choice of IS
Non complience
DGF
What is the induction immunosuppression you are going to use?
I would consider this patient as high immunological risk as he has 2 HLA mismatches and 2 previous transplantations.
I have no experiences in using alemtuzumab. Ciancio G et al showed that inferior death-censored graft survival with alemtuzumab induction compared with rATG and showed that alemtuzumab had a 14% higher hazard of death and an 18% higher hazard of either death or allograft failure compared to rATG. Gaber et al. concluded that rATG provides better allograft survival versus basiliximab among patients with higher immunologic risk.
So, my induction therapy will be Thymoglobulin -rATG.
What is your maintenance protocol?
Tacrolimus + mycophenolate mofetil combination have been proven in lower incidence of acute rejection. I would like to start him on tacrolimus maintain his trough level 8-10, MMF and prednisolone. I would avoid early steroid withdrawal approach in this case.
Additionally, I would like to do protocol biopsy and monitor DSA.
Dear All
I would not accept any DR mismatched kidney for this recipient giving him his history of rejection. I would use a short course of ATG induction and triple immunosuppression as maintenance. I agree, there may be an option for protocol biopsy on day 7 and every 3 months thereafter in the first 6 months.
*patient had 2 times aggressive t cell mediated rejection although his good mismatch ,he will considered high risk so use of ATG mandatory in this recepient fot t cell depletion
*maintenance protocol (TAC ,MMF ,Cortisol ) as previous 2 rejection we have to use standard protocol we can,t use cortisol free or other co stimulant blockade agent
Very simple and straightforward answer, well done
Thank you
In the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines, for example, risk factors for acute rejection include the following
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●Being African American (in the United States)
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
Patients with one or more of the above risk factors are considered to be at high immunologic risk for acute rejection.
So our patient have 2 HLA mismatch and history of previous 2 failed kidney transplantation
I will considered him as high immunologic risk
APPROACH TO INDUCTION THERAPY
For patients at high immunologic risk of acute rejection we recommend induction therapy with rATG-Thymoglobulin rather than an interleukin (IL) 2 receptor antagonist (basiliximab).
compared with basiliximab, rATG-Thymoglobulin was associated with decreases in de novo DSA and ABMR
INITIAL MAINTENANCE IMMUNOSUPPRESSION IN HIGH-RISK PATIENTS
patients who are high risk for acute allograft rejection we administer a maintenance regimen consisting of triple immunosuppression therapy. This includes a calcineurin inhibitor (tacrolimus), an antimetabolite (mycophenolate), and prednisone.
FOLLOW UP BY
protocol biopsy
DSA titer
Reference
1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
What Tacrolimus levels will you aim for?
In patients treated with tacrolimus, we monitor whole-blood 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively
Our C0 target levels in patients who receive antilymphocyte-depleting agents (eg, rabbit antithymocyte globulin [rATG]-Thymoglobulin) for induction therapy:
•7 to 10 ng/mL for the first month after transplantation
•3 to 7 ng/mL for subsequent months
What is the induction immunosuppression you are going to use?
He is considered to be high risk patient , so for :
depleting induction rATG or campath
What is your maintenance protocol?
tacrolimus targeting high trough level around 7-10ng/ml
MMF 1gm BID
steroids
follow up of DSA with or without protocol biopsy
The patient lost 2 previous trasnplants due to Tcell mediated rejection
although both were matched for DR locus
so he is considered a highly sensitised patient and his cross matchng is 2/6, with no DSA and negative FCXM
He needs induction with r ATG because a lymphocyte depleting agent wil be necessary
His maintenance protocol can be Tac , MMF and steroids
no previous detailed history available regarding his previous transplantation and the previous regimens used
HLA mismatching is still a critical prognostic factor for graft andpatient survival.
HLA-DR mismatching has a major impact on recipient’s graft survival.
Reference
Shi X etal .What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients.BMC Nephrology volume 19, Article number: 116 (2018).
“HLA-DR mismatching has a major impact on recipient’s graft survival. Can you elucidate this statement. How does HLA DR mismatch affect graft survival?
Dear All, excellent response
Why do you think the scenario stressed well-matched for DR loci in the previous transplants?
A kidney transplant with HLA-DR mismatch signifies a high risk transplant. It has been shown to be associated with poorer outcomes with In a meta-analysis, as compared to 0 DR mismatch, 1 DR mismatch had 12% increased risk of graft failure while 2 DR mismatch had 15% increased risk of graft failure.
So, if the patient developed acute T cell mediated rejection in this case, we need to rule out non-adherence or sub-optimal immunosuppression due to other causes in this patient.
Reference:
Shi X, Lv J, Han W, et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? a meta-analysis of 23 cohort studies involving 486,608 recipients.
I agree with Dr Amit as a well-matched DR locus allograft is expected to have a better outcome than what occurred with this case scenario.
Mismatching for HLA-A, -B, and -DR has been associated with a higher risk of HLA sensitization in both adult and pediatric patients who are relisted for a second kidney transplant
two HLA-DR mismatches at first transplant were associated with a 20 percent lower likelihood of receiving a second transplant.
Reference
Meier-Kriesche HU, Scornik JC, Susskind B, et al. A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients. Transplantation 2009; 88:23.
The answer demands more evidence and details.
There are evidences in eplet mismatches recognized. The epitope score for HLA-DR was shown to be a better predictor of the development of HLA-DR antibodies. Some patients with 0 HLA-DR MM had high eplet MM and vice versa
Kim, J., Fuggle, S. and Marks, S., 2019. Does HLA matching matter in the modern era of renal transplantation?. Pediatric Nephrology, 36(1), pp.31-40.
Wiebe, C., Pochinco, D., Blydt-Hansen, T., Ho, J., Birk, P., Karpinski, M., Goldberg, A., Storsley, L., Gibson, I., Rush, D. and Nickerson, P., 2013. Class II HLA Epitope Matching-A Strategy to MinimizeDe NovoDonor-Specific Antibody Development and Improve Outcomes. American Journal of Transplantation, 13(12), pp.3114-3122.
Mentioning Eplets can you define them how many are recognised,are they practicaly used ,diff. between Eplet MM and HLA MM
What is the induction immunosuppression you are going to use?
Two history of graft loss du to TCMR we need to check compliance before doing anther transplant .
The answer needs more meat?
This patient has history of loss of two kidney grafts due to T cell mediated rejection . The pure T cell rejection is not as common as AMR or mixed rejection , and its incidence in the era of current Is drugs specially Tac has markedly decreased . his previous Dr matching was good, no data about previous sensitization status , induction and mentinance treatments ,timing of these rejections and their management were not mentioned ,
this may indicate underimmunesuppression either non compliance , minimization protocol , malabsorpition problems or occurance of certain conditions the required minimization of IS drugs as BK nephropathy.
1- Induction treatment :
This patient is high risk as this is his 3 rd transplantations , his c PRA is unknown
The most suitable induction is ATG.
2- maintenance protocol : tribe IS ( Tac ( high trough level 8-12) , MMF 2 g /day, steroids)
Hi Fatima, Please provide evidence for your answer. Also The answer is not well organised it needs proper structure.
This patient is undergoing third renal transplant with prior history of 2 graft losses to acute T cell mediated rejection with a well-matched DR locus. Now the donor is 56 year old, with 110 mismatch.
Issues to be pondered over include:
1) Why the patient had T cell mediated rejection: Was it due to non-adherence or sub-optimal immunosuppression due t minimization/ withdrawal protocol?
2) Risk level: High due to prior 2 graft failures. Increased probability of development of de-novo anti HLA antibodies.
3) What was the timing of rejection: Did it happen in early post-transplant period, or later.
4) What is the status of DSA: Levels of DSA should be checked using luminex Single Antigen Bead as a negative DSA may be due to low levels of DSAs.
1. What is the induction immunosuppression you are going to use?
Due to high risk, the induction immunosuppression would be ATG. Alemtuzumab is not available in our setup.
2. What is your maintenance protocol?
Due to high risk, Maintenance immunosuppression would include: Tacrolimus (trough levels 8-10), MMF 2 gram per day and Steroids.
Post-trasplant close follow-up with emphasis on strict adherence with mediactions is important
In this case, DSA testing with protocol kidney biopsy should be done during first 3 months. If biopsy shows AMR, treatment should be initiated. If biopsy is negative, but DSA rising, then it should be treated as AMR. If no AMR in biopsy, monitor DSA. DSA needs to be checked whenever there is any graft dysfunction or suspicion of non-adherence.
References:
1) Kasiske BL, Zeier MD, Craig JC, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients. AJT 2009;9 Suppl 3: S1-S155.
2) Tait BD, Susal C, Gebel HM, et al. Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation. Transplantation 2013;95:19-47.
Excellent, Amit
Although we don’t know the timing and clinical scenarios of Cellular rejections we can gusess that the immune suppression was not enough, maybe minimized for some reason or something related to the patient himself. Here we have to consider the patient as a very high-risk patient in terms of sensitization (previous 2 transplants etc.) son we have the risk of both AMR, as cellular rejection (as previous). For the last donor, there is one mismatch in HLA-A and 1 mismatch in HLA B but we do not know whether the high-resolution mismatch could reveal any further mismatch at A/B or C, DR/DQ/DP
as we do not have DSA now, there may be antibodies against non-HLA antibodies. we need to evaluate these in this patient
for this special case we need depleting agents for induction (here rATG may be better). furthermore, a triple regimen with a high upper limit trough level should be aimed. close monitoring of renal function and renal biopsy when indicated should be kept in mind
I agree with what was mentioned by my colleagues that the patient would require a lymphocytic depleting agent as induction immune suppression (e,g ATG or Alemtuzumab) (1).
My suggested maintenance protocol will include:
– Triple immune suppression (Tacrolimus, MMF and Steroids).
– Frequent evaluation for the development of DSA as suggested by the attached table (2).
– Low threshold for allograft biopsy whenever urine analysis or serum kidney function tests change from the post-transplant baseline.
– Some programs will perform protocol biopsy for such high-risk cases.
– Stressing on compliance on immune suppression during each follow-up visit.
References:
1) John Vella, and Daniel C Brennan. Kidney transplantation in adults: Induction immunosuppressive therapy. © 2021 UpToDate. (Accessed on 3 January 2022).
2) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
What is the induction immunosuppression you are going to use?
He is high risk immunologically, as it is the 3rd transplant, most likely he is sensitized, so induction will be r ATG
non-adherence with the medication is an important issue to discover in such patients.
DSAs monitoring post-transplantation with protocol biopsy are highly suggestive.
What is your maintenance protocol?
Tac+ MMF+ Prednisolone
I will put him on triple therapy (tacrolimus(keep the level 8-10 first 3 months, MMF, prednisolone)
I will prefer to search for DSA, to detect the de novo DSA. some centres going for protocol biopsy.
Reference:
KDIGO clinical practice guidelines for the care of kidney transplant recipients. AJT. 2009
What is the induction immunosuppression you are going to use?
According to the 2009 KDIGO clinical practice guidelines, the patient in this scenario satisfy the definition of high risk patient. Having high risk, patient should receive aggressive induction and maintenance immunosuppression to overcome this risk (1).
Patient should receive rabbit antithymocyte globulin as induction therapy at dose of 1 to 2 mg/kg given intraoperatively followed by 2 mg/kg for 2 more days.
Several studies demonstrated that r-ATG is superior to anti- IL2 and placebo in terms of renal outcomes, because it is associated with lower incidence of acute rejections and allograft loss. Tanriover et al. reported that the incidence of acute rejection in the first year and allograft loss within 5 years of transplantation were less common with the r-ATG induction group comparing to basiliximab and no induction (2). In another study by Koyawala et al., better renal outcomes and mortality rate in the r-TG induction group (3).
What is your maintenance protocol?
Defining this patient as high risk, and based on large evidence, patient should receive triple maintenance immunosuppressive therapy, CNI based, in addition to MMF and steroids. This combination has been reported to be superior to other combinations, CNI free, and/or m-TOR based.
References
1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
2. Tanriover B, Jaikaransingh V, MacConmara MP, et al. Acute Rejection Rates and Graft Outcomes According to Induction Regimen among Recipients of Kidneys from Deceased Donors Treated with Tacrolimus and Mycophenolate. Clin J Am Soc Nephrol 2016; 11:1650.
3. Koyawala N, Silber JH, Rosenbaum PR, et al. Comparing Outcomes between Antibody Induction Therapies in Kidney Transplantation. J Am Soc Nephrol 2017; 28:2188.
Vgood
Q1: Induction with ATG or alemtuzumab is indicated
Q2: Triple therapy with tacrolimus, MMF and prednisolone as maintenance therapy
Q3: It’s third kidney TX but with low mismatch. So no need to desensitization but need a potent immunosuppression.
Two previous failed Tx.due to ACR you are right what about close follow up any suggestions!
he is high immunological risk as he is listed for 3rd transplant , he is young he had previous two transplant during his childhood or adolecscnt with previous two TCMR ,he is highly sensitized with preexstince anti-HLA abs for both class1,2, also he is at risk of DGF with 3rd transplant compared to first transplant the risk of DGF will be more than 20-30% with risk of vascular thrombosis even with LD , the recpient age 56 with two mismatches ,negative FXCM with no DSA may be false negative due to low titer of antiHLA DSA s ,still we need more sensitive and sepcific luminex SAB to decide about desensitization prior to transplant ,still his graft survival will be better comapred to thos on longwaitinglist(1).
his induction will be as high immunologocal risk with either ATG or alemutizemab followed by triple maintenane IS ( tacrolimus with target of 10-12 first 3 months then 5-7 ng after ,MMF , steriod and frequent monitroing of DSAs Post transplantion
References:
1-Graft and Patient Survival Outcomes of a Third Kidney Transplant Robert R. Redfield1,3, Meera Gupta1, Eduardo Rodriguez1, Alexander Wood2, Peter L. Abt2, and Matthew H. Levine2
2-Preoperative Evaluation of Sensitized Patients Soo-Kyung Kim and Hyosang Kim,Kidney Transplantation in Sensitized Patients, https://doi.org/10.1007/978-981-10-7046-4_3, 2020 .
Correct more specific SAB will be more clarifying of his immune profile
Is there a justification of mentioning that he is positive now for class1,classll !
definitly he need close monitoring with DSAs and or when ever thereis concern about nonadherence or change in IS plusgarft biopsy at any time he developed worsening graft dysfunction
Previous transplantation per se , is not recognized as risk factor for acute rejection, but if the previous graft loss was due to early aggressive immunological cause , this is a risk factor for acute rejection.
This patient lost 2 grafts previously due to cellular rejection , so he had high risk of acute rejection after transplantation. also the donor age increase the risk of acute rejection. He had 2/6 antigen mismatch. PRA is not provided in the scenario.
So induction with lymphocyte depleting drugs (ATG or alemtuzumab ) and maintenance with triple immunosuppressive drugs ( TAC , MMF , steroids ) with close monitoring of renal function , CNI level (to ensure drug level in the target level) , and for signs of infection. Adherence to the immunosuppressive drugs should be checked frequently.
Reference:
Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient
Danae Olaso, Miriam Manook, Dimitrios Moris, Stuart Knechtle,* and Jean Kwun*
J Clin Med. 2021 Aug; 10(16): 3656. Published online 2021 Aug 18. doi: 10.3390/jcm10163656
Fine in his follow up is there a role for DSA monitoring in this case
Can ACR induce BCell activity
Yes , acute cellular rejection can induce DSA development and monitoring of DSA is required after transplantation.
1-This is the third kidney retransplantation for this patient. He needs assessment for risk factors of acute rejection.
Risk factors for acute rejection:
1. The number of human leukocyte antigen (HLA) mismatches (A)
2. Younger recipient age
3. Older donor age
4. African-American ethnicity.
5.PRA >0%
6. Presence of a donor-specific antibody
7. Blood group incompatibility
8. Cold ischemia time >24 hours
9-retransplant
KDIGO transplant guidelines 2011
In this patient, we need PRA and time of rejection.
-IF PRA 20-80% with no DSA consider intermediate risk (basiliximab induction)
-IF PRA ˃80 or his history of rejection occur within the first year post-transplant, he considers a high-risk patient (ATG induction)
Clinical guidelines of kidney transplantation, BC 2021
KDIGO transplant guidelines 2009
Either used ATG or basiliximab for induction.
2.Maintenance immunosuppression: Tacrolimus, MMF, Prednisolone
KDIGO transplant guidelines 2009
V.good
1- induction which should be used is ATG
2-maintanance protocol tacrolimus, MMF, prednisolone
3- this patient is considered high risk patient needs aggressive induction , he had 2 previous failed transplant, the attach of cellular rejection may be due to non compliance to medications.no need for desensitization because of negative crossmatch
follow up of de novo DSA is mandatory
V.good
What is the induction immunosuppression you are going to use?
In the current scenario with 2 failed renal transplants with history of severe TCMR:
TCMR is a risk factor for incidence of ABMR and generation of de novo DSA, so he is most probably sensitized: PRA required to assess for immunologic risk. Since he has offer of living donation with 2 HLA mismatch, he is considered from the group of high immunologic risk +/- positive PRA>>Induction will be with lymphocyte depleting agent.
What is your maintenance protocol?
Triple maintenance immunosuppressive therapy consisting of Tacrolimus, MMF and prednisolone
Reference:
KDIGO clinical practice guidelines for the care of kidney transplant recipients. AJT. 2009;3: supp.9
Sensitized patients with a negative crossmatch (no donor-specific antibody) showed comparable graft survival to non-sensitized patients. even though these patients required immunosuppressive regimens which are different from non-sensitized patients (i.e., thymoglobulin with higher Tac trough level)
Rreference:
Sethi S., Najjar R., Peng A., Mirocha J., Vo A., Bunnapradist S., Jordan S.C., Huang E. Allocation of the Highest Quality Kidneys and Transplant Outcomes Under the New Kidney Allocation System. Am. J. Kidney Dis. 2019;73:605–614. doi: 10.1053/j.ajkd.2018.12.036.
Excellent you mentioned the relation with ABMR needless to say DSA follow up is mandatory
What is the induction immunosuppression you are going to use?
This is the 3rd transplant, 2 grafts were lost because of severe TCMR, now he has an offer from 56 years old donor(?? live donor), with 110 mismatch, negative XM, no DSA, no information about the cPRA,, patients with third transplant are more surgically challenging and sensitized as compared to the first transplant, so induction with ATG can be given, and if cPRA is low basiliximab induction can be used.
What is your maintenance protocol?
Triple immunosuppressive therapy consisting of Tacrolimus with trough level of 8-10 ng/ml, MMF 2gm/day, and steroids.
Follow up: DSA level and if possible protocol biopsy
References:
Excellent
What is the induction immunosuppression you are going to use?
What is your maintenance protocol?
Substantiate your answer please!
1- Timing of rejection: If rejection occurs in the first year posttransplant this is
considered high risk
2- PRA: If PRA is > 80 % it is high risk
What is the induction immunosuppression you are going to use?
This is highly sensitized patient provided his previous 2 transplants being lost because of TCMR despite matching DR.
He is negative for DSA and FCXM, but still may need VXM testing to know whether there’s antibodies in patients sera that may put the new graft at risk of added ABMR.
Regarding induction therapy in this highly sensitized patient with history of TCR and posibility of AMR, I will consider an induction agent capable of affecting both T & B-lymphocytes, Aemtuzumab or rATG. Alentuzumab is known to cause prolonged lymphocytes depletion for up to 12 months and profound Immunosuppression, it’s associated with high risk of serious infection. Using low dose at induction is associated with less risk of infection. ATG is also associated with risk of serious infection. In comparison to ATG Alemtuzumab may have the same or even better efficacy regarding episodes of rejection and it’s lymphocytes depletion effect may persist for long time than ATG(1).
Alemtuzumab Dosage in Induction :
I will consider 2 doses(age of KTR below 60) of Alemtuzumab (20-30 mg) in day 0 and day 1 post-transplantation.
MethylPrednisolone 500 mg IV in day 0 then 250 mg after 12 hours post-transplant, then 100 mg daily with taper to 5 mg over 1 month(2)(3).
Maintenance Immunosuppression :
I will consider triple Immunosuppression
Referrences
1.Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients Martina Guthoff, Kilian Berger, Karina Althaus, Thomas Mühlbacher, Tamam Bakchoul, Wolfgang Steurer, Silvio Nadalin, Alfred Königsrainer & Nils Heyne
2.Alemtuzumab induction therapy in solid organ transplantationPeter J Friend
3.Alemtuzumab: Drug information.(https://www.trf3.jus.br/documentos/natjus/Alemtuzumab-review.pdf)
4.Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient
Danae Olaso, Miriam Manook, Dimitrios Moris, Stuart Knechtle, and Jean Kwun
What is the induction immunosuppression you are going to use?
With h/o of prior 2 failed transplant , current DSA being negative but patient is at risk for denovo DSA post transplant . To prevent denovo DSA I would like to include low dose Rituximab in my induction.
D -4 = Rituximab 100-300mg
D0 and D1= ATG 1.5mg/kg
What is your maintenance protocol?
Tacrolimus maintained near the higher level of its target range .
MMF 1 gm BD ,will not taper it CBC permitting and no gi side effects.
Prednisolone 0.5 mg/kg and taper to 5mg(<60 kg)/7.5 mg (>60 kg) at 6 months
DSA and protocol biopsy at 3 months .
DUAL INDUCTION WITH ANTI-THYMOCYTE GLOBULIN(ATG) AND RITUXIMAB(RTX) IN SENSITIZED KIDNEY TRANSPLANT(KT) PATIENTS
Jin Kong et al
Analysis of Predictive and Preventive Factors for De Novo DSA in Kidney Transplant Recipients
Hirai et al
Is this patient actually sensitised or hr is a high risk due to many other issues
What is the scope of action of rATG?
If you consider him a high risk why introduce mTOR?