2. A 26-year-old lady, lost previous graft due to non-compliance, received a kidney from her brother, 112 mismatch, has DSA (B57 with MFI 3000). Cross match (FCXM) was negative. ATG was discontinued after 2 doses due to possibility of infection (low grade fever but septic screen came back negative). Discharged with s Cr 70 µmol/L. She came back to on the weekend with s Cr 230 µmol/L and reduced urine output. USS showed well perfused with RI (resistive index of 0.8). She responded partially to 3 doses of empirical methyl prednisolone (during the weekend AFTER exclusion of infective process), S Cr is stuck at 170 µmol/L.
- Describe this condition
- What is your management plan?
Dear All
This case could be steroid-resistant rejection or mixed rejection WHERE there is a partial response to steroid which can happen in both conditions (B and E). We need to do a biopsy, C4d staining and DSA level (A and E).
How would you treat steroid-resistant rejection where C4d staining and DSA level is not increased?
-Steroid-resistant rejection is treated with poly- or monoclonal antilymphocytic antibodies, with success rates of 60 to 70%. Their potential benefit must be carefully balanced against the risks of infection and lymphoma.
-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.
Reference
-H A Bock Steroid-resistant kidney transplant rejection: diagnosis and treatment J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S48-52.
prevelance of steriod resistant around 25-30% post kidney transplant Defined as an AR episode with failed response to pulse corticosteroids therapy within 14 days from initiation of treatment and patient’s serum creatinine levels not reduced by 120% from the pre-rejection baseline value and histological finiding of intimal arteritis.
second line will be polyclonal Tcells depleting agent r ATG 1.5MG/Kg for 3-4 doses, usually response rate improved to more than 75-90%. need to monitor for side effects like FBC and lyphomphocytes subset CD3 level .
in our centre we start same PMP 250-500mg for 3-5 days some times with hstological evidence of intimal arteritis with banff 11A or 1B will give ATG earlier to reduce the side effect of steriods with augmentation of the mantenance triple therapy , if no response with in 7-10 days consider repeat biopsy, role out infection like CMV , BKV , and patinet will be under CMV Prophylaxis and AB prophylaxis for PJP.
ruleout
-in case of steroid resistant rejection which may be either :refractory TCMR or mixed rejection ( coexisting AMR) .
-in both situations, augmentation of maintenance immunosupression as ( shift to tacrolimus rather than ciclosporin+ higher window of tacrolimus trough level+ ensure compliance to therapy+ frequent monitoring of DSA ) are essential components of management.
yes, by ATG
I think optimization of immunosuppression is the answer. If no contraindication to ATG I would go for it and switching CSA to Tac.
Steroid resistance should not be assumed before the fifth day of pulse steroid treatment, although histologic features of vascular rejection may indicate the need for more aggressive treatment earlier.
· steroid-resistant rejection is traditionally treated with poly- or monoclonal antilymphocytic antibodies, with success rates of 60 to 70%. Their potential benefit must be carefully balanced against the risks of infection and lymphoma.
· 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 desperate cases, with success.
Reference:
Bock HA. Steroid-resistant kidney transplant rejection: diagnosis and treatment. J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S48-52. PMID: 11251032.
if biopsy showed just cellular rejection with no evidence of ABMR
ATG 6-9 mg/kg with augmentation of all other immunosuppresions
if still no response and s.creatinine didn’t decrease to less than 10% of baseline
rebiopsy showed be done +repeat virology (phrophalctic valgancyclovir and cotrimoxazol is mandatory)
rebiopsy may show resistant cellular rejection which usually carry very poor prognosis and mostly progress to graft failure
+ or it may show mixed rejection and treatment of ABMR is needed PP,IVIG and rutiximab
By using rATG 1.5 mg/kg and following the response by lymphocyte count and CD3, if there is no response, then alemtuzumab can be used.
Steroid resistant CMR is treated with second line therapy, that is poly clonal or monoclonal anti lyphocyte antibodies, especially ATG at a dose of 2_4mg /kg for 7_14 days, with close observation for side effects particularly leukopenia and thrombocytopenia
Second option is mono clonal antibidy Alemtuzumab15_30 mg sc 2 subsequent days. which is anti CD 52 antibodies.
Optemization of current therapy with MMF and Tacrolimus base protocol is advocated.
Reference :
Mw F van den Hoogen et al. Am
J Transplantation 2913 Jan
If it is proved to be an AR , having a negative septic screen with a presumed normal blood counts . then ATG is the choice .
Treating steroid resistance rejection
References :
I agree, it could be TMA, CNI toxicity, infection, etc
But it is a highly sensitised patient who did not continue the ATG course
What are the immunological causes behind it?
Chose from the following:
A. CMR
B. steroid-resistant rejection
C. AMR
D. Recurrence of the original disease
E. Mixed rejection
You need to do one or more of the following:
A. Biopsy
B. Continue a full course of ATG
C. Give another pulse steroid course
D. Renogram to check the function and rule out urine leak
E. C4d staining and DSA level
most likley Mixed type of rejction and prtority for graft biopsy with C4 staining and DSA level .
E and E.
Mixed rejection and C4 and DSA
B & B
Most probably it is mixed rejection and requires renal biopsy
Could be mixed rejection and needs a biopsy and C4 d staining and DSA level
E. Mixed rejection (partial response to steroids, presence of pre-formed DSA0
A (Biopsy) and E (C4d staining and DSA level)
#1.B,C,D
# 2.A,B,E
1-In view of existing preformed DSA against class I B 57 with MFI of 3000 and in fact of HLA mismatch 112 and she did not receive full induction therapy,it is most probably mixed rejection.
Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute antibody-mediated rejection and early graft loss
2-You need to renal biopsy+C4d staining and DSA level to confirm AMR and offer proper management needed.
first question E
second question: A and E
mostly a mixed rejection and we need a biopsy with C4d staining and also DSA level
AMR
Biopsy
C4d staining and DSA level
It could be mixed rejection
C4d staining and DSA level
1) B , E
2) A, B, E
Mixed rejection, need graft biopsy & C4 d staining
ANSWERS IS
1-C
2-E
1/B ,D
2/A.E
E.mixed rejection
A.biopsy
E.C4d staining and DSA level
Most likely a mixed rejection. Biopsy and c4d staining and DSA check
B and E
A and E
1- B,E
2-A,E
E and E
Mixed rejection and C4d staining, DSA level
B, C,E
The patient had significant DSA with high MFI that might cause AMR
AND ATG wasn’t continued so TCR might be the cause
So its mostly mixed rejection E
There was partial response to steroids B
Biopsy withs4d staining and detection of DSA
IS mansatory for diagnosis (a, e ).
B
E
A
E
I think mostly it’s due to Antibody mediated rejection ABMR. (C)
To prove that we need to do graft biopsy (A) with C4d staining and DSA level (E).
In addition it is not mentioned but we need to do new DSA level.
What are the immunological causes behind it?
Chose from the following:
A. CMR
B. steroid-resistant rejection
C. AMR
D. Recurrence of the original disease
E. Mixed rejection
answer B,E
You need to do one or more of the following:
A. Biopsy
B. Continue a full course of ATG
C. Give another pulse steroid course
D. Renogram to check the function and rule out urine leak
E. C4d staining and DSA level
A,E
Chose from the following:
A. CMR
B. steroid-resistant rejection
C. AMR
D. Recurrence of the original disease
E. Mixed rejection
You need to do one or more of the following:
A. Biopsy
B. Continue a full course of ATG
C. Give another pulse steroid course
D. Renogram to check the function and rule out urine leak
E. C4d staining and DSA level
Answers :
First question: B and E
Second question: A and E
As patient highly sensitised with partial respond to steroid .
– to do biopsy if TCMR rATG 6-9 mg/kg and augment immunosuppression.
-if no response, repeat biopsy may resistant cellular rejection which leads to graft failure.
– If ABMR , give plasmapheresis followed by IVIG every session with or without rituximab .
This patient most probably has steroid resistant rejection which could be due to
i need to do abiopsy with c4d satining and DSA level with rATG TREATMENT
E- mixed rejection
Pt partially responds to steroids with > 10% reduction in s.cr. and this response may be due to AMR ( as he is already DSA positive (highly sensitized)
a well-perfused graft may exclude TMA,
A and B
I will do a biopsy and will continue with a full course of ATG
1- B C E
2-A B C E
Dear All
Many of you did not have a clear answer. This is a real scenario, you will come across.
You need to structure your answer
Differential diagnosis of graft dysfunction in this case :
1- Drug induced : CNI nephrotoxicity
2- Prerenal which can be excluded from history, examination
2- Vascular cause including renal thrombosis and RAS, excluded since RI is normal
3- microvascular causes including TMA
4- Glomerular causes including recurrence of glomerular disease
5- Tubulointerstitial causes including Acute rejection(TCMR, ABMR) ,CMV and BK nephropathy, pyelonephritis
So work up recommended is
The most probable diagnosis is AR, although TMA, CMV, BK nephropathy, CNI toxicity should be excluded
Empiric steroid given according to the high probability of AR and the treatment will be decided according to the result of investigations
Differential diagnosis of this case ( in order ) :
first let’s revise the given data :
This is her 2nd transplant (so DSA’s are liable to be present and they are) , due to non compliance either to medications or her follow up , so may be this occurred again , she has 2 DR mismatches , Unluckily she received only 2 ATG shots due to “fear of infection” but the markers of infection were -ve although we can’t rely on labs alone especially in this case as she already had ATG and other IS so her inflammatory markers would actually mislead us .
Any way her creatinine was great so this may exclude some differentials mainly the vascular issue ( at the end of the day we have an US which shows a good graft ) then her creatinine elevated and responded to steroids ( important point)
-TCMR
-Mixed rejection
-CNI toxicity ( essential to exclude )
-ABMR alone ( unlikely as she partially responded to steroids)
Thus Renal biopsy with C4d staining , follow up DSA’s are of great importance , strict follow up tac trough levels ( assuming she is on Tac) and if not then shifting from cyclosporine to Tac will be helpful in many points( may not wait the biopsy to do so ) : if CNI toxicity or TCMR either alone or part of mixed
then treatment according to biopsy
patient with high risk with the previous transplant, with graft loss due to non-compliance on treatment, despite negative flow cytometry crossmatch, patient had DSA with MFI of 3000, presented with rising KFTs with partial response to solumederol shots
Transplanted kidney duplex excluded partial surgical causes ,with partial due to response to solumederol mostly its due to mixed rejection or TCMR.
Investigations
CBC
CRP
CNI level
CMV PCR
urine analysis
LDH
Renal Biopsy + C4d
DSA assessment
What is your management plan?
Maintenance therapy
shift cyclosporine to tacrolimus with target high level
High dose MMF
According to renal biopsy
resistant T cell-mediated treatment with ATG
if mixed rejection in addition to ATG we will need plasma exchange and IVIG if no response adding rituximab
the patient has partial response to steroid
may be steroid-resistant rejection or mixed rejection
so we need to do biopsy , staining for C4d and measurement of DSAs in the serum
to exclude concomitant AMR
if steroid resistant rejection : treated with ATG or Alemutezumab
if there is AMR : PE +IVIG
This is a case of TCMR combined with AMR ( because of response to steroids ,
DX must with BX with C4d staining , lab DSA level
1) Describe this condition.
Partially Steroid Responsive Acute Graft Rejection.
2) What is your management plan?
Investigations
Allograft biopsy for AMR with c4d stain, Plasma DSA.
Infective screening, Blood and urine culture. Plasma CMV , BKV PCR.
Plasma CNI toxicity , diabetic control.
Treatment : ATG. May consider alemtuzumab.
How would you treat steroid-resistant rejection where C4d staining and DSA level is not increased?
-Steroid-resistant rejection is treated with poly- or monoclonal antilymphocytic antibodies, with success rates of 60 to 70%. Their potential benefit must be carefully balanced against the risks of infection and lymphoma.
-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.
Reference.
in case of steroid resistant rejection which may be either :refractory TCMR or mixed rejection ( coexisting AMR) .
This patient had high immunological risk for antibody mediated rejection because she had second transplant with 2 DR mismatch and preformed DSA and she didn’t complete her induction regimen with ATG; so when she partially respond to methylpredinsilone this make the possibility of steroid resistant cellular rejection or mixed rejection (ACR plus AMR) so we need to do kidney biopsy with C4d stain and DSA level again, start ATG plus or minus plasmapheresis and IVIG
1) Describe this condition.
Partially Steroid Responsive Acute Graft Rejection.
2) What is your management plan?
Investigations
Allograft biopsy for AMR with c4d stain, Plasma DSA.
Infective screening, Blood and urine culture. Plasma CMV , BKV PCR.
Plasma CNI toxicity , diabetic control.
Treatment : ATG. May consider alemtuzumab.
Deferential diagnosis 1- AMR this patient young with past history of rejection due to non compliance presence of DSA with MFI 3000 so the possibility of AMR is high 2- Cellular rejection .3- Mixed rejection 4 Acute CNI toxicity it is more frequent in early period .5 Acute tubular necrosis 6-Recurrent of primary GN kidney disease . Management 1-biopsy with C4d staining .2-TAC trough level 3-DSA level . treatment methyl prednislone , ATG If DSA is increased and biopsy result confirm AMR plasma exchange + IVIG should be add
Second transplant, 1st lost due to non-compliance with IS (rejection likely)
DSA positive, 4 mismatches with 2 DR
this means the recipient is highly sensitized, and unluckily she did not receive full ATG course.
she partially responds to steroids may give us clue to AMR mixed with TCMR
a well-perfused graft may exclude TMA so my priority in treatment will be to continue ATG course and not to rush to plasmapheresis first.
first, she needs a graft biopsy with C4d staining.
monitor for DSA level and specificities
CNI trough level
Viral screen (CMV and BK)
change her CsA To tacrolimus and continue with oral prednisolone
she needs to continue her antiviral prophylaxis
other treatments will depend on the biopsy and DSA results
the senario mostly refer to steroid resistant renal rejection.
in this patients, i would the following:
1- Kidney transplant biopsy
2- IV pulse steroid
3- plasmapharesis
4- recosider ATG
5- DSA monitoring
A Second transplant for a highly sensitized patient who lost his previous graft because of non-compliance, 2 HLA mismatches with class 1 DSA (MFI 3000).The FCXM was negative. Unfortunately, only 2 doses of ATG was given.
Early rise of serum creatinine, US excluded surgical causes and infectious screen was negative.
Partial response to steroids after 3 doses
Diagnosis:
After exclusion of surgical causes, infection, CNI nephrotoxicity or TMA, the diagnosis is most likely a steroid resistant rejection(TCMR or a mixed rejection)
o We need to do a renal biopsy and check for C4D to exclude any associated AMR
o Frequent Monitoring of DSA levels
o Augment immunosuppression and ensure proper compliance. Use full dose MMF and switch from cyclosporine to Tacrolimus if not used (maintain high trough level)
o In steroid resistant rejection, move to second line therapy using ATG that improves the response rate(follow FBC and C3D) or Alemtuzumab and balance the benefits against the risks especially infections and malignancy. Ensure prophylaxis against PJP and CMV
o If biopsy showed evidence of ABMR (use PP+IVIG with or without Rituximab)
References:
Hand book of kidney transplant 6th edition
Steroid-resistant kidney transplant rejection, diagnosis and treatment. J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S48-52.
Given condition
The case appears to be steroid resistance since the patient responded partially to 3 doses of methyl prednisolone.
Management plan
Patient was given 2 doses of ATG. This can be followed by a full course of ATG. However, looking at the possibility of infection, alemtuzumab can be used.
Steroid pulse therapy can be used. This is daily pulse administration for a period of 5 days of methyl prednisolone in the doses of 0.25 to 1 g. There is insufficient data to show that higher doses are more effective.
Temporary increase in immunosuppression or adding a new immunosuppressant. MMF is a good option. Another is rapamycin that might be suitable.
Patients can be resistant to tacrolimus and sensitive to cyclosporine and hence it has to be decided on a patient to patient basis. There is no significant advantage of tacrolimus with respect to nephrotoxicity or infection risk when compared with cyclosporine.
Prophylactic treatment for Fungi and pneumocystis should be considered – Fluconazole 50 mg per day and cotrimoxazole 960 mg 3 times a week respectively.
High risk patient with:
1- previous transplantation, this her second renal graft.
2- Non-compliance.
3- MM 112
4- Positive DSA B57, MFI 3000.
5- She didn’t complete ATG course because of ?? sepsis.??
Now presents with AKI in her graft function, normal renal graft USS, RI 0.8.
Partially responded to pulse methyl-prednisolone.
AKI for DD:
1. Acute rejection, either TCMR or ABMR or mixed-à needs biopsy, staining for C4d.
2. Drug toxicity–à check CNI levels.
3. Steroid resistant rejection.
4. Infections: check CMV, BK, and other causes of sepsis.
Management depends on the diagnosis:
ABMR: Pulse steroids, plasma exchange, IVIG +/- Rituximab.
Monitor DSA every 14 days then 3 monthly.
ATCMR: Pulse steroids, ATG, augmenting IS (Tac+MMF+steroids).
Infections: manage accordingly.
Q1- A mixed cellular and antibody mediated rejection should be considered.
Q2- Kidney biopsy.
DSA monitoring
ATG
Plasmapheresis and IVIG
A case of rejection partially resistant to steroids vs the possibility of Mixed rejection.
Exclusion of CNI toxicity and infections must be done
Management plan :
Check RFTs , proteinuria, CNI Level , DSA ,
Renal Biopsy IF or IHC , C4d
Search for Infections eg CMV , BK
Treatment
ATG may be used unless contraindicated
Shift Cyclosporin to MMF
shift Azathioprine if used to MMF
Strict Follow up of trough level
Plasmapharesis, IVIG may be required
Describe this condition
This patient is highly sensitized with previous lost graft due to non-compliance, 112 HLA mismatch, with DSA against class l HLA with MFI 3000, with incomplete rATG induction doses presented in a very short time post-transplant with allograft dysfunction responding partially to steroid therapy ,favors rejection likely steroid resistant TCR or mixed (AMR plus ACR) as surgical causes like obstruction or any urine leak / urinoma / hematoma have been ruled out. Other differentials which need to be ruled out include: infections (CMV or BK virus nephropathy. )TMA, Drug toxicity(CNI).
What is your management plan?
Admission with strict intake /output charting , Rehydration –Allograft Biopsy with C4d staining as early as possible for diagnosis, classification of pathology and determine severity of lesions-
Also send complete investigations (urinalysis, CBP, blood film , RFT ,LFT , PT PTT, CNI drug level, septic screen )
Then treatment according to the cause :
Intensification of immunosuppressive medications: Change to Tacrolimus, if on cyclosporine.Change to MMF, if on azathioprine.
If steroid resistant TCMR –then rATG after infection ruled out.
If Mixed type rejection I will give rATG plus TPE 5 session(1-1.5 volume) with IVIG(100mg/kg) after each session and Rituximab (375mg/m2)in case of no response.
Close monitoring and follow up with DSA and serum creatinine and proteinuria.
REFERENCE:
Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020 Mar 6;15(3):430-438
Differential diagnosis of graft dysfunction in this case :
So work up recommended is
Hospital admission for more investigation and good hydration plus recheck for complete septic workup then
Describe this condition
THIS PATIENT HAS AHIGH RISK OF REJECTION BECAUSE
accordingly differential diagnosis of this scenario are
1- ABMR
2- Mixed rejection.
3- IIB,III type of TCMR
OR OTHER NON IMMUNOLOGICAL CAUSE OF GRAFT DYSFUNCTION
What is your management plan?
biopsy is mandatary for histopathological diagnosis .
investigation send according to above diagnosis .
empirical rATG is indicated in this patient ( after adequate history of -allergic reaction ,total dose received ,WBC count ,PLT count ,exclusion of infection )
then according to biopsy result the treatment is directed
if diagnosis IS ABMR . then treatment will be
if no response we may think of
augmentation of immunosuppression with DSA monitoring
motivation of patient regarding sticking to drug as a treatment of non adherence .
Differential diagnosis of graft dysfunction in this case :
So work up recommended is
Hospital admission for more investigation and good hydration plus recheck for complete septic workup then
A case of mixed rejection vs steroid resistance rejection
Needs Renal allograft biopsy , C4D and DSA Level
What is your management plan ?
Investigation:
-Biopsy with c4 d stain .
– CNI trough level .
– CBC , peripheral blood film.
– urine examination.
– DSA level after 2 weeks then monthly then every 3 month then every 12 month.
– CNI trough level.
– council patient for immunosuppressive compliance .
Management:
– admission.
– good hydration.
– if TCMR : rATG .
– if mixed : rATG + plasma exchange followed by IVIG WITH RITUXIMAB 375 mg once weekly for 2 weeks .
– ABMR: plasma exchange + IVIG + Rituximab
– if no response; repeat biopsy .
Describe this condition :
-26 y old female classified as high immunological risk ( highly sensitised from previous transplant who lost previous graft due to non compliance ).
– 112 mismatch DSA against HLA class 1.
– MFI 3000 incomplete ATG due to infection.
– patient presented with acute allograft dysfunction early post-transplant and respond partially to steroid therapy .
* differential diagnosis :
– ATCMR.
– ABMR .
– Mixed rejection.
– pre-renal ( infection but septic screen negative).
– recurrence of primary disease .
– obstruction : to be ruled out .
-CNI toxicity ( trough level to be checked).
– vascular cause.
-TMI .
– surgical cause : graft u/s to rule out.
A case of acute rejection
Due to high previous DSA and incomplete of Induction doses (ABMR) so ttt is plasmapheresis and IVIG
But also partial response to steroid mean that it may be cellular rejection
Mixed rejection to-be ttt with (ATG-pulse steroids-plasmapheresis-IVIG)
Patient has acute allograft dysfunction with possible causes including acute rejection either TCMR,ABMR or mixed rejection ,CNI toxicity, post transplant TMA, viral infection and recurrent primary disease.
Management lines include renal biopsy for clue of acute tubulitis or/and evidence of acute tubular injury ,glomerulitis , or TMA, immunofluorescence to looking for C4d staining in peritubular capillaries and glomerular capillaries, DSA level and CNI levels,
Based on results: mixed rejection needs ATG after ruling out infection, Plasma exchange and IV IG ,if not responding , Rituximab is given aiming to return graft function near to baseline.
acase of ayoung sensetized lady from previous transplant faliure due to non compliance, DSA againest class 1 (B57 with MFI 3000), negative cxm, patient didnt continue induction with atg due to possiblity of sepsis,decreased uop with relative high RI received 3 doses of mp.condition going with ABMR which could be described as steroid resistant due to weak cc response.
patient need readmission for more investigation and good hydration plus recheck for complete septic workup (urina analysis culture acr blood culture serology for viral infection)
need graft biopsy plus c4d stain.
CNI toxicty is apossiblity need cni trough level
if no signs of infection ATG could be started then rituximab if failed for plasmapharesis and IVIG.
DSA follow up every 3 months for first year.
The patient had DSA and did not complete ATG induction properly due to side effect
Describe this condition
It is a steroid resistant acute rejection or mixed rejection
What is your management plan
I would repeat DSA and kidney biopsy
now, creat is 170, regarding the need for treatment would love to discuss regarding newer agents such as bortezomib and eculizumab has shown benefit in rejection
1- Describe this condition
The patient has the first return because she started a rejection condition related to the fact that she did not complete the induction treatment with ATG. However, pulse therapy with steroids also did not bring a satisfactory response, raising the hypothesis that it is also a steroid resistance.
2 – What is your management plan?
I would choose as drugs to use for immunosuppression: Tacrolimus + mycophenolate mofetil , in combination with daclizumab. Studies have already shown that this regimen is as effective at preventing acute rejection after renal transplantation.
Reference: Corticosteroid-Free Immunosuppression with Tacrolimus, Mycophenolate Mofetil, and Daclizumab Induction in Renal Transplantation – (Transplantation 2005;79: 807–814
This is an example of transplantation in a highly sensitised patient ( previous graft failure with non adherence to medications besides having detected DSA , eventhough cross match is negative for the new donor ) . Having an incomplete ATG course makes alloimmunisation highly likely .
there are no given information about the pattern of fever and whether it was related to ATG infusion ? also nothing is given about her blood counts .
However , having a partial responce to steroid with detectable DSA makes the “mixed ” rejection more likely .
A kidney biopsy must be done .Meanwhile , management should cover both types of rejection besides a full work up to exclude non immunologic issues .
Describe this condition
What is your management plan?
1. Describe this condition.
2. What is your management plan?
Management plan is Renal biopsy and see for LM and C4d stain. This would clue to existence of associated AMR in addition to ACMR.
I would treat the patient with Inj ATG 3-5mg/kg IV as infusion over 5 hours diluted in RL/NS. I would use Inj hydrocortisone 100mg IV, Tab paracetamol 500mg and Inj AVil as premedication. I would monitor differential count and CD3 subset to avoid profound immunosuppression. I would wait for one day in between if there is profound lymphopenia. I would keep the patient on cotrimoxazole and vaganciclovir prophylaxsis. If the renal biopsy shows feature of glomerulitis with peritubular capillaritis with C4d i would treat as ABMR with IVIG and plasmaphresis. I would decide the further course of action depending on which one is severe form in the current biopsy
Differential diagnosis of graft dysfunction in this case :
Acute rejection(TCMR, ABMR) ,CNI nephrotoxicity , Dehydration , TMA , infection.
work up:
Renal biopsy with C4d staning
Tacrolimus trough
Urine analysis, ACR
Fu DSA level
CMV IgM, BK virus load
Treatment:
case of mixed rejection ;
1-methyl prednisolone 500 mg daily for 3-5 days
2- plasmapheresis
3- Augment immunosuppressant levels .
3- DSA and graft function monitoring
In case of steroid resistance rejection ATG can be used .
ATG showed success rates of 60 to 70% .
Mycophenolate mofetil has been successfully used to treat steroid-resistant rejection.
Describe this condition
Highly sensitized patient who did not tolerate ATG due to suspected infection and underwent a new course of corticosteroids, but without the expected response.
The possibility of infection was excluded at first, but how the investigation was carried out was not described.
As the response was partial, rejection may be mixed or refractory to corticosteroids. Reintroduction of ATG would be the option, but plasma exchange, IVIg and rituximab should be considered. Before reintroducing it, I would do a broad panel investigation for viral infections and dosage of immunosuppressants.
What is your management plan?
The patient in this scenario is highly sensitized by previous transplant ,
High DSA
Didn’t complete ATG dose so she become liable to TCR
Presented with rising s creatinine that showed incomplete response to pulse steroids so it might be either mixed rejection or steroid resistant rejection or mixed rejection.
biopsy and c4d staining
DSA level all are mandatory for diagnosis
Treatment
Exclude infection especially cmv and bk virus
Check tac level as there is history of non compliance .
For steroid resistance rejection ATG can be used
In case of mixed rejection pulse methyl prednisolone 500 mg daily for 3 days.
plasmapheresis +IVIG
This patient could potentially have acute rejection or an acute infective process presenting as rejection.
The ultrasound scan has ruled out mechanical causes of early dysfunction like obstruction, arterial or venous thrombus formation.
The other cause o early graft dysfunction is CNI toxicity. I would assume that this has been considered and excluded.
Although the patient had a low level DSA the crossmatch was negative. Acute rejection may be a possibility.
I suspect something like BK virus infection. I would like to check for BK PCR viral load.
I would consider reduction of immunosuppressant medications, particularly stopping the antimetabolic drugs like Azathioprine or MMF.
Differential daignosis
* Any sensitized patient with high MFI develop develop acute allograft dysfunction with decrease urine output short period post transplantation most likely Ab mediated rejection and any empirical therapy should cover that if biopsy not accessible .
*Mixed rejection: pure Ab mediated rejection rare since Ab mediated rejection occur after full cellular immune maturation.
*TCMR possible no thing against that in absence of biopsy.
*Recurrent of primary disease: although least likely in differential diagnosis but not impossible, case reported of recurrence of primary disease even in two day post transplant EX(FSGS).
Management Plan
*if there is no contraindication , graft biopsy urgently and highly recommended .
*full infection screen include blood and urine culture and imaging study since most immunocompromised patient not have sign and symptoms of infection (poor inflammatory response );and we arrange to use potent immunosuppressive drug post steroid resistant .
*Send for drug level CNI.
Anti rejection therapy:
Now if diagnosis obtained with tissue biopsy specific treatment should be direct against
underlying cause according to guideline .
if no biopsy continue on empirical anti rejection therapy which include
ATG 1.5mg/kg for 7 day and assessed response .
IV Ig , with plasma exchange (albumin replacement) .
(+,- )rituximab or bortezomib
Any rejection should be treated by an atleast temporary increase in basal immunosuppresion , which includes increase in CNIs target levels, addition of MMF or switch from CsA to Tacrolimus. The addition of rapamycin may also be considered. Steroid resistance should not be considered before 5th day of pulse steroid,
Steroid resistant is treated by poly or monoclonal antilymphocyte antibodies, MMF for cellular type, plasmapheresis and IVIg in some cases
recent transplant with dearranged kidney function
u/s and doppler excluded any surgical complications
she recieved 3 doses of methyle prednisolone with partial response
after optimization of all causes of dearranged kidney function like tac level and hydration status and viral screening
it could be any lesion but most probably:
-tcell meidated rejection class 2 or above which usually show resistant to steroids and need ATG 6-9 mg/kg
-mixed cellular and ABMR and need ATG ,P.pharesis and IVIG
so biopsy is mandatory
-ATN post transplant
-recurrent of 1RY KIDNEY DISEASe
kidney biopsy and treatment according to finding
Immunologically is high risk recipient due to his previous kidney transplant , 4 HLA mismatch ( 2 DR) presence of DSA .
His recent S Cr stuck at 170 mmol/L. His partial respond to steroid raise the possibility of steroid resistant .While his immunological history and discontinuation of ATG in addition to partial steroid response make mixed rejection possible diagnosis.
DSA plus kidney biopsy with C4d are important to reach the diagnosis .
Treatment ;
In case of mixed rejection ;
1-methyl prednisolone 500 mg daily for 3-5 days
2- plasmapheresis (1-1,5 volume on alternative days + IVIG following each session )
3- Augment immunosuppressant levels .
3- DSA and graft function monitoring
In case of steroid resistance rejection ATG can be used . ATG showed success rates of 60 to 70% . Mycophenolate mofetil has been successfully used to treat steroid-resistant rejection, but only of the interstitial (cellular) type.
.
Reference;
1-Gabriel M Danovitch MD. Handbook of kidney transplantation
2–H A Bock Steroid-resistant kidney transplant rejection: diagnosis and treatment J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S48-52.
This is a highly sensitized patient who did not complete the ATG course. Rejection is a high possibility in the list, keeping in mind his partial response to steroids.
However, other possibilities should be kept in mind, which could present concomitant with rejection and can be also responsible for partial response to steroids if the rejection is present. Such as:
Management:
A kidney biopsy is a must.
DSA monitoring
C4d staining
Describe this condition
Recipient with high immunological risk, second transplant, young age, pre transplant DSA (which predict AMR), HLA-A,B,DR mismatch which predict T cell mediated rejection.
post transplant, risk of acute rejection is mainly determined by immunosuppression regimen didn’t receive all doses of ATG, and the patient didn’t receive all doses of ATG.
Differential diagnosis:
Acute rejection (high probability due to the increased immunological risk), mixed rejection is considered due to the partial response to steroids as TCMR is often responsive to steroids while AMR require more aggressive immunotherapy
other causes of graft dysfunction: drug toxicity, obstruction (excluded by ultrasound), infection (the screen was negative), CMV infection, TMA
What is your management plan?
Renal allograft biopsy to allow diagnosis, classification of pathology and determine severity of lesions (early diagnosis is important to avoid accelerated graft loss)
C4d staining
DSA level
CNI trough level
CMV PCR
treatment will be determined according to result of biopsy:
T-cell mediated rejection: continue 5 doses of solumedrol and r ATG mg/Kg for 5-7 days
antibody mediated rejection: plasmapheresis and IVIg after each session.
Wehmeier C, Ho¨nger G, Cun H, Amico P, Hirt-Minkowski P, Georgalis A, Hopfer H, Dickenmann M, Steiger J, Schaub S: Donor specificity but not broadness of sensitization is associated with antibody-mediated rejection and graft loss in renal allograft recipients. Am J Transplant 17: 2092–2102, 2017
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.
This is a high immunological risk recipient ( previous lost graft due to non-compliance, 112 HLA mismatch, with DSA against class l HLA, MFI 3000 with incomplete rATG induction doses ) presented with acute allograft dysfunction early post transplantation responding partially to steroid therapy , the differential diagnosis will be either :
1-ATMR (sever ,higher stage )
2-ABMR
3- mixed type (AMR and TMR )
4-per renal cause
5- obstruction (ruled out)
6- CNi toxicity
7-infection ( Ruled out )
8-TMI
So my management plan will be :
Admission
Rehydration
Biopsy with C4d staining
Send complete investigations (urinalysis, CBP, blood film , RFT ,LFT , PT PTT, CNI drug level,septic screen , USG )
Then I will treat according to the cause :
If
ATMR ( severe not responding to steroid ) so I will give rATG
If
Mixed type rejection I will give rATG plus TPE 5 session with IVIG after each session
If still no response I will give single dose of Retuximb 375mg /m2 and if no response give Velked vial (bortezomib )
If ABMR we do TPE pluse IVIG pluse RTx
In edition to follow up with RFT , DSA level .
If no response to the above treatment consider repeat the biopsy searching for other cause .
In our case, we have multiple factors for rejection. first of all, this is a highly sensitized patient due to a previous transplant. history of non-compliance is also important. inability to use full-dose ATG because of sıspected infection. we have a resistive index slightly increased. although alone doesn’t mean rejection but draws attention to it. here only 3 doses were given. we have a partial response. For steroid resistance, a period of 5 days is needed but in our case, the response although not dramatic, is still present. A renal biopsy is essential in this case. The Probable rejection is very early. Drug level is important but supposing it was adjusted before discharge the under-immunosuppression is less probable. after readmission and biopsy, DSA level control, hydration, and optimization of drug level. In case of CNI toxicity, I will continue maintenance with a high-dose steroid (1mg/kg after the fifth day). here there is oliguria not only a high level of creatinine . So I have to check CNI level along with hydration. I have to be cautious with CNI if patient is dehydrated. with serial monitoring of drug level and renal function tests. urine output monitoring is essential
plan:
steroid 5 days, CNI according to renal output and drug level
considering ATG again, DSA monitoring and Plasampheresis if needed
This patient is high risk due to previous transplant, DSA and 4 mismatches
Differential diagnosis
1- CNI toxicity
2- Micro vascular disease like TMA
3- Recurrence of original disease
4-Mixed rejection
How will you investigate this patient
Start with blood CP/ESR and CRP
Urine Albumin to creatinine ratio.
Check CNI Trough levels
Check DSA level
Screening for viral infections
Biopsy &c4d staining
How will you treat
In case of mixed rejection ATG can be used after excluding infections.
In case of AMR IVIG and plasmaphresis can be used. This case can be due to steroid resistance which can be treated with monoclonal antibodies If it is interstitial type rejection then MMF can be used
Reference
Gabriel M Danovitch MD. Handbook of kidney transplantation
According to the risk stratification she is high risk because:
1.previous transplant
2.DSA
3. 4 Miss match
In addition to poor compliance so the differential diagnosis are
1.Mixed rejection
2.steroid-resistant rejection
Investigation :
1.Renal biopsy looking for histological feature of graft injury + C4D
2. DSA
To confirm the diagnosis
Treatment plan if it’s mix
Pulse methyl prednisolone + plasmapheresis + IVIG.
If it’s steroid resistance rejection treated with poly-clonal antilymphocytic antibodies, with success rates of 60 to 70%.
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.
Reference
-H A Bock Steroid-resistant kidney transplant rejection: diagnosis and treatment J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S48-52.
Sensitized patient and not complete the course of ATG possible mixed rejection and partial response to steroid, still we should roll out CNI toxicity
further management
Graft biopsy,stain for c4d and DSA level
. What is your differential diagnosis?
1.Mixed rejection
2.CNI toxicity
3.Recurrent renal disease
4.Infections .
How would you manage this patient based on your available resources. For example, do we need a biopsy?, if yes, what are you looking for?
Invesigations:
-DSA
-Renal biopsy and C4d staining
-CNI trough
-urine analysis (ACR)
-Screening for CMV and BK
-CBC,CRP,ESR.
How would you treat it?
-Supportive treatment : rehydration,…
-Specific treatment according to the result of investigations and underline cause.
Lady with 2nd transplant, the previous failed due to non-adherence.
She is high risk patient for transplant due to previous sensitization by another graft, 4 mismatch with her brother, DSA so she needed ATG as induction but unfortunately only 2 doses given
What is missing in this scenario
=========================
The discharge medications
the time of deranged RFT post-transplant
history of adherence to the immunosuppressives in this time
Differential diagnosis
================
1- rejection (AMR or mixed)
2- TMA
3- infection
4- CNI toxicity
5- surgical complications like renal vasculature thrombosis or ureteric leakage
Plan of management
================
1- admission
2- Urgent KUB ultrasound (done)
3- send blood investigations (cbc, crp, CMV IgM, lft,, peripheral blood smear, coagulation profile , CNI drug level
Justification: r/o ongoing infection/sepsis, r/o drug toxicity or drug subtherapeutic level, check for markers of TMA, prepare for biopsy so need coagulation profile
4- send urine routine analysis and urine culture
5- chest x-ray (r/o chest infection)
6- start empirical methyl prednisolone with precautions of opportunistic infection and gastritis
7- prepare for urgent graft biopsy
8- accurate fluid chart and monitoring of renal function
9- treatment of the cause accordingly
US excluded gross surgical issues
This patient is a high risk patient as has 112 mismatch , preformed DSA with significant MFI level and incomplete ATG induction
Presented with AKI that may be caused by
1- Acute rejection : either ABMR ( preformed DSA) or TCMR ( incomplete ATG induction).
2- Prerenal causes of AKI : dehydration
3- Drug coplications As TMA secondary to CNI
4- Vascular causes : initial RI is starting to increase
5- Recurrent GN
6- Infection : CMV , BK ( suggested by fever and impaired graft function , but sepsis screen was negative)
Her parial response to pulse steroid suggest a form of acute rejection either ABMR , TCMR or mixed type
So we need to
1- Graft biopsy with C4d staining.
2- Augment hydrational status .
3- Follow up RI.
4- FK
5- PCR for CMV and BK
6- Augment IS level.
7- Monitoring DSA and graft function.