3. A 39-year-old male received a deceased donor (41 years old) kidney, with 111 mismatch, no pre transplant DSA, and primary function. He had basiliximab induction, triple immunosuppression (tacrolimus 4 mg BD, MMF 500 mg BD and prednisolone 20 mg OD) as maintenance with planned rapid steroid withdrawal. His S Cr on day 4 came down to 180 µmol/L with a good urine output. Two days later, his S Cr went up 360 µmol/L with reduction of the urine output. US scan showed well-perfused kidney with RI of 0.8, no collection or hydronephrosis. Biopsy should ACR (Banff grade 2A/B, see the biopsy below). 3 doses of MP pulses where given. After initial improvement, s Cr increased 380 µmol/L.
- What is differential diagnosis?
- Any other test required to confirm the diagnosis?
- What do you call this condition?
- What are your therapeutic options?
Thanks All
Yes, if ATG can not be used, Alemtuzumab can be used however it is not licensed for this treatment.
Noted prof
thank you
Dear All
Assume that you could not give ATG as many of you mentioned, what else you could give for a steroid-resistant rejection?
In case ATG cannot be given, Alemtuzumab 30 mg can be given
Excellent
Where are your references Amit?
References:
1) van den Hoogen MW, Hesselink DA, van Son WJ, Weimar W, Hilbrands LB. Treatment of steroid-resistant acute renal allograft rejection with alemtuzumab. Am J Transplant. 2013 Jan;13(1):192-6. doi: 10.1111/j.1600-6143.2012.04328.x. Epub 2012 Nov 21. PMID: 23167538.
2) Basu A, Ramkumar M, Tan HP, Khan A, McCauley J, Marcos A, Fung JJ, Starzl TE, Shapiro R. Reversal of acute cellular rejection after renal transplantation with Campath-1H. Transplant Proc. 2005 Mar;37(2):923-6. doi: 10.1016/j.transproceed.2004.12.019. PMID: 15848576.
Alemtuzumab anti -CD52 monoclonal AB have been used for treatment of sever steroid resistant ACR banff1B and rescue therapy as a single dose of 30mg IV along the evidence limited to case reports with good patient survival up to 95% and graft survival of 73% in patients with good compliance, can give another dose but with balance the risk of serious infection in 34% and PTLD(1,2).
also used for treatment of refractory rejection in pediatric age group with the conclusion that it may prolong the graft survival but not prevent the recurrence of rejection especially with the non-adherence to immunotherapy, evidence limited to case series (3).
we don’t have experience with almetuzumab ,not available in our center
References:
1-Reversal of acute cellular rejection after renal transplantation with Campath-1H.
Basu A, Ramkumar M, Tan HP, Khan A, McCauley J, Marcos A, Fung JJ, Starzl TE, Shapiro RTransplant Proc. 2005;37(2):923.up to date 2022.
2-Campath-1H as rescue therapy for the treatment of acute rejection in kidney transplant patients.Csapo Z, Benavides-Viveros C, Podder H, Pollard V, Kahan BD
Transplant Proc. 2005;37(5):2032.
3-Safety and efficacy of alemtuzumab in the treatment of late acute renal allograft rejection.Upadhyay K, Midgley L, Moudgil A Pediatr Transplant. 2012;16(3):286. Epub 2011 Nov 24.
Excellent
campath-1H
Anti CD 52 monoclonal antibody(Alemtuzumab)
Campath 1-H
Alemtuzumab {campath |anti CD52
camapath
Allergy or poor response to ATG use third line drug Alemtuzumab which is monoclonal Ab used for treatment of CLL , MS and in renal transplant used (refractory T cell mediated rejection) .
Alentuzumab (anti CD52)
ATG resistant cases also can be treated with alemtizumab
Alemtuzumab can be used for steroid resistant case with no response to ATG
cell depleting antibody therapy is the treatment of choice for severe or glucocorticoid-resistant kidney transplant rejection.The most commonly used T cell depleting agent is rabbit antithymocyte globulin (rATG), but in recent years, the use of alemtuzumab to treat rejection has gained popularity.
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells. Ligation of alemtuzumab with CD52 induces apoptosis and lysis of immune cells through antibody- and complement-dependent cytotoxicity, which leads to profound and long-lasting lymphocyte depletion. Studies in kidney transplant patients given alemtuzumab as induction therapy have shown that low T cell numbers persisted for more than 1 year and that CD8+ T cells reach baseline levels earlier than CD4+ T cells.7
REFERENCES
1. van den Hoogen MW, Hoitsma AJ, Hilbrands LB. Anti–T cell antibodies for the treatment of acute rejection after renal transplantation. Expert Opin Biol Ther. 2012;12:1031–1042. [PubMed] [Google Scholar]
2. Thomas PG, Ishihara K, Vaidya S, et al. Campath and renal transplant rejection. Clin Transplant. 2004;18:759–761. [PubMed] [Google Scholar]
3. Csapo Z, Benavides-Viveros C, Podder H, et al. Campath-1H as rescue therapy for the treatment of acute rejection in kidney transplant patients. Transplant Proc. 2005;37:2032–2036. [PubMed] [Google Scholar]
4. Basu A, Ramkumar M, Tan HP, et al. Reversal of acute cellular rejection after renal transplantation with Campath-1H. Transplant Proc. 2005;37:923–926. [PubMed] [Google Scholar]
5. van den Hoogen MW, Hesselink DA, van Son WJ, et al. Treatment of steroid-resistant acute renal allograft rejection with alemtuzumab. Am J Transplant. 2013;13:192–196. [PubMed] [Google Scholar]
Alemtuzumab ( campath) 30 mg
Anti CD 52 monoclonal antibody(Alemtuzumab)
although rATG and Alemtuzumab have not proof by FDA but Alemtuzumab 30 mg i.v (anti-CD52 Abs) has been used in steroid resistant ACMR
Alternative to ATG
Alemtuzumab can be used for steroid resistant rejection, and it has been seen to related to fewer infusion related effects such as infection in comparison with ATG.
Reference:
Dear All
The biopsy has confirmed CMR (this means, histologically, and also DSA is negative and C4d staining is negative), but I like your answer of looking also at the C4d staining and ensuring negative DSA.
Delayed graft function ,infection ,TC rejection could be lead to Ab mediated rejection
so almost always search for mixed rejection , on other hand pure Ab mediated rejection some time rare .
What is differential diagnosis?
1- TCMR
2- ABMR
3- BK Infection
4- mixed AR
5- steroid resistance AR
Any other test required to confirm the diagnosis?
DSA, C4d staining, CNI trough level, viral PCR test
What do you call this condition?
steroid resistance AR
What are your therapeutic options?
ATG
1.DD : TCMR , AMR, Mixed cellular rejection , CMV infection, BK virus infection , Steroid resistant rejection.
2.Other tests : US and duplex on Renal graft , C4D staining Biopsy , DSA level , Infections monitoring as ;CMV PCR , Tac trough level.
3.Steroid resistant rejection.
4.In case of Steroid resistant TCMR: rATG: 1.5 mg/kg(5-7 doses) daily or
Alemtuzumab is a possible alternative(allergy or resistance to ATG) Single dose 30 mg and Optimize maintenance immunosuppression & DSA monitoring regularly.
This is AKI in the first week post transplant after initial good graft function so we had many differential diagnosis: ATN ,CNI toxicity,High BP,cellular rejection or AMR or mixed
The abdominal ultrasound show high RI which go with rejection and the biopsy confirmed the diagnosis of cellular rejection so the treatment should be pulse methylepredinsilone and ATG
But after rising of the cr again the AMR should be consider as mixed rejection so we should check for DSA and did C4d stain
1)What is differential diagnosis?
-AMR TCMR
-CMV, BKV Viraemia.
-UTI.
-Allograft vascular thrombosis.
-FK Toxicity.
2)Any other test required to confirm the diagnosis?
Routine blood test : Full blood count, Liver function test.
Infective screening: Urine and blood culture, CRP.
Urinalysis.
Protocol biopsy of the allograft for C4d stain.
FK level.
Renal doppler.
CMV, BKV PCR
Serial DSA.
3)What do you call this condition?
Steroid resistance renal allograft rejection.
4)What are your therapeutic options?
ATG
Alemtuzumab
T cell mediated rejection
AMR
CMV infection, BK virus infection
Steroid resistant rejection
a case of steroid resistant rejection.
ATG – PLEX – STEROID.
1. Steroid resistant ACR .
2. Mixed rejection (TCMR and ABMR).
3. Infections CMV infection, BK virus infection
o C4D staining(IHC,IF)
o DSA level
o Infections screening (CMV, BK)
o Tacrolimus trough level
Steroid resistant acute cellular rejection
In case of Steroid resistant TCMR:
1.rATG: 1.5 mg/kg(5-7 doses) daily, maximum 10-14 days
Monitor FBC and CD3 if available
Reduce to half dose if WCC<3000 or PLT < 75,000
Hold if WCC <2000, PLT< 50,000
Hold MMF and TAC during the course of treatment
Prophylaxis against CMV and PPJ(co-trimoxazole and valganciclovir during treatment)
2. Alemtuzumab-Anti CD52 is a possible alternative(allergy or resistance to ATG)
Single dose 30 mg, good compliance, patient and graft survival
3.Optimize maintenance immunosuppression:
After IV methyl prednisolone 500 mg for 3-5 doses, reduce dose to oral prednisolone 20 mg, keep for 1 month, taper gradually(avoid steroid free protocol) . Resume TAC after ATG and keep trough level 8-10 ng/ml, resume MMF after checking WCC and keep a dose of 1 gm BD
IF biopsy showed features of Mixed rejection:
Treatment with PP(5-10 sessions) alternate with ATG+ IVIG 100 mg after each PP session, with or without Rituximab 375 mg/m2(1-2 doses)
DSA monitoring:
Should be carried frequently at 4weeks , 8 weeks , 3 months , 12 month then Bi-annually.
References:
1.Andreas B. Steroid-Resistant Kidney Transplant Rejection: Diagnosis and Treatment .J Am Soc Nephrol 12: S48–S52, 2001
2.Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020 Mar 6;15(3):430-438.
3.Csapo Z, Benavides-Viveros C, Podder H, Pollard V, Kahan BD. Campath-1H as rescue therapy for the treatment of acute rejection in kidney transplant patients. Transplant Proc. 2005;37(5):2032
Differential diagnosis
Other tests
Given condition
Therapeutic options
References
What is differential diagnosis?
Acute TCMR, Acute ABMR, Mixed Rejection, steroid resistant TCM
CMV nephropathy, BK nephropathy.
Any other test required to confirm the diagnosis?
Work up of AKI in renal transplant : Stain biopsy for C4d, Tacrolimus level, DSA level
FBC, blood film, LDH, haptoglobin, CMV PCR, BK PCR
What do you call this condition?
Steroid resistant early rejection
What are your therapeutic options?
TCMR: Pulse MP, ATG, augment IS
ABMR: Pulse MP, Plasma exchange, IVIG
Mixed rejection: both for TCMR and ABMR
What is differential diagnosis?
1-ACMR
2-MIXED REJECTION
3-INFECTION(PYELONEPHROTIS&BK VIRUS
4-DRUG TOXOCITY.
Any other test required to confirm the diagnosis?
1-DSA LEVEL.
2-C4 STAIN
3-BK AND CMV AND URINE CULTURE
4-TACROLMUS DRUG LEVEL.
1-Webster AC, Wu S, Tallapragada K, Park MY, Chapman JR, Carr SJ: Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. Cochrane Database Syst Rev 7: CD004756, 2017 [PMC free article] [PubMed] [Google Scholar]
2- Roberts DM, Jiang SH, Chadban SJ: The treatment of acute antibody-mediated rejection in kidney transplant recipients-a systematic review. Transplantation 94: 775–783, 2012 [PubMed] [Google Scholar]
3- Wan SS, Ying TD, Wyburn K, Roberts DM, Wyld M, Chadban SJ: The treatment of antibody-mediated rejection in kidney transplantation: An updated systematic review and meta-analysis. Transplantation 102: 557–568, 2018 [PubMed] [Google Scholar].
– pulse steroid therapy for 5-7 days.
– ATG(1-1.5)mg/Kg(1-1.5)mg/kg for 5-7 days with close follow up of cbc and stop if WBC <2000 or PLT < 50,000.
-maintain tacrolimas level 8-10nglml.
– zinc supplementation enhance signaling in steroid pathway and induce steroid response.
– prophylaxis against preemocystic carnii and CMV.
– early acute rejection and steroid resistance one.
– DSA level .
-c4d statin.
-CMV PK virus PCR.
-Tacrolimus level.
What is differential diagnosis?
-ACTMR.
-MIXED REJECTION .
-INFECTION ( pyelonephritis) .
1.steroid resistant TCMR
2. Mixed rejection
3. infection
4. drug toxicity
DSA level post transplant
C4d staining
Drug level
screening for infection
Steroid resistant cell mediated rejection
Reevaluation of immunosuppression is required:
– Check CNI level and maintain trough drug levels.
– Increase dose of MMF to 1000 mg twice a day
– Add steroids in the maintenance immunosuppressive regimen.
– Zinc supplementation
– In view of severe T cell mediated rejection (Banff Ib or more):
Treat with rATG 1.5 mg/kg/day x 5-7 doses or until recovery, in addition to the steroids.
In case of ATG hypersensitivity, Alemtuzumab can be used.
CMV and pneumocystis prophylaxis should be given.
The Diagnosis in this patient is Steroid resistant Acute cellular rejection. The differential diagnosis of the renal biopsy maybe Acute interstitial nephritis which maybe due to drugs, CMV or BK. Given the time frame of the event post transplant, CMV or BK virus is rare. Concomitant C4d staining of the renal biopsy is needed to rule out co existing AMR and DSA testing will rule out AMR. But the renal biopsy did not show any histologic evidence of AMR.
Molecular methods of confirming ACR are all experimental and used in few studies with no uniformity. They include urinary FOX P3 levels which will be decreased in the urine in acute cellular rejection, CD68 staining of the macrophages in the renal biopsy
The treatment of the steroid resistant ACR is by using ATG. Rabbit ATG is used in the dose of 1.5mg/kg IV for 5 to 7 days. Premedications include Inj metyprednisolone 125 mg IV, Inj diphenhydramine and Tab Paracetamol 650 mg before every dose to prevent allergic reactions to ATG. The differential count and CD3 to CD4 ratio needs to be monitored to avoid over immunosuppression. The other concomitant therapies include to increase the dose of MMF to 1gm twice a day and to keep the tacrolimus trough levels to 8 to 10ng/ml. Patient needs valganciclovir and cotrimoxazole prophylaxsis to prevent
CMV and PCP.
Alemtuzumab 30mg can be tried for those cases with poor response to rATG. The response in few studies have been beneficial. The use however is not licensed
differential diagnosis: Steroid Resistance TCMR.
Or Mixed rejection.
confirm the diagnosis by *C4d staining. *DSA levels. *Tests for infections such as CMV and BK
call this condition,: Early Acute Cellular Mediated Rejection CMR and Steroids Resistant.
Treatment :
ATG 2.5mg /kg per dose total of { 2-3 }doses
Alemtuzumab ( humanized anti CD52 monoclonal depleting agent )
If it’s mixed rejection treatment plan should include plasmapheresis and IVIG
This is a acute rejection with resistance to steroid use.
In this case, we have differential diagnoses of acute rejection with Tacrolimus toxicity and cellular rejection.
Biopsy is needed to confirm acute rejection and identify whether it causes humoral or cellular.
To rule out Tacrolimus toxicity, its serum dosage is necessary.
For the diagnosis of steroid resistance, no further tests are required after failure to use it.
Steroid resistant rejection
ATG is mainly used for the treatment of steroid-resistant. Other possibilite is the murine derived Muromonab-CD3 (OKT3) is a monoclonal.
A.My differentials are-
1.steroid resistant TCMR
2.Mixed rejection
3.BKV Nephropathy(less likely)
B.DSA level with c4d staining
CD-8,CD-138,CD-20 Staining with urine foxp3
level.
Bkv pcr.
C.steroid resistant TCMR
D.ATG-1.5-3mg/kg/day ,with total dose of 6-9
mg/kg with augmentation of maintenance
Immunosuppression.
Pcp and cmv prophylaxis.
☆What is differential diagnosis?
1.steroid resistant TCMR
2. Mixed rejection
☆Any other test required to confirm the diagnosis?
DSA level
Tacrolimus level
Viral screening eg: CMV BK VIRUS ,hepatitis B and C
Biopsy and C4d staining
☆What do you call this condition?
Steriod resistant acute cellular rejection
☆What are your therapeutic options?
▪︎Steroid-resistant renal allograft rejections are commonly treated with rabbit antithymocyte globulin (RATG)
▪︎Alemtuzumab (15-30 mg s.c. on 2 subsequent days) is an alternative of ATG.
▪︎ Avoid rapid steroid wisdrawal
▪︎ Addition of Zinc
▪︎ Monitor Tacrolimus trough level
__________________
Ref:
Am J. “Treatment of steroid-resistant acute renal allograft rejection with alemtuzumab”. Transplant. 2013 Jan.
What is differential diagnosis?
Any other test required to confirm the diagnosis?
What do you call this condition?
What are your therapeutic options?
What is differential diagnosis?
Steroid resistance TCMR
Mixed type rejection
Infection (pyelonephritis)
Inadequate IS
Any other test required to confirm the diagnosis?
DSA
C4d dosage
Urinalysis and culture
CNI level
What do you call this condition?
Steroid resistance Acute TCMR
What are your therapeutic options?
ATG in a dose of 1.5 mg /kg for 7-10 days
If the patient allergic to it ,we can move to alemtuzumab although not licensed
Increase immunosuppression
Avoid early steroid withdrawal
What is differential diagnosis?
rise of s creatinine on day 6 after initial graft function with transient response to steroid
with normal USG and RI
So DD :
*Steroid resistant rejection
*Mixed rejection
*infection
•Any other test required to confirm the diagnosis?
DSA level
tacrolimus level
C4d staining
infection CMV and BK viruses PCR
What do you call this condition?
Steroid resistant rejection.
What are your therapeutic options?
-pulse steroid for 5 days
-rATG 1.5 mg/kg for 7 to 10 doses.
-Keep tacrolimus trough level between 8-10 Ng/ml.
–alemtuzumab can be used if we can’t give ATG
Reference
Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION
What is D/D?
Acute mediated rejection
Steroid resistance acute rejection
infection
Drug Toxicity
Are other test required to confirm diagnosis?
DSA level post transplant
C4d staining
Drug level
screening for infection
What do you call this condition
it’s tubulointerstitial nephritis refractory to steroid
or acute rejection refractory to steroid
What are therapeutic options?
IV Ig +iv ATG + plasma exchange + Rituximab
if not responded can give Alemtizumab ( anti clonal Ab against CD 52
# What is differential diagnosis?
* Acute TCMR (This is a form of acute renal transplant rejection known as acute cellular tubulointerstitial rejection because most of the inflammation is in the interstitium. The glomerulus seen here is normal, but the tubules are infiltrated by many lymphocytes at the upper right.)
* According to clinical scenario it could be
steroid refractory (patients whose symptoms never responded to corticosteroids and those who respond initially but developed recurrence while continuing treatment.)
* Mixed TCMR & ABMR
* CNI toxicity
# Any other test required to confirm the diagnosis?
-c4d staining
– DSA
– Drug level
– Diagnosis of acute cellular rejection depends on biopsy, CD20 staining for refractory cases, negative C4d staining, presence of markers of activating lymphocyte, and proteomic study.
# What do you call this condition
– Acute cellular tubulointerstitial rejection
-Steroid refractory
# What are your therapeutic options?
– pulse steroid for 5 days
– ATG
– More recently, mycophenolate mofetil has been successfully used to treat steroid-resistant rejection, but only of the interstitial (cellular) type.
Switching from CsA to tacrolimus for treating recurrent or antibody-resistant rejection is successful in approximately 60% of cases. Plasmapheresis and intravenously administered Ig have been used in some cases.
Administration of ATG according to the absolute T lymphocyte count during therapy for steroid‐resistant rejection
KR Clark, JLR Forsythe, BK Shenton, TWJ Lennard, G Proud, RMR Taylor
Mohammad-Reza Ganji et al. Iran J Kidney Dis. 2007 Oct.
**differential diagnosis
1- Steroid resistant cellular rejection
2- CNI toxicity
-3- infection (pylonephritis)
**other Test required
1- C4d staining of biopsy and
DSA titer To exclude associated AMR
2-CNI level
2- GUE and culture
** it is steroid resistant acute cellular rejection
**Treatment
give ATG for 4-10 days 1.5 my/kg/day
2- avoid regime of steroid withdrawal
3- alemtuzumab can be used if we can’t give ATG
4- antiviral prophylaxis (CMV)
5- evaluate the doses and drugs level of maintenance immunsuppressive drugs, TAG, MMF,Steriod,
Reference
Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION
What is differential diagnosis?
This 39 year old patient received graft from deceased donor with 111 mismatch, no previous DSA and initial graft function which later declined and showed a transient improvement with pulsed steroid therapy. The differential diagnosis will be –
Acute rejection steroid resistant
Mixed Rejection
Any other test required to confirm the diagnosis?
DSA levels
C4d staining
Tacrolimus trough levels
What do you call this condition?
Steroid resistant rejection
What are your therapeutic options?
Because of steroid resistance we will have to start ATG at 1.5 mg/kg for 7-10 days with close monitoring. Continue steroid and better avoid an early withdrawal. Addition of zinc may enhance steroid responsiveness. Keep Tac trough levels between 8-10 ng/ ml. In case of allergy or poor response to ATG ,Alemtuzumab can be used though it is not licensed
Reference:
Neils V Reckers et al. Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection.Transplant immunology vol 38 2016 page- 2-14
•What is differential diagnosis?
In this case scenario the recipient showed rise of s creatinine on day 6 after initial graft function.
Vascular and obstructive causes were normal
No DSA befor transplantation
Biopsy showed acute cellular rejection which responed parially to pulse steroids.
DD
-Steroid resistant rejection ( AR episode is considered steroid resistant when the patient’s serum creatinine levels do not return to within 120% of the pre-rejection baseline value after pulse therapy with corticosteroids within 2 weeks after the start of the steroid therapy, minimal time period for assessment of the response to steroids is five days after initiation of the pulse therapy)
-Mixed rejection
•Any other test required to confirm the diagnosis?
DSA level
C4d staining
CMV and PK viruses PCR
tacrolimus level
What do you call this condition?
Steroid resistant rejection.
What are your therapeutic options?
-ATG mainly used for the treatment of steroid-resistant AR and recurrent AR.act mainly depletion of circulating T cells and other leukocytes
-rATG 1.5 mg/kg for 7 to 10 doses .with close follow up of cbc
-Steroids 1mg / kg
Avoid early withdrawal
-Keep tacrolimus trough level between 8-10 Ng/ml.
-Addition of zinc recipients who express high intragraft levels of MT and TIMP1 during AR might benefit from extra zinc intake for optimal GC signaling.
Steroid resistant cellular rejection
Mixed rejection
C4d staining
DSA level
Tacrolimus trough level
Steroid resistant cellular rejection.
Continue pulse steroids for 5 days
Anti-thymocyte globulin 1.5mg/Kg for 5-7 days, follow up TLC and platelets count, ATG should be stopped if TLC<2,000 and/or platelets <50,000, prophylaxis against pneumocystis carinii for three months
Adjust dose of MMF to 1gm BID and keep Tacrolimus trough level between 8-10
If the patient is allergic to ATG, Alemtuzumab can replace it, but further randomized controlled trials are required to determine its efficacy and long-term results in treatment of acute rejection
Cooper JE. Evaluation and treatment of acute rejection in kidney allografts. Clinical Journal of the American Society of Nephrology. 2020 Mar 6;15(3):430-8.
Danovitch GM, editor. Handbook of kidney transplantation. Lippincott Williams & Wilkins; 2009 Oct 1.
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of alemtuzumab and its use in kidney transplantation. Clinical pharmacokinetics. 2018 Feb;57(2):191-207.
Although there is no preformed DSA, the dose of MMF 500 mg BD in the early post transplant period is not sufficient to achieve adequate immunosuppression.
What is differential diagnosis?
according to the clinical presentation , the biopsy finding ,the pre transplant immunological risk , the post transplant immunosuppression and the current management with methyl prednisolone .
1. Steroid resistant TCMR .
2. mixed TCMR and ABMR.
Any other test required to confirm the diagnosis?
Exclude mixed rejection by;
1- confirm the absence of c4d deposition
2- confirm absence serum DSA
What do you call this condition?
Steroid resistant TCMR
What are your therapeutic options?
1- Banff class II or vascular rejection generally does not respond to pulse steroids alone, needs additional r ATG.
2. ATG resistant cases also can be treated with alemtizumab.
3-Mycophenolate mofetil has been successfully used to treat steroid-resistant rejection, but only of the interstitial (cellular) type.
4-Plasma pheresis and IV IG had been used in some cases
Addition measures;
1.Augmentation of Immunosuppression levels.
2-.zinc supplementation may enhance signaling in steroid pathway and induce steroid responsiveness.
3- prophylaxis against pneumocystis jiroveci and CMV in Thai patient .
Reference;
H. ANDREAS BOCK. Steroid-Resistant Kidney Transplant Rejection: Diagnosis and Treatment .J Am Soc Nephrol 12: S48–S52, 2001
What is differential diagnosis?
Steroid resistance TCMR
Viral Infection – BK and CMV (Too early)
Any other test required to confirm the diagnosis?
DSA
C4d dosage
PCR CMV and BK
What do you call this condition?
Steroid resistance Acute TCMR
What are your therapeutic options?
ATG induction
Increase immunosuppression
Exclude infection
This is an acute rejection, as no preformed DSA detected and according to biopsy is cellular, not AMR. here it is most probably due to insufficient immunosuppression. the resistive index is not high (more than 0.8 may be due to ATN, Tx rejection either acute or chronic, renal vein thrombosis, drug toxicity ureteric obstruction etc) but time is early may be ongoing process so still may be ATN as ddx but biopsy proves rejection already. we need the drug level (may be drug toxicity). Perinephric collection does not document (could be a reason for high RI). ACR grade 2A/B means arteritis more than 25%.
ATN is one of the major ddx here so we need to ask about previous medications
polyoma virus is not expected very early (as here!!)
we need ATG and steroid (already given) but still we may need to wait 5 days before saying steroid-resistant)
This case ( rising creatinine early post transplant+ biopsy showing evidence of glomerulitis ( lymphocytes infiltration of glomerular capillaries), tubulitis ( infiltration of renal tubules plus vasculitis ( infiltration of wall of arterioles)) which means means TCMR Banff class II or more.
1. Differential diagnosis of steroid resistant TCMR:
a. Sever TCMR or Higher Banff class II or more ( most probable here) /vascular rejection.
b.mixed TCMR and ABMR.
2. To confirm diagnosis …may need to confirm absence of c4d deposition and serum DSA to exclude mixed rejection. Also new techniques such as CD8 and monocytes infiltration and decreased urinary FOXP3 can be utilized to predict steroid resistant AR
3. This condition called early acute rejection and steroid resistant one.
4. Therapeutic options:
a. Banff class II or vascular rejection generally does not respond to pulse steroids alone, needs additional r ATG.
b. ATG needs follow up CBC + if TLC less than 2000 or plt less than 75000) stop ATG.
c.previous allergy to ATG or rabbit sensitization by raising or eating excess rabbit meat, indicates its avoidance and substitution with alemtizumab.
d. ATG resistant cases also can be treated with alemtizumab
e.Augmentation of maintenance Immunosuppression ( higher tacrolimus trough level at 10 Ng/ml+ avoidance of steroid withdrawal in such patient who experienced such early acute rejection episode). However, withholding MMF during treatment with ATG and alemtizumab is usually done.
f.zinc supplementation may enhance signaling in steroid pathway and induce steroid responsiveness
g. Continue TMX_ TMP prophylaxis against pneumocystis jiroveci and ganciclovir against CMV in Thai patient with such immune-ablation therapy
No history of DSA,mismatch 111, not responding to methypred
The slides showed – monocytes infiltration in tubules and arteries , no Acute tubular injury ,no neutrophil infiltrations in peritubular or glomerular capillaries or fibrinoid necrosis
No IF – to look for C4d staining
What is differential diagnosis?
Any other test required to confirm the diagnosis?
What do you call this condition?
Acute T cell mediated rejection
What are your therapeutic options?
Alentuzumab is a humanized monoclonal antibody towards CD52 which as efficacious as ATG in treating steroid resistant rejection
References
M.W.F. (Martijn) van den Hoogen et al 2013 https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-6143.2012.04328.x
What is differential diagnosis?:
*T cell mediated rejection .
*mixed rejection .
*Infection (pylonephritis ).
– CMV and BK virus( viremia and nephropathy) rare and unlikely in the first week.
– Delayed graft function ,infection ,TC rejection could be lead to Ab mediated rejection
so almost always search for mixed rejection , on other hand pure Ab mediated rejection some time rare .
Any other test required to confirm the diagnosis?:
peritubular capillary C4d.
What do you call this condition?:
Steroid resistant T cell mediated rejection.
What are your therapeutic options?:
Steroid resistant rejection go to second line :
ATG 1.5 mg per Kg for 7 to 14 days.
Allergy or poor response to ATG use third line drug Alemtuzumab which is monoclonal Ab used for treatment of CLL , MS and in renal transplant used (refractory T cell mediated rejection) .
positive C4d mean mixed rejection need to add on treatment for AB mediated rejection IV Ig and plasma exchange .
Good to recognize the cognate relation between Tcells that can produce Tfh that induces a B cell response which needs to be excluded in steroid resistant Tcell rejection.
Your first option should have been a steroid resistant TCMR
-DD
Steroid resistance T cell mediated rejection
Mixed rejection
Bk Nephropathy
CNI toxicity
-Other tests required to confirm the diagnosis
C4dstaining , DSA level monitoring ,viral serology , Tac trough level.
-What do you call this condition?
Steroid resistance T cell mediated rejection
-What are your therapeutic options?
r ATG Thymoglobulin at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg. as biopsy shows Banff grade 2A/B
if not available alemtuzumab as a single IV dose of 30 mg.
Mycophenolate mofetil has been successfully used to treat steroid-resistant rejection, but only of the interstitial (cellular) type
Plasma pheresis and IV IG had been used in some cases(1)
Reference
1-H. ANDREAS BOCK. Steroid-Resistant Kidney Transplant Rejection: Diagnosis and Treatment .J Am Soc Nephrol 12: S48–S52, 2001
What is the definition of differential diagnosis?
1-ATCMR 2-MIXED REJECTION
3-TCMR RESISTANT TO STEROId
4-BK nephropathy
Is there anything further that needs to be done to confirm the diagnosis?
– DSA levels and C4d staining to rule out mixed rejection.
CMV and BK virus PCR
– Tacrolimus trough levels, SV-40 staining
So, what are your treatment alternatives?
Steroid-resistant T-cell mediated rejection
1- optimize the immunosuppressive medications
2- ATG (1-1.5 mg/kg) for 7-10 doses,
3- If Alemtuzumab is available can be used as an alternative to ATG
4- If the mixed rejection is shown, plasmapheresis and IVIG
Always correlate the clinical situation and the histology so it is a steroid resistant ACR followed by the rest to be excluded.
What is differential diagnosis?
ACUTE CNI TOXICITY, STEROID RESISTANT REJECTION TCMR, PRERENAL DEHYDRATION, CMV, BKV .
Any other test required to confirm the diagnosis?
TACROLIMUS TROUGH LEVEL,ALBUMIN CREATININE RATIO
VIRAL SEROLOGY
URINE ANALYSIS AND CULTURE
What do you call this condition?
STEROID RESISTANT REJECTION TCMR.
What are your therapeutic options?
ATG
IN REPLY FOR DR AHMED HALAWA IF ATG IS NA Anti CD 52 monoclonal antibody(Alemtuzumab)COULD REPLACE.
Try to arrange your answers as highest probability followed by the rest.
Differential diagnosis:
-Steroid resistant TCMR can be treated with ATG or alternatively Alemtuzumab
-Underling ABMR: Need C4d staining and DSA level to rule out ABMR and treatment of ABMR has to be added in the form of PLEX,IVIG and Rituximab
-This condition called steroid resistant rejection or mixed rejection
The differential diagnosis here includes;
Steroid resistant rejection
Acute CNI toxicity
Delayed graft function
AKI due to causes other than rejection pre-renal, ATN
Tacrolimus trough level
Urine protein
Steroid resistant rejection
The next agents to be used here would include
ATG
Alemtuzumab
Delayed graft function is ruled out as he had an initial good function.
Try to add the clinical course with the histology this will lead you to the logical diagnosis then start to ask for further tests.
Keep trying.
What is differential diagnosis?
1- Steroid resistant TCMR .2- Acute CNI toxicity
Any other test required to confirm the diagnosis? CNI trough level
What do you call this condition?
Steroid resistantTCMR What are your therapeutic options ? Intensify the immunosuppressive drugs.
ATG 1.5mg/kg /day flow CBC absolute lymphocyte count,we
Should add CMV and pneumocyctic prophylactic . Avoid steroid free regimen
How can you exclude a mixed rejection.?
OR
2.Alemtuzumab
OR
3.OKT3 ; currently not withdrawn from the market due side effects
4.Zinc supplementation ; there are some literature about important of Zinc in glucocorticoid signaling pathways
The patient has presented with acute graft dysfunction in early post-transplant period.
The differential diagnosis in this scenario include:
1) Pre-renal cause: unlikely in view of no history
2) Obstruction: unlikely as ultrasound has shown no collection or hydronephrosis.
3) Vascular cause: unlikely as RI is 0.8
4) Glomerular: Recurrence of the basic disease – basic disease not known.
5) Tubulointerstitial cause: Rejection
6) Infection: No clinical history available.
The kidney biopsy shows Banff grade 2A/B acute cellular rejection.
He initially responded to 3 doses of empirical methyl prednisolone.
It implies that he either has severe TCMR/ steroid resistant cell mediated rejection, or mixed rejection.
1) Kidney graft biopsy: Histopathological examination with C4d staining
2) CNI drug level
3) CBC, peripheral blood film, LFT
4) Urine routine and microscopic examination, urine protein creatinine ratio
5) DSA level
If available, immune biomarkers of steroid resistance including:
1) Increased cytotoxic T lymphocyte – NK cell signature (increased FasL mRNA, decreased FoxP3 in urine and increased dense granulation stain in biopsy),
2) B lymphocyte signature (increased CD20 and B lymphocyte associated immunoglobulin in the graft), and
3) intraglomerular and interstitial macrophage signature (CD68)
4) Increased CD25-CD3e ratio and LAG-3 (lymphocyte activationgene-3).
Non-immune biomarkers include removal of zinc ion by increased intragraft metallothioneins (MT) and TIMP-1 (tissue inhibitor of metalloproteinase-1) and F2R (coagulation factor II receptor).
This is steroid resistant acute T cell mediated rejection (if C4d negative and no DSA)
Reevaluation of immunosuppression is required:
Check CNI level and maintain trough drug levels.
Increase dose of MMF to 1000 mg twice a day
Add steroids in the maintenance immunosuppressive regimen.
Zinc supplementation
In view of severe T cell mediated rejection (Banff Ib or more):
Treat with rATG 1.5 mg/kg/day x 5-7 doses or until recovery, in addition to the steroids.
In case of ATG hypersensitivity, Alemtuzumab can be used.
CMV and pneumocystis prophylaxis should be given.
References:
1) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020 Mar 6;15(3):430-438. doi: 10.2215/CJN.11991019. Epub 2020 Feb 17. PMID: 32066593; PMCID: PMC7057293.
2) Rekers NV, de Fijter JW, Claas FH, Eikmans M. Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection. Transpl Immunol. 2016 Sep;38:3-14. doi: 10.1016/j.trim.2016.07.005. Epub 2016 Jul 29. PMID: 27480047.
How do you approach a steroid and ATG-resistant Severe Acute Cellular Rejection without AMR?
we can use monoclonal ab anti CD52 ALEMTUZIMAB
Reevaluation of immunosuppression is required:
Check CNI level and maintain trough drug levels.
Increase dose of MMF to 1000 mg twice a day
Add steroids in the maintenance immunosuppressive regimen.
Zinc supplementation
In view of severe T cell mediated rejection (Banff Ib or more):
Treat with rATG 1.5 mg/kg/day x 5-7 doses or until recovery, in addition to the steroids.
In case of ATG hypersensitivity, Alemtuzumab can be used.
CMV and pneumocystis prophylaxis should be given.
Reference:
1) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020 Mar 6;15(3):430-438. doi: 10.2215/CJN.11991019. Epub 2020 Feb 17. PMID: 32066593; PMCID: PMC7057293.
Excellent, thank you, Amit
maximizing IS medications+ Campath
Since crt has started to increase again it is most likely steroid resistant ACR however I would consider BKVAN
Mixed ACR/AMR
Would look for DSA
C4d staining
BKV PCR
CMV PCR
Markers for steroid resistance like CD8 infiltration etc
Therapeutic option is ATG or Alemtuzumab
Is it not too early for BKVAN?
Yes ,It could be to early for BKVAN but this is important differential diagnosis if your facing allograft dysfunction and histology showed interstitial inflammation. of plus other causes as well
Yes it is too early for BKVAN however in presence of interstitial inflammation it is recommended to do chk for BKV
ACR.
Mixed rejection
CMV infection.
BK infection.
Pyelonephritis.
Acute tubulointerstitial nephritis.
Immunofluorescence:
C4d negative if not accompanied by concurrent antibody mediated rejection
· Silver and trichrome stains are useful for identifying fibrinoid necrosis
· SV40 and C4d immunohistochemistry.
· Molecular / cytogenetics description:
Molecular techniques will provide novel pathogenetic insights that will allow for the
identification of more accurate diagnostic, prognostic, and therapeutic targets. (1)
Study of Genome in kidney transplants, some genes Correlate with TCMR.
Molecular phenotype for TCMR.
Steroid-resistant renal allograft rejection.
ATG-Thymoglobulin at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg.
Alemtuzumab as a single IV dose of 30 mg.
To patient:
History of allergic reaction to rATG-Thymoglobulin
Those with a white blood cell count less than 2000/microL or a platelet count less
than 75,000/microL.
Alemtuzumab, rather than rATG-Thymoglobulin, to patients who have a previous
history of significant rabbit exposure (i.e., history of having raised or ingested
rabbits)
References:
Benjamin Adam , Michael Mengel. Transplant biopsy beyond light microscopy.BMC
Nephrol 2015; 16:132.
???can rabbits ingestion cause hypersensitivity to rATG
case report of different exposure i.e. contact and ingestion of rabbit.
Raghavervebder Boothpur,Karen L.Hardinger et al .Serum Sickness
After Treatment With Rabbit Antithymocyte Globulin in Kidney Transplant
Recipients With Previous Rabbit Exposure. Am J kidney DIS.2010
Jan;55(1):141-143.
What is differential diagnosis
1- Mixed AMR and TCMR
2- Steroid resistant TCMR
Any other test required to confirm the diagnosis?
1- DSA level , C4d staining to exclude mixed rejection
2- CMV and BK virus PCR
3- IS trough levels .
What are your therapeutic options
1- Augment IS drugs
2- Add ATG (1- 1.5 mg /kg) for 10-14 doses with monitoring WBC count .
3- If no response to ATG, consider alemtuzumab .
4- If mixed rejection is proved , add plasmapharesis and IVIG
Unlikely to be mixed rejection. See my answer above, but good way of thinking
Acute cellular rejection .
mixed cellular and antibody mediated rejection.
1- DSA , C4d staining to exclude concomitant antibody mediated rejection.
2- TAC level : to ensure that her dose of TAC is adequate.
Steroid resistant acute cellular rejection.
Depleting anti-lymphocytes antibodies ( r-ATG or anti-CD52 alemtuzumab ).
since this patient had acute rejection , it would be too risky to do early steroid withdrawal , and i would continue on standard corticosteroid regime.
Reference:
James E. Cooper.Evaluation and Treatment of Acute Rejection in Kidney Allografts.CJASN Mar 2020, 15 (3) 430-438; DOI: 10.2215/CJN.11991019
What is differential diagnosis?
Either steroid resistant TCMR or mixed rejection if DSA present and C4d staining positive
Any other test required to confirm the diagnosis?
Markers of steroid resistant AR e.g. CD8 infiltration, extensive WBC infiltration of PTC, high expression of MT or TIMP-1 in graft tissue, and urinary miR-210 levels
DSA level
Infectious screening e.g. CMV DNA PCR,PCR FOR BK VIRUS ,hepatitis B and C
Drug level ( Tac level)
What do you call this condition?
Steriod resistant acute cellular rejection
What are your therapeutic options?
If confirmed steroid resistant T cell rejection Banff class11A/B ,negative screen for infection, then
Pulse Methylprednisolone which is already given followed by oral prednisolone tapering till reaching maintenance dose (20 mg prednisolone)
rATG (1.5mg /kg-3mg/kg) per dose up to a total of 5-10 mg/kg (2-5 days) ,depending on the response in creatinine and CD3 level or WBC count and platelet count (dose withheld if TLC<2000 /ul or plt count <75000/ul, Dose halved if TLC is 2000-3000/ul and plt count is 75000-100,000/ul) ,if ATG contraindicated then Alemutuzumab ( humanized anti CD52 monoclonal depleting agent), can be used (MMF to be stopped during ATG)
Intensification of maintenance immunosuppression targeting tacrolimus trough level between 8-10, optimize MMF dose to 1gm BD.
All patients who received ATG, or Alemtuzumab and high dose corticosteroids should receive antiviral and Pneumocystis pneumonia (PCP) prophylaxis for atleast 3 months
If associated with ABMR ,then PLEX (5-10 sessions) with IVIG 100 mg/kg after each session and 500 mg/kg after the last session, followed by 1 dose of Rituximab after at least 01 week of IVIG if biopsy evidence of active micro vascular inflammation. DSA monitoring should be done at 4weeks , 8 weeks , 3 months , 12 month then twice annually.
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 9[Suppl 3]: S1–S155, 2009
2- James E. Cooper.Evaluation and Treatment of Acute Rejection in Kidney Allografts.CJASN Mar 2020, 15 (3) 430-438; DOI: 10.2215/CJN.11991019
Well done
= What is differential diagnosis?
Severe form of Acute cellular rejection .
Plasma cell rich acute rejection.
Mixed rejection.
=other test required to confirm the diagnosis.
1-c4d and DSA to exclude association of AMR.
2-stain the biopsy with CD 138 , kappa and lambda if came positive and plasma cell more than 10-20 % its mainly plasma cell rich acute rejection. (1).
3- Immunostainings of biomarkers of resistance like( Immunostainings for CD68, B cell marker CD20 and mRNA expression levels of cytotoxic T cell) (2).
– Non-immunological biomarkers: high intra-graft expression of metallothioneins (MT) and tissue inhibitor of metalloproteinase-1 (TIMP1) during acute renal allograft rejection is associated with steroid resistance.
4-Also need to check To as low immunosuppressive state is a common cause of early rejection and plasma cell rich rejection.
What do you call this condition?
Early steroid resistance acute cellular rejection.
What are your therapeutic options?
1-Avoid steroid withdrawal protocol.
2-To optimize tacrolimus level and other immunosuppressive drugs.
3- ATG 1.5mg/kg /day for 4-7 days according to response and f/u CBC with prophylactic medications.
4-Alemtuzumab sometimes also has a role.(3)
References:
1- Successful Treatment of Plasma Cell-Rich Acute Rejection Using Pulse Steroid Therapy Alone: A Case Report .2017;2017:1347052. doi: 10.1155/2017/1347052. Epub 2017 Jan 10.2- Niels V.Rekersab etal Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection, https://doi.org/10.1016/j.trim.2016.07.0053- Martijn W F van den Hoogen etal, Anti-T-cell antibodies for the treatment of acute rejection after renal transplantation. 2012 Aug;12(8):1031-42. doi: 10.1517/14712598.2012.689278.
I liked your list of differentials.
What do you mean by severe ACR? Define histology!
What is specific about plasma cell-rich ACR?
This is a good question Prof Ala
Plasma rich ACR ,rare 2-14% , not included in the Banff classification and indicate sever type of acute cellular rejection with or with out AMR , with intense interstitial inflammation ,early reduction of IS like in this case MMF was 500mg BID ( we should screen for super-added infection viral like BK , CMV or may be intentionally reduced due to lecupenia
prognosis poor and bortezemab as second line of treatment with optimazing triple IS(1)
references:
1-Saudi J Kidney Dis Transpl 2021;32(2):387-397 © 2021 Saudi Center for Organ Transplantation
Severe ACR implies Banff grade Ib or more (with severe tubulitis or arteritis)
Plasma cell rich ACR is a rare form of rejection with mature plasma cells comprising more than 10% of the inflammatory infiltrate in the graft kidney. It usually appears late, is associated with infections and under-immunosuppression and the graft survival is poor in this type of rejection.
References:
1) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020 Mar 6;15(3):430-438. doi: 10.2215/CJN.11991019. Epub 2020 Feb 17. PMID: 32066593; PMCID: PMC7057293.
2) Plaza Lara E, Hernández García E, Ruiz Fuentes MDC, Caba Molina M, De Gracia Guindo MDC, Osuna Ortega A. Plasma Cell-Rich Acute Rejection in Renal Transplantation: A Case Report. Transplant Proc. 2020 Mar;52(2):512-514. doi: 10.1016/j.transproceed.2019.12.015. Epub 2020 Feb 12. PMID: 32059940.
Thanks Prof ALa
I meant by severe, according to Banff classification that B II(severe intimal arteritis V2).
Specific about Plasma cell -rich ACR:
Plasma cell rich ACR(Histologically, the proportion of interstitial plasma cells, mean interstitial inflammation, and tubulitis score are higher in the PCAR group compared with cases with ACR).(1)
Plasma cell about 10-20 %.
Resistant to steriod .
Specific IH stain for plasma cell.
Associated mainly with non-adhernce.
Reference:
1-R Gupta , A Sharma, P J Mahanta et al (Plasma cell-rich acute rejection of the renal allograft: A distinctive morphologic form of acute rejection?).2012 May;22(3):184-8. doi: 10.4103/0971-4065.98753.
Reference:
Lara EP, García EH, Fuentes MDR , Molina MC , Guindo MDD, Ortega AO. Plasma Cell-Rich Acute Rejection in Renal Transplantation: A Case Report. Transplant Proc. 2020 Mar;52(2):512-514.
What is differential diagnosis?
Acute TCMR.
Mixed acute rejection
Any other test required to confirm the diagnosis?
C4d; by IHC or IF
Test for DSA
Screening for infections (CMV, BK, etc)
Tacrolimus trough level
What do you call this condition?
Steroid refractory acute TCMR
What are your therapeutic options?
# Methyl prednisone IV (250 to 1000 mg daily) given for 3 to 5 days.
It targets T cells, B cells, & macrophages
# ATG – IV (1 to 1.5 mg/kg) for 7 to 14 doses based on the response & WBC count (Cd3 level is the ideal, but might not be readily available in most centers)
# Optimize the dose & the level of the maintenance immunosuppressive drugs.