1. A 23-year-old lady, highly sensitised due to pregnancy and blood refusion. Her calculated reaction frequency/calculated panel reactive antibodies (cRF/cPRA) were 93% due to mainly anti class II antibodies, received a kidney from her sister with 222 mismatches.
Flow cytometry crossmatch (FCXM) was negative. ATG induction was discontinued after 2 doses due to possibility of infection (low grade fever but septic screen came back negative). Discharged with serum creatinine of 74 µmol/L. She came back to on the weekend with serum creatinine of 265 µmol/L and tender graft. US scan showed well-perfused swollen kidney. The biopsy showed:
- What is your diagnosis?
- Comment on the biopsy
- What is meant by cRF/cPRA?
- Any more tests required to confirm your diagnosis?
- What is your management plan?
- Would you offer her a better option rather than a direct transplantation?
-Based on immunological profile and induction therapy that was not completed and kidney biopsy this is Acute cell mediated rejection
– Biopsy showed lymphocytic infiltration of tubules and tubular is ,but no blood vessels or glomeruli to complete the BANF score
– cRF/cPRA is the precentage of donors expected to have HLA antigens that are unacceptable. The percentage of donors against whom the antibodies are tested are widely distributed across many range of population. Patients with cPRA >80% are avoided 4 more extra points in UNOS allocation system and give priority for them on deceased donor renal transplant program
– Here I will start methylene prednisone pulses and Thymoglobulin ,repeated biopsy
– Before transplantation pt should have desensitization with IVIG and plasmapheresis and the best option is to avoid desensitization (Paired donor exchange)
1- What is your diagnosis?
2- Comment on the biopsy
3- What is meant by cRF/cPRA ?
4- Any more tests required to confirm your diagnosis?
5- What is your management plan?
1-Patient has cute cellular rejection.
2- The biopsy ( light microscopy)showed lymphocytic interstitial infiltration and tubulitis .
3-What is meant by cRF/cPRA. Percentage of unaccepted Ags among large pool of donors in 10,000identical blood group donors in certain country.
4- Any more tests required to confirm your diagnosis?
Serum DSA level, biopsy C4d staining, IS trough level and Virology screening.
5-Pulse methyl prednisolone plus/minus ATG . Presence of AMR patient need IVIG + plasma exchange +Rituximab , DSA level monitoring.
6- The HLA match is 222 ,she is already sensitized , better to proceed for paired exchange .
REFERENCES:
Cecka J.M. Calculated PRA (CPRA): The New Measure of Sensitization for Transplant Candidates.American Journal of Transplantation 2010; 10: 26–29.
* What is your diagnosis?
ACR but it is inadequate biopsy.
* Comment on biopsy?
Tubulitis , interstitial infiltration with lymphocytes.
* What is meant by CRF/CPRA?
Antibodies screening test to exclude unacceptable antigens.
It uses standard pool of 10000 donor lymphocytes.
Any more tests required to confirm your diagnosis?
-DSA SAB .
– trough level of CNI.
– virology.
* What is your management plan?
– pulse steroid therapy + ATG
– modification of immunosuppression.
– ATG given with close monitoring if ABMR occurs
Plasmapheresis + IVIG + Rituiximab.
Would you offer better option than a direct transplantation?
Patient FCXM negative we can do with no desensitisation protocol.
Acute Rejection
Biopsy shows tubules and interstitium with no glomeruli or vessels, there is evidence of mononeuclear infiltration within interstium ad tubules , which may signify acute cellular rejection most probably yet keep in mind the possibility of viral infection
PRA is testing of patient serum against a sample donor pool representative of the population, % PRA predicts positive cross matching and is indicative of the chance of getting a graft with negative cross matching. . cPRA, is a computerized calculation based on larger numbers of donors (10000
in UK, 12000 in US between 2003-2005), which is more representative of the actual potential organ donor population
1) Serum DSA level
2) C4d staining for biopsy
3) Immune suppression medication trough level
4) Virology screening, IgG ,IgM ( EBV, BK, CMV)
If virology profile came negative , no evidence of DSA or C4D consider Acute cellular rejection TTT would be:
Pulse eteroids, ATG
Paired exchange
Acute Cell mediated graft rejection
Tubulointerstetial infiltration by lymphocytes.
Calculated PRA test determines the percentage of unacceptable donor relying upon HLA antigen for specific patient.
1- DSA titre
2- C4d staining
3- immunosupressive drug levels
4- Basal metabolic Panel
1- 1 gm solumedrol daily for 3 days, then oral steroid.
2- resume ATG induction
3- regular DSA titre and immunosupressive monitoring.
Paired renal exchange if feasible.
This patients has acute rejection (ATCMR or may be mixed rejection). As shown in this biopsy tubulitis and lymphocyte infiltration are seen which meet the criteria of acute T cell mediated rejection. But there is no glomerule or vessel in this sample so antibody mediated rejection can’t be rule out completely. So another biopsy sample is required. CPRA is a computer based calculation based on unacceptable antigens in sensitized patients which defines that how many percent of probable donors won’t be suitable for transplantation. Performing another kidney biopsy, C4d staining and investigation for DSA are required to rule out a mixed type rejection. Corticosteroid pulse for 3-5 days are necessary and if suitable response isn’t seen ATG may be considered.
In terms of presence of AMR (confirmed by DSA or C4d positivity) plasmapheresis, IV Ig and rituximab may be indicated. This lady is sensitized, so instead of transplanting a fully mismatched kidney, another options such as paired kidney donor TX or at least desensitization should be considered.
What is your diagnosis?
The patient had history of highly sensitised with cPRA 93% towards class 2 and highly mismatched kidneys with history of swollen graft kidney, I would like to think of acute allograft rejection as my primary duagbisis, TCMR or AMBR.
Comment on the biopsy
The HPE showed cellular infiltrations in tubules but no glomerulus and vessels
What is meant by cRF/cPRA?
cPRA is calculated by determining the frequency of incompatible donor HLA phenotypes based on the unacceptable class 1 and class 2 HLA antigens. It reflects the thru probability of an incompatible donor based on the unacceptable antigen that listed for a patient
Any more tests required to confirm your diagnosis?
I would ask for re-biopsy of allograft kidney with serum DSA level
Would request for C4d staining
Trough level of immunosuppression medication
Screening for CMV , BK virus
What is your management plan?
It depends on the biopsy findings for ABMR or TCMR
In ABMR, Plasma exchange ×5 followed by IVIG 100-200 mg/kg after every session
Rituximab 375mg /m2 following last session
Imilfidase or IvIG endopeptidase or Eculizumab may have role in resistant ABMR
if TCMR,Pulse methylprednisolone 500 mg for 3-5 days then oral prednisolone 60 mg tapering to maintenance dose and keep her on triple immunosuppression.
In both, adjust the dose of immunosuppression tacrolimus level trough between 8-10mg/dl and MMF at a dose of 2 gm /day
Would you offer her a better option rather than a direct transplantation?
Paired kidney exchange would be better choice for highly sensitized patients.
1.What is your diagnosis?
●Acute cellular rejection .
2.Comment on the biopsy?
●Lm shows increase cellularity and lymphocytes .
4Any more tests required to confirm your diagnosis?
●DSA level by Luminex-SAB , cd4 stain on biopsy.
5What is your management plan?
●Pulse steroid fir 3_5 days
Continue induction with ATG .
If cd4 +and start plasma pheresis +ivig .
●Would you offer her a better option rather than a direct transplantation?
paired donor exchange
acute rejection mostly cellular as the biopsy showing tubulitis, patient is highly sensitized with 6 mismatches and didn’t complete her induction therapy
tubular cut section with multiple lymphocytes in the tubule, no glomeruli and no arteries
It determines the probability of having incompatible donor based on unacceptable antigens that is listed for the patient
cPRA 93% means that 93% of deceased kidney donors will have unacceptable antigen and will not be offered to this patient
DSA by single antigen assay to exclude AMR
C4d stain of biopsy
CNI drug level,
Pulse steroids for 3-5 days
continue thymoglobulin induction as septic screen is negative, with diphenhydramine and acetaminophen before ATG to avoid adverse reaction during drug administration
If DSA is positive and C4d positive, the patient should receive plasmapheresis with IVIG
paired donor exchange would be a better option to find a donor with a better match
Handbook of Kidney Transplantation. GM Danovitch (Editor) Wolters Kluwar, 2017, 606 pp. ISBN: 9781496326157.
The swollen US kidneys draw attention to acute/hyperacute here acute (as she was discharged). her discharge cr 76 mmol (0.8 mg/dl). I guess this is a 7-10 days event including the first admission to the next admission. swollen tubules and tubulitis are present but we need evidence of capillaritis and cd4 staining. anyhow, we guess this is an expected scenario of antibody-mediated reaction because of inadequate immune supression which was due to incomplete depletion of probable preformed DSAs. we need to check SAB assays. readmission with 265 mmol/L (3 mg/dl) kreatinin entails high dose steroid plus rituximab or IVIG and maybe plasmapheresis (after making sure about antibody reaction)
Acute cell-mediated rejection is a possible diagnosis, tubulo-interstitial type (type1B). there is infiltration of lymphocytes in the tubulointerstitial region with tubulitis.
cPRA is calculated by determining the frequency of incompatible donor HLA phenotypes based on unacceptable class I and class II antigens that have been listed for each candidate. The cPRA reflects the true probability of incompatible donor based on unaccepted antigens.
In other words, the level of sensitization (called reaction frequency [RF]) for a patient is calculated by finding the percentage of blood group identical, HLA-incompatible donors in the donor pool, for example if the patient’s serum reacts with 50% of a panel of sera that is representative of the donor pool, then half of donors would be expected to give a positive cross-match and be unacceptable.
This biopsy sample includes only tubules, better biopsy samples with arterioles and glomeruli, and IF and EM evaluation for detection of probable mixed rejection (for example, presence of C4d deposition) may be helpful.
Evaluation for DSA by Luminex-SAB may be helpful to assess simultaneous antibody mediated rejection, because the patient is highly sensitized and flow cytometry crossmatch is not as precise and sensitive as Luminex-SAB assay.
If only CMR is our diagnosis, the treatment will be methylprednisolone pulse in combination with thymoglobulin. But if mixed rejection is our diagnosis, treatment with plasmapheresis, IVIG and ultimately rituximab should be considered.
What is your diagnosis?
AKI most likely due to rejection.
Comment on the biopsy?
LM stained with mixed Silver, Hematoxylin & Eosin . It shows tubulitis and inflammatory interstitial infiltration suggesting acute active TCMR. No visible glomeruli or blood vessels so we cannot rule out AMR
What is meant by cRF/cPRA?
calculated reaction frequency (cRF)or calculated panel reactive antibodies (cPRA), reveal the extent of HLA sensitization as it relates to deceased donor HLA haplotype frequencies
Annette M. Jackson, Miriam Manook,Tracking HLA Antibody Changes among Kidney Waitlist Candidates: One Protocol May Not Fit All ,JASN Nov 2019, 30 (11) 2042-2044; DOI: 10.1681/ASN.2019090946
Any more tests required to confirm your diagnosis?
What is your management plan?
Would you offer her a better option rather than a direct transplantation?
Paired exchange program
The diagnosis is acute cellular rejection of highly sensitized female with 222 mismatch and high PRA level, graft biopsy shows tubules and interstitium with lymphocytic infiltration with no glomeruli, repeating biopsy is important to exclude antibody mediated rejection ABMR by C4D staining and she needs to monitor DSA .
Intensive management by 3 doses methylprednisolone and ATG 1.5 to 2.5 mg / kg with good antibiotic and antiviral coverage ,if ABMR is proved PLEX and IVIG and rituximab needed .
Better option for her is pre transplant desensitization protocol and keeping her on triple immunosuppressants, regarding her donor better to find another donor.
Given the history of a highly sensitized young lady , with 222 mismatches & cPRA93%, the diagnosis was most probably acute cellular rejection, with or without acute antibody-mediated rejection.
The kidney biopsy did not give a whole picture, although, there was lymphocytes infiltration to interstitial & tubules indicating tubulitis which was strong evidence of ACR diagnosis, we need re-biopsy & comments on glomeruli, blood vessels, C4d & serum DSA.
cPRA is the computer system calculating the percentage of donors expected to have unacceptable HLA antigens to the recipient.
The management plan will be as the followings :
Pulse steroid, Intensify the immunosuppressive meds ,in the same time, repeat kidney biopsy to confirm the diagnosis & ask for DSA , SAB & prograf level . if no response start ATG doses with infectious prophylaxis. it seems to be the results of investigations requested before including kidney biopsy came back & confirm the diagnosis.
If approved AMR , need plasma exchange, rituximab & IVIG.
The better options for this lady are , paired exchange, search for another donor excluding siblings & finally desensitization depending on DSA,SAB & MFI.
What is your diagnosis?
Inadequate biopsy but compatible with ACR
Comment on the biopsy?
The biopsy shows no glomeruli,tubulitis t3, interstitial infiltrations i3 and no blood vessels.
What is meant by cRF/cPRA?
It’s antibodies screening test in which patient’s serum is tested with standard pool of 10000 donors’ lymphocytes.
Results percentage is taking in account both class 1 and 2 reactivity together.
Strongly correlated to real practice and actual possible donors after excluding unaccepted antigens.
Any more tests required to confirm your diagnosis?
Even before results of this biopsy pulse steroids should be started at once and ATG also can be initiated and Dsa single antigen bead should be sent.
Steroids responders and negative DSA could be enough to diagnosis (risks and benefits assessment).
If still no response still invasive kidney biopsy unreplaceable and there’s no serological test can replace it but
1)DSA single antigen bead will be needed
2) virology screen cmv pcr quantitative
3)CNI trough level
What is your management plan?
1)Steroids pulse 3-5mg/kg for 5-7 days
2) intensifying her current immune suppression medications..full dose MMF and tac level around 7-10
3)ATG 5-7mg/kg divided dose with close monitoring of her vital signs and CBC
4)plus/minus plasma exchange and rutiximab if there’s evidence of ABMR
Would you offer her a better option rather than a direct transplantation?
Direct transplant without desensitization is accepted option as her flowcytometry cross match is negative but we can offer her paired donation option for better matching if possible
Repeat renal biopsy we need to see blood vessels glomeruli to exclude AMR C4d stain . DSA Level
-Diagnosis:
Tubulitis with inflammatory cells infiltration -TCMR .
-Biopsy :
LM with tubulitis , Banff score can’t be applied for grading the TCM , the presence of vascular rejection or AMR can’t be ruled out.
CPRA is used to assess sensitization level of the recipients , which means she is sensitized to 93% of the donors , so her chances are relatively low .
-Further tests:
Trough FK level, inflammatory markers , DSA’s by luminex – virtual cross match , C1q , C4d on the biopsy , Duplex and US full report including the RI of the graft .
– Management plan:
-If it’s only TCMR then Methylprednisolone for 3-5 days , ATG 1-1.5mg / kg with close monitoring by CBC , vitals , pre – during and post markers of infections if suspected any .
-If mixed type of rejection with AMR then we have to start with plasma-exchange 4-8 sessions with IVIG 2gm/kg total dose followed by rituximab 375mg /m2 , week after and two doses with CMV prophylaxis .
Consider re-biopsy if no response or if insufficient previous one.
-With negative FXCM and highly sensitized recipient , Solid phase assays should be used for better assessment .
My diagnosis: Acute rejection
The biopsy: There are no glomeruli in the biopsy specimen. However there are inflammatory cells in the tubules and interstitium, a lot of them.This is indicating of a tubulitis.This may be a T-cell mediated tubulointersttial rejection.
cPRA is an estimate of the percentage of donors in the pool of donors to whom the recipient is incompatible to. The higher the cPRA, the less likely the recipient will be able to get a donor from the donor pool.
*The diagnosis is:
Acute T cell mediated rejection, we can’t exclude Acute Antibody mediated rejection because inadequacy of renal biopsy which should include section for the glomeruli ,arteries and peri tubular capillaries staining for C4d
*Comment on the biopsy
-interstitial infiltration by lymphocyte .
-tubulitis
*What is meant by cRF/cPRA?
The calculated CPRA
is based upon unacceptable HLA antigens to which the patient has been sensitized and which, if present in a donor, would represent an unacceptable risk for the candidate or the transplant program.
The terms “calculated HLA antibody reaction frequency” (cRF) and “calculated panel reactive antibod- ies” (cPRA) are used synonymously to describe the level of allosensitization, where 0% cRF is nonsensitized, 50% cRF is antibody incompatible with half of a random donor pool, and 90% cRF would be antibody incompatible with 9 out of 10 random donors.
*Any more tests required to confirm your diagnosis?
Patient have FCXM negative but CPRA of 93% so we need to check for presence of DSA by more sensitive method using luminex assay
Another biopsy sample to show glomeruli and peri capillary C4d staining
*What is your management plan?
In patients with biopsy-proven Banff gradeIA or IB TCMR (with no evidence of ABR).. We administer pulse IV methylprednisolone daily dose of 500 mg for 3-4 days
After a glucocorticoid pulse, oral glucocorticoids are tapered immediately to the maintenance dose of oral prednisonethe patient had been taking prior to the episode.
In patients with Banff grade IB TCMR and few or no chronic histologic lesions who present less than one year posttransplant, we give rATG-Thymoglobulin in addition to pulse glucocorticoids at 1.5 to 3 mg/kg per dose over one to three days for a total dose of 3 to 6 mg/kg in the first year. In such patients, methylprednisolone is administered 500 mg prior to each dose of rATG-Thymoglobulin.
In patients who are diagnosed with active ABMR within the first year posttransplant, we treat with a combination of glucocorticoids, plasmapheresis ,intravenous (IV) immune globulin (IVIG), and rituximab
*Would you offer her a better option rather than a direct transplantation?
1-paired donation.
2-Wait for suitable donor.
J. M. Cecka. Calculated PRA (CPRA): The New Measure of Sensitization for Transplant Candidates.
American Journal of Transplantation 2010; 10: 26–29
Up to date 2021
Dear All
Thank you for your excellent contribution. You noticed that this biopsy is inadequate and there is tubulitis.
Those who recommended re biopsy, what do you need to know more?
This biopsy is inadequate, well done, but showed strong evidence of ACR. WHAT INFORMATION YOU NEED TO KNOW MORE??????
1- This is a high risk pt due to highly sensitization level, high degree mismatch and incomplete induction therapy, presented with rapid rising S Cr and tender graft .The most probable diagnosis is acute rejection either AMR or CMR
2- This section of the biopsy show no glomeruli so considered Insufficient. There is heavy infiltration of interstial tissue with inflammatory cells, tubules are odematous , Mostly acute cellular rejection.
3- To confirm diagnosis of rejection
1-consider rebiopsy for more adequate one
For AMR
2- C4D staining
3- DSA detection by luminex
4- Management plan
a- Hospital admition
b- Assess (volume status, UOP)
c- Doplux on graft vessels
d- FK level
e- CMV PCR
f- Treatment of rejection according to its type
1-AMR :
PE for 5 session followed by IVIG 2 gm /kg then rituximab 375 mg /m2
2-TCMR
Pulse methylprednisiline 500 mg for 3-5 days followed by oral prednisone 1 mg /kg /day
5- Other options
1- paired kidney donations if available, with better matching
2- desensitization before transplantation with PE , IVIG and rituximab .
What is your diagnosis?
This lady is highly sensitized by 2 different events receiving kidney with 222 mismatch ;
No comment on her DSA level by SAB befor transplantation
She didn’t receive full dose of ATG.
her s creatinine increased in the first weak posttransplantation mosty acute rejection either TCMR, ABMR.
•Comment on the biopsy
Biopsy showed cellular infiltration of both tubules and interstitium by inflammatory lymphocytes
no glomeruli or arteries were seen so inadequate biopsy
•What is meant by cRF/cPRA?
The cPRA estimates the percentage of donors with whom a particular recipient would be incompatible.
CPRA is a tool for characterizing and monitoring sensitization. Unlike PRA, the CPRA provides a meaningful estimate of transplantability for most patients, because it is calculated from unacceptable HLA antigens that will preclude offers from predictably crossmatch incompatible donors.
Any more tests required confirming your diagnosis?
First we have to rule out non immunological causes ;
Trough level of immunosuppression medication
Screening for CMV , BK virus
Hemodynamics
Next step;
Detect DSA level.
Rebiopsy as its gold standard for diagnosis of acute rejection.
What is your management plan?
It’s acase of acute rejection based on biopsy results
It is either acute TCMR or AMR
MANAGEMENT if AMR BY
Plasma exchange ×5 followed by IVIG 100-200 mg/kg after every session
Rituximab 375mg /m2 following last session.
If TCMR according to Banff classification
1Pulse methylprednisolone 500 mg for 3-5 days then oral prednisolone 6o mg tapering to maintenance dose and keep her on triple immunosuppression.
Adjust the dose of immunosuppression tacrolimus level trough between 7-10mg/dl.
And MMF at a dose of1 gm /12H
alemtuzumab may be used as she didn’t tolerate ATG .
Would you offer her a better option rather than direct transplantation?
No data was provided about DSA before transplantation i will ask for Luminex to detect DSA and if the patient had DSA i will do desensitization befor transplantation
And i will prefer to find other donor with better match .
Well done
two terms which surely you would have mentoined :C4d,paired exchange.
Yes i missed it
Thank you Dr Dawlat
•What is your diagnosis?
This lady is highly sensitized by 2 different events receiving kidney with 222 mismatch ;
She didn’t receive full dose of ATG.
her s creatinine increased in the first weak posttransplantation mosty acute rejection either TCMR, ABMR.
•Comment on the biopsy
Biopsy showed cellular infiltration of both tubules and interstitium by inflammatory lymphocytes
no glomeruli or arteries were seen so inadequate biopsy
•What is meant by cRF/cPRA?
Any more tests required confirming your diagnosis?
Trough level of immunosuppression medication
DSA level
Screening for CMV , BK virus
What is your management plan?
It’s acase of acute rejection most probably ATCR
MANAGEMENT WITH
1Pulse methylprednisolone 500 mg for 3-5 days then oral prednisolone 6o mg tapering to maintenance dose and keep her on triple immunosuppression.
Adjust the dose of immunosuppression tacrolimus level trough between 7-10mg/dl.
And MMF at a dose of1 gm /12H
alemtuzumab may be used as she didn’t tolerate ATG .
If acute ABMR is diagnosed start 6 sessions of plasmapheresis followed by 100 mg/kg IVIG, after the last session give 500 mg/kg once to complete total cumulative dose of 1gm/kg of IVIG1 week after plasmapheresis, IVIG give Rituximab only if there is biopsy-proven ABMR with evidence of active microvascular inflammationAntiviral and Pneumocystis pneumonia (PCP) prophylaxis for 3 monthsOptimize volume state and stop ARBS if given
Would you offer her a better option rather than direct transplantation?
Yes … if we do Luminex SAB and if DSA detected desensitization offer an option before transplanting this high-risk patient.
Am sorry i was copying my comment to editit i copied another one instead of shereen my comment is the first one i tried to remove the scond comment but i couldn’t
1&2- This highly sensitized lady has an Acute Rejection. There is heavy lymphocytic cell infiltrates, involving interstitium & tubules (tubulitis).
3- PRA is a complement-fixating assay to test the ability of the recipient’s serum to lyse a panel of T-cells from a group of potential donors. For a PRA of 20%–80%, there is a 50% chance to be transplanted compared to non-sensitized patients while the chance is only 5% for PRA greater than 80%. PRA detects only anti-HLA I antibodies and does not reflect all donors. A positive T-cell cross-match has a high risk for hyper-acute rejection and is considered an absolute contraindication to kidney transplantation. A positive B-cell cross-match indicates the presence of anti-HLA I and/or II antibodies. The presence of anti-HLA II alloantibodies is associated with a high risk of hyper-acute rejection.
4- DSA monitoring and therapeutic drug levels (CNI level).
5- I will pulse her with methylprednisolone and monitor kidney function and urine output. Also to consider maximizing immunosuppressants, e.g change to tacrolimus from CSA. Add steroids if not on. Might need plasma exchange and IV IG if confirmed AMR
6- A paired kidney exchange might be a good alternative in her case.
Please revise and rewrite cPRA
IF you exclude AMR and she does not respond to the steroid pulses would you resume her ATG course with good premedications.
1- Diagnosis:
Acute Rejection Properly T cell-mediated rejection
2- Biopsy comment
There is lymphocyte infiltration involved the tubules (tubulitis) and interstitium
No glomeruli were seen in the biopsy and no artery was seen
The sample is inadequate in my opinion.
3- What is meant by c RF/ c PRA
cPRA is a standardized way to define the probability that a recipient will have DSAs by comparing the antibody specificities (detected on the solid-phase assay) to the defined frequency of HLA alleles in a certain population.
4- Any more tests required to confirm your diagnosis?
· Repeat biopsy
· Stain biopsy for C4d
· DSAs monitor
5- What is your management plan?
· Hospital admission and other non-specific therapy (Bp/ fluid)
· If the patient om cyclosporine change to Tacrolimus
· IV methylprednisolone
· If not improved on steroid add ATG or alemtuzumab
· CNI tough level
· Viral screen (CMV/ BK)
· plasmapheresis/ rituximab if AMR
6- Would you offer her a better option rather than direct transplantation?
7- The patient is highly sensitized better to advise her to wait for a deceased donor or discuss with her paired donation
welldone
diagnosis is AKI most probably due to acute rejection which may be cellular or antibody mediated in highly sensitized patient with 000 HLA match
the biopsy showed renal tubules with edematous cells and prominent nuclei and interstitial cellular infiltrates , no glomerulus seen so considered inadequate.
cRF/ cPRA is the percent of unaccepted antigens among large pool of donors in certain region or country.
management plan:
1- hospital admission, monitor blood pressure, fluid status and urine output.
2-repeat biopsy by another radiologist.
3- decrease dose of CNI according to serum creatinine and UOP.
4- give ATG for coverage and treat possible acute cellular rejection.
5- repeat cross match if positive will go for plasmapharesis and IVIg
6-if still negative cross match , wait for the result of biopsy and of course will request confirmation of the presence of antibody mediated rejection.
7- the patient may improve with ATG and before the appearance of the result of biopsy, this will exclude antibody mediated rejection.
8- signs of improvement is increased urine output and decrease serum creatinine.
will offer her paired donor transplantation
Dr Riham, I do not agree with going to give ATG for coverage. Would you not pulse the patient if you suspect ACR. Please provide evidence is favour of your statement for repeat cross match. What is the role of DSA’s?
Highly sensitized patient, receiving HLA incompatible graft , incomplete induction therapy , came with AKI with no surgical complications,
She most probably is having acute rejection , which might be cellular or antibody mediated acute rejection
Biopsy contains no glomeruli so considered in adequet
Calculated PRA is the percentage of unacceptable donor antigens , it is prepared from larger pool of actual donors in the community .
I would measure circulating DSAs , post transplant cross match may also help .
I would ask for re biopsy
Tacrolimus trough level
Cmv pcr
I would start with pulse methylprednisolon , followed by ATG ,
I would start plasma pharesis with IVIG if there is evidence of AMR
In retransplantation , I would screen her for DSAs using luminex SAB , and offer her a desensitization protocol before transplant.
Dr Wessam , your answer is incomplete. What else would you like to be sent in biopsy ( clue complement degradation product), please comment on role of DSA’s. I would say that the biopsy image is classical and not entirely inadequate. What are your views about paired exchange?
I do agree that we need more pictures to assess arteries and glomeruli and your your statement for inadequate biopsy is correct
Thank you to those who put Paired Kidney Donation as a first alternative option? Please justify your decision for this particular patient.
What is your diagnosis?
Comment on the biopsy
What is meant by cRF/cPRA?
Any more tests required confirming your diagnosis?
What is your management plan?
Would you offer her a better option rather than direct transplantation?
Yes … if we do Luminex SAB and if DSA detected desensitization offer an option before transplanting this high-risk patient.
Very nicely framed answer . What are views about paired donation? Secondly patient did not tolerate ATG as induction due to slight fever. Would you consider another agent if patient is ATG intolerant for management of rejection.
What is your diagnosis?
Based on the given findings in this biopsy which i considered inadequate as no glomeruli or arteries are shown (adequate biopsy sample contain at least 10 glomeruli and 2 blood vessels), I put the diagnosis of acute T cell mediated rejection.
Comment on the biopsy
Biopsy sample stained with H&E staining method showing tubules and interstitium, no glomeruli or arteries seen, there is interstitial inflammation and oedema and tubulitis.
What is meant by cRF/cPRA?
Unacceptable HLA antigens to which the patient has been sensitized and which if present in the donor would represent an unacceptable risk for the candidate. It is computed from HLA antigens from a large number of donors.
Any more tests required to confirm your diagnosis?
What is your management plan?
At time bening, I’ll give pulse MP 500mg for 3-5 days and watch the response, if inadequate response and I don’t have the results of new biopsy sample and DSA level, then I’ll give ATG 1.5 mg/kg, then and if there is evidence of ABMR then i’ll treat with plasmapheresis and IVIG with intensification of immunosuppressive medications.
Would you offer her a better option rather than a direct transplantation?
For this sensitized patient with high cPRA and high degree of mismatching, I prefer paired donation.
References:
welldone
The diagnosis is: Acute rejection – Acute T cell mediated rejection, with probable association of Acute Antibody mediated rejection (Not sure about AMR because of lack of information regarding DSA and inadequate biopsy)
The biopsy shown is an inadequate biopsy: As it shows only tubules and interstitium (no glomerulus and artery visible).
An adequate biopsy sample contains minimum 10 glomeruli with minimum 2 arteries.
The biopsy is a hematoxylin and eosin stained sample showing tubules and interstitium with inflammatory cells infiltrating both tubule (>10 cells in tubule: t3) and interstitium (>50% of interstitium: i3)
Banff Grade Ib (i3, t3)
cPRA (calculated PRA) is a refined version of PRA which involves cross-matching of the patient’s serum with a panel consisting of lymphocytes from a large pool of actual kidney donors representing the true picture vis a vis cross-match incompatibility. (1) The assessment for sensitization is more accurate with cPRA as it involves both class I and class II HLA specificities in the final calculation. The overall effect of cPRA is that there is a higher chance of getting a negative cross-match organ for the patient.
So if cPRA is 93%, it implies that 93% of the donors will have unacceptable antigen for the recipient
Tests required include:
1) Complete kidney biopsy picture, and if inadequate, a repeat biopsy
2) C4d stain of the kidney biopsy
3) Single Antigen Bead assay for DSA
4) CNI trough levels
Management includes tests and treatment:
Tests required include:
1) Complete kidney biopsy picture, and if inadequate, a repeat biopsy
2) C4d stain of the kidney biopsy
3) Single Antigen Bead assay for DSA
4) CNI trough levels
Treatment: (2)
1) Pulse IV methyl prednisolone: 500 mg/day x 3-5 days
2) Inj ATG: Induction therapy should be completed as the fever seen might be the febrile reaction to ATG, in view of a negative sepsis screen.
3) Adequate trough CNI level to be maintained by adjusting the dose of CNI
4) Prophylaxis for CMV (Valganciclovir), Pneumocystis (Cotrimoxazole) and antifungal prophylaxis.
5) If Antibody mediated rejection:
a) Plasmapheresis followed by low dose IVIG for 5 sessions (until serum creatinine comes to 20-30% of baseline)
b) Inj Rituximab 375mg/m2 after last plasmapheresis treatment (if microvascular inflammation present on biopsy)
This patient is a sensitized patient, who has been offered a 222 mismatch kidney. Considering her offer of a living kidney from her sister, it is important to counsel the family about all the pros and cons of transplanting this kidney versus other options including paired kidney transplant or waiting for a deceased donor kidney with a better match.
So, first option would be to try for a paired donation rather than going ahead with this donor.
The patient can wait for some time as cPRA is 93% and if an offer is made, it is associated with higher chances of acceptability.
If we have to go ahead with the same donor, pre-transplant single antigen bead assay should be done to find out the MFI of DSA and then desensitization should be done prior to transplant.
References:
1) Cecka JM. Calculated PRA (cPRA): The New Measure of Sensitization for Transplant Candidates. Am J Transplant 2010;10:26-29.
2) Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN 2020;15:430-438.
Great answer Amit. Just a few queries, please provide evidence for “Single Antigen Bead assay for DSA”. Can you have DSA negative but biopsy proven ABMR?
There was a mistake on my part: when FCXM is negative, no need of desensitization. Single antigen bead assay (Luminex) is done to assess the presence of different anti-HLA antibodies and its strength in the recipient.
A DSA negative and biopsy proven ABMR can be seen with non-HLA antibodies
What is your diagnosis?
Acute rejection TCMR and AMR cannot be rule out .
Comment on the biopsy
The biopsy is not sufficient to confirm a histological diagnosis (not contain glomeruli or artery ) .
Light microscopy showed tubulitis and diffuse interstitial infiltration by lymphocyte .
What is meant by cRF/cPRA?
The calculated panel-reactive antibody, which provides an estimate of the percentage of deceased organ donors that will be cross match incompatible for a candidate provides both consistency and accountability.
Any more tests required to confirm your diagnosis?
– Repeat the biopsy if possible + C4d .
– DSA
– CNI trough level
What is your management plan?
Type IA or IB acute cellular rejection (no evidence of vascular or antibody-mediated rejection) can be treated with Methylprednisolone 500mg IV daily for 3 doses . Consider ATG if steroid resistant cellular rejection .
Would you offer her a better option rather than a direct transplantation?
Paired exchange is the best option
Reference ;
Hand book of transplantation .Danovitch G ,6th edition .
Calculated PRA (CPRA): The new measure of sensitization for transplant candidates: Special feature December 2009American Journal of Transplantation 10(1):26-9
Good succinct answer but did not touch if rejection was ABMR. Please add the management if DSA’s are present and C4d is positive.
thanks prof
ABMR can be treated with plasma exchange+ IV Ig and rituximab
AKI for DD, Most likely acute TCMR, but AMR can not be excluded.
inadequate biopsy, severe interstitial infiltrate with lymphocytes and moderate\sever Tubulitis. one peritubular capillary appears normal.
repeat the biopsy should be considered.
send for DDcfDNA( If available), CNI Level, DSA, BKV, CMV PCR. and stain the biopsy with c4d stain and sv40. repeat blood culture and urine culture.
start pulse steroid for 3-5 days according to the response. if creatinine is still high, for ATG. If no response the patient most likely has underlying AMR(Plasma exchange+iv IG+- rituximab).
I think the best option for this patient is to be on the paired exchange. he can find a better match than his sister’s kidney with a better result. and this should be discussed with the patient before going for the transplantation.
I do not agree with your statement “If no response the patient most likely has underlying AMR(Plasma exchange+iv IG+- rituximab).’You ought to have objective evidence for ABMR.
What is your diagnosis?
From clinical scenario, highly sensitized patient, cPRA 93%, MMM 222, didn’t complete induction immunosuppression therapy, well perfused renal graft.
My first diagnosis is acute rejection until proved other wise
Comment on the biopsy?
Inadequate biopsy, there is no glomeruli, only multiple tubules with inflammatory cells invading the tubules and interstitium-àtubulitis and interstitial nephritis.
Looks to be acute cell mediated rejection, however antibody mediated rejection can’t be rule out from this inadequate sample
Needs Repeat biopsy.
Any more tests required to confirm your diagnosis?
Repeat Kidney biopsy stain for C4D, check DSA, check level CNI (if she was discharged on any)
What is your management plan?
IV pulse methyl prednisolone
Complete ATG course.
Intensify immunosuppression: CNI, MMF, steroids
Prophylaxis against CMV, PJP, and fungal.
Repeat kidney biopsy, DSA to rule out ABMR.
If ABMR—>the above management in addition to the following:
Plasma exchange (at least 5 Ssessions)+ IV IG followed by Rituximab.
Monitor DSAs.
Would you offer her a better option rather than a direct transplantation?
1- In a highly sensitized patient, high c-PRA 93%, living donor with 6 mismatches, I would have preferred to wait for a more matched donor via a paired exchange system.
2- Luminex SAB assay detects preformed HLA antibodies subclasses I, II and complement binding capacity would have helped in decision before transplantation.
3- Discussion regarding outcome of mismatched graft vs staying on the waiting list.
4- Desensitization protocol before transplantation could have been offered.
What is meant by cRF/cPRA?
cPRA is the percentage of donors expected to have HLA antigens that are unacceptable for a recipient.
In other words, it is a probability for the patient to give a positive cross-match against of a panel of donors.
A computer system will calculate the cPRA using the unacceptable HLA antigens.
Candidates with a CPRA value of 80% or higher (highly sensitized) will receive points in the kidney allocation system.
cPRA is value based on the presence of HLA-Antigens that are considered unacceptable for renal transplant as it carries high risk of rejection and inferior graft outcome.
References:
1- Handbook of Transplantation. Danovitch G. 6th edition, chapter 2, 6, 10.
Nicely answered. How do you think IVIG and plasmapheresis act.
Acute cellular mediated rejection
There is tubulitis with inflammatory cells infiltration in the interstitium (E and H stain)
The percentage of the people from general population carring that unacceptable Ag is the CPRA of that patient
CPRA provides a more accurate estimate of sensitization because it include both class l and class lol HLA specificities in the calculation which is a major shift from the traditional PRA where class l and class lol specificities are measured separately.
In traditional PRA, a high value mean a high probability of a positive crossmatch.
While in CPRA, a high value should mean a high probability of a negative crossmatch.
I need to confirm the presence of DSA
Repeat biopsy
Looking for C4D to exclude AMR
Managed by pulse steroid 3-5 doses
ATG
Intensifying immunosuppressant
I will chose to desensitized her
Paired exchange kidney donor
Looking for deNOVO DSA
Deseased donor offer
Please justify “While in CPRA, a high value should mean a high probability of a negative crossmatch.”
1- Mixed rejection acute cellular and antibody mediated rejection
2-Tubeulitis , lymphocytic infiltration and arteritis
3- cPRA is screening test for common antibodies sheared in the population
4- we need specification for this antibodies looking for DSA and C4d stain for the biopsy
5-pulse steroid +or – ATG then plasmapheresis if DSA
6- yes I would did PRA specifications before transplantion and if there’s DSA I will apply desensitization protocol
Please expand your answer. It is very brief and does not touch very essentials of the management
What is your diagnosis?
-It is T cell-mediated rejection.
Comment on biopsy?
-LM showed lymphocytes infiltration in the basement of tubules (Tubulitis) and interstitial edema with infiltration by lymphocytes.No glomeruli or blood vessels were detected in the biopsy. Inadequate biopsy ??
What is meant by cRF/cPRA ?
cPRA is defined as the percentage of blood group identical donors expected to have HLA antigens that are unacceptable for a recipient. It is a probability for the patient to give a positive cross-match. This is patient cPRA 93% that means 93% of donors would be expected to give positive cross-match and be unacceptable.
Any more tests required to confirm your diagnosis?
-This patient is highly sensitized and needs screening for DSA if it positive used SAB.
-If we can repeat renal biopsy is better to exclude AMR.
-C4d staining for biopsy.
-Immunosuppression level.
What is your management plan?
-IV pulse steroid 250-500mg/day for 3-5 days, there is a common good response of Banff class 1.
-rATG: if there is lymphocytic infiltration of vessels.
-If the repeated biopsy showed AMR add plasmapheresis, IVIG, Rituximab.
-Optimized immunosuppressive drugs level.
-Monitoring of DSA.
Would you offer her a better option rather than direct transplantation?
1. Trial of paired donor exchange: if failed↓↓
2. Desensitization : if fail ↓↓
3. wait in the deceased donor list.
References
1.James E. Cooper.Evaluation and Treatment of Acute Rejection in Kidney Allografts. CJASN March 2020, 15 (3) 430-438.
2.Douglas S. Keith and Gayle M. Vranic .Approach to the Highly Sensitized Kidney Transplant Candidate. CJASN April 2016, 11 (4) 684-693.
This patient was transplanted and this means that there was a negative crossmatch. Would you still opt for desensitisation?
-Diagnosis ;To be able to evaluate the renal biopsy at least needs the presence of seven glomeruli with one artery as it will be marginal, and ≥ 10 glomeruli with at least two arteries is considered .At least seven slides, three stained with hematoxylin and eosin (H&E), three stained with PAS, and one stained with trichrome stain should be evaluated.(1)
But it is mostly acute active TCMR rejection as it is charectarised by tubulitis
-Biopsy; Hematoxylin and eosin stain showing tubulitis and inflammatory cell infiltration of the interstitium
Banff classification
Category 3 Suspicious (borderline) for acute T cell-mediated rejection
Type IB Severe tubulitis and moderate interstitial inflammation t3i3 (1)
– cPAR is the percentage of donors expected to have unacceptable antigens indicated on the waiting list .
Unacceptable antigens are defined by laboratory detection of HLA-specific antibodies for the different racial groups in proportion to their representations in the national deceased-donor population using a solid-phase immunoassay .(2)
-Further tests to confirm the diagnosis
As the biopsy is inadequate rebiopsy is needed
C4d staining to exclude antibody mediated rejection although it is not a must
De novo DSA level
– Management
Since septic screen came back negative so ATG induction can be continued
Possibly Banff 1b so
Intravenous steroids solumedrol 500 mg 3×5 days
and rTAG 1.5 mg/kd 3×5 days since septic screening is negative as this therapy remain the standard therapy for T cell–mediated rejection
-better options
Desensitisation by plasma pharesis,IVIG , Rituximab
Paired exchange program can be offered
Reference
1-Jeong H J. Diagnosis of renal transplant rejection: Banff classification and beyond. Kidney Res Clin Pract. 2020 Mar 31; 39(1): 17–31.
2- Bertram L. Kasiske, Jeffrey J. Connaire, Selection of Prospective Kidney Transplant Recipients .Primer on Kidney Diseases (Fifth Edition), 2009
Negative FCXM with positeve sab means that it is a low titre of antibodies so you will need a better confirming histopathology however aTCMR with anti class 2 is bad combination.
Diagnosis:
Acute cellular rejection.
Biopsy show:
T3 I2.
Interstitial lymphocytic infiltrate, foci of severe tubulitis.
Tubulitis with more than 10cell in tubules and i3 as >50% involve of parenchyma, so
Grade IB.
CPRA:
Calculated panel reactive antibody (CPRA) values are based on the HLA antigens that
are listed as unacceptable for renal transplant candidates.
The unacceptable HLA antigens can be identified by the presence of HLA antibodies in
the sera of transplant recipients.
Any more tests required to confirm your diagnosis?
Drug level.
What is your management plan?
· Pulse steroid therapy for grade I acute T cell mediated rejection (TCMR) .
· Anti-T cell agents for grade II acute TCMR
· Grade III acute TCMR is resistant to therapy.
· Newer immunosuppressive agents with more potent activity are emerging.
Would you offer her a better option rather than a direct transplantation?
Wait for suitable donor.
Paired exchange donation.
Desensitization:PLEX,IVIG,RITX.
What if your prescribed anti TCMR fails would you not add rATG with tight precautions
-Diagnosis: From the histopathological picture of only tubules it is most probably TCMR with diffuse lymphocyte infiltration. But as per guidelines sufficient renal biopsy sample has to contain 8-10 glomeruli with one or two arteries to get the proper diagnosis.
-Comment on the biopsy: Renal tubules with H&E stain, high power revealed moderate to severe tubulitis with diffuse interstitial inflammatory cells infiltration(lymphocytes and mononuclear cells) (i2-i3 and t2-t3).
-What is meant by cRF/cPRA?
CPRA or the Calculated Panel Reactive Antibodies. The system will calculate the CPRA using the unacceptable HLA antigens. Candidates with a CPRA value of 80% or higher (highly sensitized) will receive points in the kidney allocation system.
-Any more tests required to confirm your diagnosis?
-A patient with high cPRA mainly against Class II HLA antigens,6 HLA mismatch with negative FCXM (means no DSAs):
*For Luminex SBA to detect low levels of DSA
*Sufficient renal biopsy sample examined with LM, Immunofluorescence and immunohistochemistry to detect presence of C4d and EM. The aim to rule out vascular rejection or mixed TCMR and ABMR.
–What is your management plan?
We have a case of possible acute TCMR in highly sensitized patient according to histopathological picture it is Banff class IA or IB for pulse Methylprednisolone 500-1000 mg for 3-5 days according to severity. If we consider it Banff class IB ATG has to be added 1-1.5 mg /Kg
–Would you offer her a better option rather than a direct transplantation?
*Paired exchange
*Full Desensitization protocol
Welldone for mentioning added points to patients with high cPRA in an attempt to reduce their waiting time.
-Whats your diagnosis?
Sever tubulitis with dense inflammatory cells infilteration (TCMR ).
–Commmnet of the biopsy :
LM with silver stain shows dense inflammation with tubulitis , need better image to look for possible vascular injury with vascular rejection , PTC , glomerular lesions , with this picture I could only appreciate the finding of sever tubuliltis , means TCMR and i cant apply banff score for grading the TCM also can not role out the presence of vascular rejection or antibody mediated rejection (AMR) .
-What is meant by cRF/cPRA?
CPRA is based on unacceptable HLA antiges ,to assess sensitization level of the recipients ,so this patient with 93%CPRA , which mean she is would be highly sensitized to 93% of the donor , so her chance to get matched donor will be low .
-Any more tests required to confirm your diagnosis?
-she had FCXM negative with CPRA of 93% i would ask for fruther testing by more senstive SAB with more charachterization of the performed DSAs class and intesity by SAB assay(3).
-bertter review of the current graft biopsy and if inadequate wil ask for repeat one
-full septic screen
-CNI Trough level
– if im in centre with available C1-q assay , C4D staining will give me more informations and help in managemnt and prognosis of this graft however complement independent AMR possible in her case .
-What is your management plan?
Acute rejection in sensitized patient with preformed anti-HLA class 2 DSA despite negative FCXM its serious and high risk for early and late poor garft survival and outcome
the management will depend on final diagnosis if its only pure TCMR then PMP for 3-5 days if no response and full infection screen negative will give ATG 1-1.5MG / KG with close monitoring by FBC, lymphocytes percentage, if C3 monitoring available will be best to adjust the doses with lower cost and side effects
if mixed type of rejection with AMR then we have to start with plasma pheresis minimum 5 sessions with IVIG 2gm/kg total dose followed by rituximab 375mg /m2 ,week after for one or two doses , with CMV prophylaxis , PJP prophylaxis and antifungal cover
if no response we have to repeat the graft biopsy and treat accordingly, monitoring for DSAs BY SAB assay as she is high risk for future Dn DSA , so need frequent monitoring every 3 months , consider reepat biopsy at any piont she had graft dysfunction or protienuria with high DSAs level
-Would you offer her a better option rather than a direct transplantation?
-she is young sensitized recipient with high CPRA , could wait for better match or paired exchange donation program woukd be better option
-with negative FXCM and highly sensitized recpient better to go for Luminex SAB assay which can fruther characterize the preformed HLA antibodies subclasses , class1, 11 and complement binding capacity .as this will help in decison making prior to transplantion .
References :
-Calculated PRA (CPRA): The New Measure of Sensitization for Transplant Candidates,American Journal of Transplantation 2010; 10: 26–29.
-Donor-Specific Antibodies in Kidney Transplant Recipients ,Rubin Zhang,lin J Am Soc Nephrol 13: 182–192, January, 2018
-UP to date medicine ,kidney trasplant in adults: overviewof HLA sensitization and crossmatch testing.
Welldone also for mentioning the seriuos coexistance of DSA anticlass2 and TCMR
Diagnosis:
ACUTE TCMR WITH POSSIBLE ABMR.
BIOPSY FINDINGS:
What is meant by cRF/cPRA?
cPRA is value based on the presence of HLA-Antigens that are considered unacceptable for renal transplant as it carries high risk of rejection and inferior graft outcome. In this case 93% cPRA means that 93% of Donor HLA antigens having an antibodies in the recipient serum which carry high risk of rejection unless further testing minimizes it’s impact on transplantation process.
Any more tests required to confirm your diagnosis?
What is your management plan?
Aiming at management of acute TCMR:
Aiming at management of possible acute ABMR: according to KDIGO GLs
Provided that she received 2 doses ; I will continue on ATG for a total of 4 doses as septic screen proved negative. (Dose: 1.5mg/kg in 250mls 0.9% NaCl to run over a minimum of 6 hours for 4 days (Day 0,1,2,3) for a cumulative of 6mg/kg).
Beside pulses of MethylPred and intensification of immunosuppressive agents I will consider PLEX and IVIG 100 mg/kg × 3-5 doses, then IVIG 2 g/kg every 3 weeks × 4 doses, and rituximab 375 mg/m2/week × 2 doses.
Would you offer her a better option rather than a direct transplantation?
1-Denatured Class I Human Leukocyte Antigen Antibodies in Sensitized Kidney Recipients
October 2014Transplantation 98(7):738-744
DOI:10.1097/TP.0000000000000229
SourcePubMed
2-False-Positive Reactions Against HLA Class II Molecules Detected in Luminex Single-Antigen Bead Assays
September 2014Annals of Laboratory Medicine 34(5):408-10
DOI:10.3343/alm.2014.34.5.408
SourcePubMed
3-False Positive Class II HLA Antibody Reaction Due to Antibodies Against Denatured HLA Might Differ Between Assays: One Lambda
vs.Immucor
Borae G. Park , M.D., Ph.D.1 , Younhee Park , M.D., Ph.D.2 , Beom Seok Kim , M.D., Ph.D.3 , Yu-Seun Kim , M.D., Ph.D.4 and Hyon-Suk
Kim , M.D., Ph.D.2
Thankyou for mentioning the importance of SAB to rule. Out low level DSA and denatured HLA
So histology is defiantly needed
THANKS Professor for your valuable comment
PRA is used to identify the sensitized recipients, it is a percentage of donor pool that the recipient had Abs against their Ag. cPRA mean unacceptable Ag that the recipient is sensitized against it.
The above photo show a section of renal tubules stained with silver stain. There is a tubulitis ( infiltration of tubular epithelium with lymphocytes) & interstitial infiltration by lymphocytes. These findings on biopsy are support the diagnosis of acute rejection ( T-cell mediated rejection).But due to absence of glomeruli & blood vessels in biopsy photo we can’t exclude presence of AMR, so we need C4d stain of renal biopsy & DSA measurement & non HLA Ab. Our plan of management will include of IV pulse steroid with ATG, & if there is AMR the patient will treated with plasmapheresis & IVIG.
The recipient with high cPRA & high HLA mismatch need desensitization pre transplantation with plasmapheresis & IVIG with or without rituximab & can put her on kidney paired donation program.
References:
Concise to the point
Desensitization before the tx ? Remember she did not get her ATG induction
Comment on the biopsy and what is your diagnosis?
The biopsy is not adequate as no glomerulus is identified in this sample.
The image shown comes from a high risk kidney transplant patient with acute kidney injury. The image provided shows lymphocytic tubulitis and surrounding lymphocytic inflammation. These findings are most commonly seen in acute T-cell mediated rejection (Banff IA or IB).
In the absence of vessels and glomerulus we can not conclude a final diagnosis , as in the more severe stages , vessels and glomeruli are affected and even acute antibody mediated rejection could be present.
What is meant by cRF/cPRA?
CPRA values are based on the HLA antigens listed as unacceptable for renal transplant candidates which can be identified by the presence of HLA antibodies in transplant recipients. cPRA of 93% means that the patient has preformed antibodies to 93 % of donors having unacceptable HLA antigens.
Any more tests required to confirm your diagnosis?
Redo kidney biopsy is recommended to guide us with diagnosis and treatment.
As the mismatch is 222 and cPRA 93%, the possibilityof presence of DSA is high although FCXM is negatve, we should do SAB assay.
What is your management plan?
The septic workup was negative, and the fever likely due to rATG or could be related to the rejection itself so optimization of immunosuppression is indicated.
rATG shoud be given, pulse steroids, checking levels of CNI if on CNI, or shift to CNI if was not maintained on CNI.
Would you offer her a better option rather than a direct transplantation?
As the patient is highly sensitized , desensitization with plasmapheresis/ IVIG and rituximab should be performed before direct transplantation.
The patient has many risk factors for rejection and the induction therapy was not given adequately.
Paired exchange program is another option for better matching , and less risk of immune responce
Very good plan for what is further required
Good to postpone further management for ABMR before
DSA and rebiopsy for histology cal evidence
Remember C4d could be negative
However Early DSA +ACMR is serious
Dear Dr Mohamed,
Thanks for the wonderful contribution. you mentioned the main points of this case in a clear and concise answer that I have nothing to add more than what you mentioned.
Only one comment regarding desensitization. Usually, desensitization is done if we have a pre-transplant high level of DSA that cause positive crossmatch, so we apply variable desensitization protocols aiming to lower the titre of DSA to the level acceptable by the transplant center.
In this scenario, there was no mention of detectable DSA before transplantation and her FCXM was negative.
Thank you Dr for the explanation
this pt hasnot completed her induction thearpy and fever was most probably atg realted which we see commonly in real life .
What is your diagnosis?
Comment on the biopsy?
the biobsy showed above only tubules , no glomes no vesseles , with this defecient biobsy i will go for acute t cell mediated rejection , revaling lymphocyte infiltration of the tubules (moderate to severe tubluitis ) BANF CLASS 1A OR 1B.
What is meant by cRF/cPRA?
as this pt has acPRA of 93 % this means that she has antibodies to likely of 93 perecnt of donors that she will be offered and her chance of transplantion is very unlikely as she is highly sensitized.
Any more tests required to confirm your diagnosis?
i will send for her DSA screening ,tac level , c4d stainning for the biobsy .
What is your management plan?
this pt didnot complete her induction immunsupprison , so i will complete her induction immunsuprresion with atg with cumulative dose of (4-6 mg/kg/total dose), and pulse steroid also for 3 consuctive days .
Would you offer her a better option rather than a direct transplantation?
pt is highly sensitized , with highy cPRA 93%, she offerd a kidney from her sister with 6 mimatch .
is this a good choice now or she can wiat a good match in paired exchange programm if avilable .
this issues should be discussed with the pt and her donor and counselling should be done regarding the effect of good match on overall out come of graft survival , and waiting time for matching a good offer in paired exchange list .whai if her blood group is o ?
national kidney paired exchnage porgramm faciltiating good matched kidneies with pts having positive cross match or different blood groups , but pt with negative cross match and many mismatches should be carfully selected to be listed in this programme as they increase the pool numbers but they delay their chance to be transplanted as soon possible as the may be exposed again to sensitizing events or getting more complicted to be transplanted.
Thankyou Mohamad good analysis of the case:
She is highly sensitized with class II antibodies
You will need DSA and even before the biopsy and C4d
ACMR + DSA is serious
You are right the sisters would need counseling to decide
Dx: acute cellular rejection.
Description :The biopsy shows lymphocyte infiltration of the tubules ( more than 13) ( sever tubulitis) also there is mononuclear infiltration of interstitium .
There is no vessel to comment on , but we should look for the vessels because vascular involvement means more sever disease and need more aggressive treatment.
We need to check for C4d and DSA to exclude concomitant AMR and we need to check for CNI level because subtherapeutic drug level is associated with rejection.
Trearment : If there is no vascular involvement (Banff I) , 3-5 doses of pulse steroids and if no response , ATG should be used. Immunosuppressive drugs optimization ( ensure CNI blood level in the therapeutic range , oral steroids in prescribed and MMF 2 gram/day)
If there is vascular involvement (Banff II- III) , we should add ATG to pulse steroids initially .
This patient had high cPRA and had 6 mismatches so she had high risk of rejection . Paired donor exchange ( with better HLA matching), if available before transplantation, would be better option.
References:
(1)American Journal of Transplantation 2009; 9 (Suppl 3): S21–S22
(2)Gabriel M. Danovitch, MD Handbook of Kidney Transplantation SIXTH EDITION 2017
(3)John Feehally, Jürgen Floege, Marcello Tonelli, Richard J. Johnson,
Comprehensive Clinical Nephrology sixth edition 2019
With this ACR she has to cmplete her ATG course first before even waiting for the biopsy.
What is your diagnosis?
This pt highly sensitized receiving non compatible kidney , not receiving full induction
Presented with deteriorating RFT and swollen tender graft , this picture compatible with acute rejection either TCMR, ABMR
Comment on the biopsy:
Both tubules and interstitium are heavily infiltrated by inflammatory cells but No arteries or glomeruli seen , so this biopsy is considered insufficient
No data about C4d staining
What is meant by cRF/cPRA?
PRA (Panel Reactive Antibody) is a test used in pre transplant period to evaluate the patient sensitization hence helping to prevent graft loss . It measures the recipient Abs against HLA Ags in candidate donors in the regional pool ….it is done by mixing the the lymphocytes of the candidate donors with recipient serum and calculate what is percentage of the positive reactions.
A recipient with 80% PRA this means that his crossmatch will be incompatible with 80% of donors.
cPRA (calculated PRA) is more accurate than PRA , it is based on unacceptable HLA Ags to which the recipient has been sensitized and if these Ags present in a donor , are considered an unacceptable risk for the candidate
Any more tests required confirming your diagnosis?
Re-biopsy with C4d staining as biopsy is not sufficient
DSA screening
Tacrolimus trough
CMV IgM, BK virus load
What is your management plan?
Give Pulse methylprednisolone 500 mg for 3-5 days followed by oral prednisolone tapering to maintenance dose used
Intensification of maintenance immunosuppression :
tacrolimus level trough between 7-10
Start rATG / alemtuzumab with follow up cbc
If acute ABMR is diagnosed start plasmapheresis ( 6 sessions )followed by IVIG
and Rituximab only if there is biopsy-proven ABMR
What is your diagnosis?
T cell mediated rejection
Comment on the biopsy
>10 cells in tubular cross section(t3),cannot comment on v and i. concomitant AMR needs to be ruled out .
What is meant by cRF/cPRA?
A transplant coordinator enters the unacceptable antigens for a patient. The system will calculate the CPRA using the unacceptable values. To determine the CPRA value, the computer system will use an established formula and HLA frequencies derived from the HLA types found in more than 12,000 donors. Candidates with a CPRA value of 80% or higher will receive points in the kidney allocation formula.
Any more tests required to confirm your diagnosis?
CNI level
DSA
C4 d staining on biopsy
What is your management plan?
inj methylprednisolone 500mg iv OD x 3-5 days with daily rft monitoring for Banff 1. If resistant to methylprednisolone after 5 days or Banff 2 and 3 ,then ATG 1.5MG/KG od x 5-7 days .if concomitant AMR then plasmapheresis,Ivig and rituximab added.
Would you offer her a better option rather than a direct transplantation?
Will do Luminex SAB pre transplant and if DSA <1000 go ahead with ATG induction. If DSA > 1000 -10000 advice paired exchange or if not possible desensitisation. If DSA >10000 or multiple DSA positive then avoid transplant and look for paired exchange .