3. A 36-year-old renal transplant recipient. He received a kidney from his brother, 111 mismatch, and has been on triple immunosuppression (Tacrolimus, MMF and steroid). There was no DSA at the time of transplantation. Discharged home with S Cr 101 µmol/L. He developed a de novo DSA (DQ 4 with MFI 1400) 6 months later and s Cr 112 µmol/L. There was no proteinuria.
- What is your management plan?
- What is the most significant prognostic factor in this case?
Dear All
At what MFI level do you start worrying about de novo DSA against the following:
1. HLA A
2. HLA B
3. HLA C
4. HLA DR
5. HLA DQ
6. HLA DP
5 -HLADQ
This is not the right answer
_The cut off level of MFI for HLA class I (A, B , C) if more than 3000.
And for class II (DP, DQ and DR) if more than 5000. These are levels to start to worry about and take an action.
However, lower levels need close follow up as if the titer is rising, it will be significant.
HLA C follows HLA DP and DQ. More than 5000 MFI would cause concern
cut off for anti class I antigen [ HLA A, B and C] Antibody titer of 2000 MFI is significant.
and for anti class II antigen [HLA DR, DQ, DP] antibody titer of 5000 MFI is significant.
reference:
Dr. Ahmad Halawa lecture.
There is variation concerning MFI levels and it is center dependent. Examples
According to UNOS > 3000
According to BST > 5000
Note ;
MFI should be taking alone to make decisions
MFI levels don’t necessarily correlates well with the clinical outcomes
DSA > 3000 mostly for class I & DSA> 5000 for class II
The MFI cut-offs of 3000 for class 1 DSAs and 5000 for class 2 DSAs
-The common cutoffs of 3000 for class 1 (HLA A/B/C)DSAs and 5000 for class 2 (HLA DR/DQ/DP )DSAs as clinically significant mean fluorescence intensity and we start to worry.
Although different among laboratories, many laboratories set a cutoff of 3000 for class I and 5000 for class II. keeping in mind that not all MFI values are with the same effect for different alleles, I will worry about the any level above these but will monitor even any DSA above 1500
Very wise if this is the first reading the fate is not known either stable and even disappear or continue to rise so follow up is essential.
cutoff levels of 2000 for class I DSAs and 5000 for class II DSAs
Currently, there is no standardization of the solid-phase bead assays. The thresholds reported for clinically significant mean fluorescence intensity (MFI) differ between studies from 1000 to 10,000 depending on the antigen specificities (1,2,3,4).
common cutoffs value of 3000 for class 1 DSAs(HLA A-B-C) and 5000 for class 2 DSAs(DR,DRQ,DP).
In our lab even lower cutoff of 1000 for class1 and 3000 for class 2
Limitations of the solid phase bead assay :
False positive due to denatured antibodies
False negative with prozone effect ( inhibitors ) very common up to 71% in the presence of multiple DSAs (4).
References:
1-Filippone EJ, Farber JL: Humoral immune response and allograft function in kidney transplantation. Am J Kidney Dis 66: 337–347, 2015.
2-Valenzuela NM, Reed EF: Antibodies in transplantation: The effects of HLA and non-HLA antibody binding and mechanisms of injury. Methods Mol Biol 1034: 41–70, 2013.
3-Ma J, Patel A, Tinckam K: Donor-specific antibody monitoring: Where is the beef? Adv Chronic Kidney Dis 23: 317–325, 2016.
4-Tambur AR, Herrera ND, Haarberg KM, Cusick MF, Gordon RA, Leventhal JR, Friedewald JJ, Glotz D: Assessing antibody strength: Comparison of MFI, C1q, and titer information. Am J Transplant 15: 2421–2430, 2015.
The cutoff level of MFI for class I is above 3000 & for class II is above 5000.
the threshold for clinically significant MFI level varies widely between the studies from 1000 to 10000.
in England as prof Ahmed report it is:
for class I HLA antibodies cutoff MFI level is 2000
class ii HLA antibodies MFI level is 5000
For class I MFI higher than 3000 , and for class 2 MFI higher than 5000 requires intervention
MFI level in class 1more than 3000{A-B-C}
MFI level more than 5000 in class II
there is no standard MFI level for denovo DSA and different from one transplantation center to another
some points should be considered like
-MFI differs from lab to lab and changes with time so MFI is not the only parameter to count on also the nature of DSA and if it is a complement fixing or not, against which HLA class
-there is what is called the prozone effect which may result in false -ve SAB although there is a high MFI titer
-antigen denaturation can cause false +ve
but usually the cutoff for class I is 3000 and class II is 5000
although there is no standardization of cut off level , and there is different cut of level in different centers. but generally
for class I ( HLA-A,HLA-B,HLA-C) cut of MFI more than 30000 and for class II (HLA DR,HLA-DP,HLA-DQ) a cut off MFI of more than 5000 should considered risky .
although any level of DSA should be monitored as any positive Ab is harmful.
MFI level
Low MFI 1000-3000
Moderate MFI 3000 – 5000
High MFI > 5000
For class I; HLA the cut off value < 3000
For class II; the cut off value < 5000.
Dear All
Thank you for your reply. I ask you to reconsider your answers. 25% of patients develop de novo DSA. Most of them disappear without inducing graft damage.
This mean that I can only follow up the DSA level as the patient has no proteinuria and his kidney functions are fine (did not exceed 10% increase from baseline)?
True
Many de novo DSA are not complement-fixing. We need to think if the biopsy would change your management or not
De novo DSA AMR was associated with low eGFR and proteinuria compared with pre-existing DSA AMR at the time of diagnosis and here no proteinuria.
Graft dysfunction slowly may be sub-clinical or chronic rejection.
Just monitoring of DSA and F/U RFT.
But I think still the biopsy is considered.
Agree
Well done
As I answered in my reply to original question, HLA DQ4 de novo DSAs is commonly encountered post transplant, its level is not high, with no significant change in renal function, and no proteinuria. we need to observe closely the DSAs level, renal function and proteinuria.
Tac. trough level to be checked and dose adjusted accordingly.
Agree
Well done
Reasonable cause patient developed De novo DSA 6 month with no proteinuria and
stable renal function(less than 25%) .
What do you think about kidney function in the index case?
Stable renal function(less than 25% increased from base line).
Will you biopsy?
By definition Acute allograft dysfunction defined by one or more of the following:
1-Increase in serum creatinine of ≥25 percent from baseline within a one-to-three-month time period
2-Failure of the serum creatinine to decrease following transplantation
3-Proteinuria >1 g/day
And Chronic allograft dysfunction defined is slow, progressive loss of graft function associated with hypertension and proteinuria.
In the current scenario, The patient with standard immunologic risk, no preformed DSA and with primary graft function followed by development of ds DSA against DQ4 with low strength and no evidence of allograft dysfunction by definition.
If will do protocol biopsy may or may not discover histopathological picture of subclinical rejection, so at the time we need to treat.
Well justified, well done.
However, I would not biopsy, I may augment his immunosuppression and monitor graft function (creatinine and proteinuria) and the DSA. Also, remember that the DSA level is low for DQ to worry about.
Agree
Well done
We should focus on certain factors related to the patient that might contribute to the development of dnDSA post transplantation and can predict the graft survival
1- History of nonadherence with IS
2- History of previous viral infection that intentionally lead to reduction of immunosuppression in particular BKV nephropathy
3- previous sensitization history
In addition to the DSA characteristics like the dn DSA type and the MFI value by serial monitoring ,DSA IgG subclass, and the time elapsed till the development of dn DSA .also the histological finding as according to the result from the reference below , they found that patients with dn DSA of 1000 MFI whom underwent graft biopsies still good numbers have histological finding of chronic active ABMR or mixed type rejection while rejection free biopsies only found in 22.4%.
so all the above factors together will help in decision making about further treatment knowing the fact that presence of dn DSA is independent risk factor for graft loss over time and need serial monitoring .
References:
1-Schinstock CA , Dadhania DM, Everly MJ, Smith B , Gandhi M, Farkash E, et al. Factors at de novo donor-specific antibody initial detection associated with allograft loss: a multicenter study. Transplant International 2019; 32: 502–515.
Agree
Well done
Agree
Well done
The majority of patients with de novo DSA present signs of rejection in allograft biopsies, even in the absence of proteinuria or eGFR loss. Since the prognosis of rejection therapy crucially depends on early diagnosis, it appears reasonable to perform an allograft biopsy after the detection of de novo DSA, irrespective of proteinuria or eGFR loss.
Reference ;
Nickerson PW. What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation? Am J Transpl. 2020;20(Suppl 4):12–22. doi: 10.1111/ajt.15859. [PubMed] [CrossRef] [Google Scholar].
Agree
But remember the MFI for DQ is not that high. I start worrying if it is above 5000.
1. The patient does not require treatment as he does not fulfill the definition of graft dysfunction.
_ no increase in serum creatinine by more than 25% from base line
– no significant protinuria more then 1 gm/day
2. Kidney function considered stable graft function. Exclusion of pre_renal causes as decreased fluid intake or recent losses may be considered together with adherence to prescribed medications. If every thing is good and well, just follow up titer of DSA (rising or vanishing) .
Agree
Well done
It is the right approach.
In this scenario, when the serum creatinine rise is only by 10%, and low level new onset DSA, the patient does not require treatment, but a cautious and close follow-up of serum creatinine and DSA levels.
The serum creatinine has increased by 10%. A new increase in serum creatinine by >25% from baseline should be worrisome. In this scenario, as the increase is less, we should have a close follow-up.
I think we need histological confirmation of the damage. If present, we have to treat that. If not, we can follow up conservatively with serial monitoring of both DSA and Renal function tests. Keeping in mind the late elevation of serum creatinine as a marker of damage.
This patient has minor rise of s creatinine about 10% of the base line with no proteinuria so i agree with you sir no ttt required just close monitoring of kidney function and DSA
What do you think if I told you that this patient does not require any treatment?
There is about 10 % rise in serum creatinine levels. There is no proteinuria. New DSA with low MFI. Not all denovo DSA are harmful, especially with low MFI. Biopsy not indicated but I will like to monitor the situation and follow
What do you think about kidney function in the index case?
Creatinine increase by 10% only. I will follow and if it increase by >25% then it will be worrisome .
although this patient not require treatment but still need monitoring for KFT and De novo DSA MFI titre as de novo class11 DQ has high rate of antibody mediated rejection and chronic damage .
KFT rising is non sign fence as less than 25%
-Yes, no need for any treatment apart from optimizing his immunosuppressive medication if TAC level is subtherapeutic.
– His kidney function here is still ok as the increase in s Cr is just10%
HLA DQ4 de novo DSAs is commonly encountered post transplant, the level here is not high its level is not high, renal functions are not significantly elevated and no proteinuria. I think we should follow up DSAs level closely, kidney functions , FK trough levels , adjust accordingly , biopsy may be considered .
De novo DSA not complement fixing DSA lead to chronic rejection and late AMR ,there are no poor prognostic features so we can just follow him .
yes sir, as this patient has relatively stable graft function i e there is no significant increase in serum s creatinine level , no proteinuria, non significant level increase in Ab level (low MFI ). All these data can make me to monitor this patient without treatment .especially this patient may has a chance of weaning of this Ab level with time .
close monitoring is required.
2.What do you think about kidney function in the index case?
can be considered relatively stable as there is elevation of less than 25% percent of baseline
1)What is your management plan?
Protocol allograft biopsy with c4d stain.
Serum FK level
CMV and BKV PCR to exclude CMV or BKV viraemia.
if evidence of AMR : Pulse with IV Methyprednisolone.
In steroid refractory : Plasmapheresis and IV IG
2)What is the most significant prognostic factor in this case?
renal profile
proteinuria
DSA tire.
MFI has no standered for de novo DSA and differ between labs
False negative MFI can be caused by prozone effect with cause high MFI titer
the patient develop de novo DSAs against DQ MFI 1400 , which is not problem , as the cut off of DQ which have negative impact is MFI more than 5000
no specific treatment , no biopsy needed now just ensure compliance for treatment
frequent monitoring of DSAs and kidney function and urine analysis for proteinuria
Significant prognostic factors
no proteinuria
normal kidney function
low level DSA
no history of desensitization
This case has almost stable graft function with de novo DSA for class II HLA at low MFI level(1400) and no proteinuria or sinister of rejection.
Plan of management:
· To continue the same plan of management with Tacrolimus drug level at the upper limit of target.
· No need for biopsy right now
· To continue observation and follow up with, KFT, urinalysis and DSA monitoring.
Prognostic factors in this case:
· Stable graft function and no proteinuria are of good prognosis.
· De novo DSA, although at low level, caries poor prognosis.
Management plan
o Around25% in non-sensitized patients develop de novo DSA(usually class 2) in first year post-transplant but this may occur late. This patient developed de novo DSAs 6 months post-transplant against HLA-DQ4 with MFI of 1400.
o The MFI cut off varied between different labs. However, a cut off of 2000 for class 1 and 5000 for class 2 are considered significant. MFI should not be taken alone to make clinical decisions as de novo DSAs can wean & wave and in most cases disappear with no graft damage .on the other hand , their presence can result in slow graft dysfunction, sub-clinical or chronic rejection(this patient has 10% increase in his serum creatinine with no proteinuria)
o No treatment is required at this stage as the findings given do not satisfy the criteria for graft dysfunction.
o Follow up of renal functions and proteinuria is required, beside, monitoring for DSAs by Luminix SAB every 3 months in year 1, then bi-annually. Moreover, checking for BK virus, TAC level and the patient compliance to immunosuppression which are important risk factors in developing de novo DSAs.
Most significant prognostic factor n this case:
o No history of sensitization
o No proteinuria
o 10%increase in serum creatinine
o Low level of de novo DSA-DQ
References:
Bertrand D, Gatault P, Jauréguy M, Garrouste C, Sayegh J, Bouvier N, Caillard S, Lanfranco L, Galinier A, Laurent C, Etienne I. Protocol biopsies in patients with subclinical de novo donor-specific antibodies after kidney transplantation: a multi centric study. Transplantation. 2020 Aug 1;104(8):1726-37
Having a class II DSA confers higher risk of graft loss.
What is your management plan?
Check his compliance on his medications
Check CNI level
Continue follow up DSAs, no change in his immunosuppression
What is the most significant prognostic factor in this case?
Stable graft function, stable creatinine, Proteinuria, De novo DSA against DQ4 with MFI 1400 (cut off point to worry if above 5000)
This patient has an elevation in serum creatinine despite having low level of DSA DQ 1400 (low risk ) and absent proteinuria
So we have to follow up if there is a subsequent elevation in DSA (Elevation trend) plus
Clinically: full history and clinical examination to exclude pre-renal failure e.g dehydration , hypovolemia , Hypotension etc
Lab : serial KFTs , DSA levels , tac trough level , urine analysis for proteinuria , casts , WBCs and RBCs
Imaging US to exclude obstruction and Dupplex to check for RI index
Biopsy may be needed to detect AMR if present
Best management is to manage the correctable causes and check DSA Levels
Most important prognostic factor is the proteinuria
this patient now has non significant low MFI dnDSA , no proteinuria and no significant increase in S creatinine level less than 25% of baseline .
1i will direct my history , examination and investigation to exclude any treatable cause of this S creatinine elevation which could be
if these factors excluded then i will monitor this patient by
if any increase in S creatinine level or development of proteinuria or increase in DSA to a significant level above MFI 5000
Then a renal biopsy will be indicated .
otherwise this mild level of DSA may disappeare with time without any pathologic consequences.
the most significant prognostic factor in this case is
normal renal function
no proteinuria
low dnDSA MFI level.
this patient is a low-risk patient and developed DSA against DQ with low MFI and now her creatinine increased from 101 to 112 without proteinuria
-the increase in her s.creatinine showed be investigated like
1-any prerenal cause like decreased oral intake or fever or diarrhea
2-her tac level now and previous tac level
3-hx of compliance on her IS medications
4-her virology screening like CMV and BK
5- is there any hx of nephrotoxic drug
6-any symptoms or signs of infection either viral or bact.
if there are any explanations for this elevation of her s.creatinine in the absence of proteinuria and after correction of this predisposing factor her creatinine improved so just follow-up and optimization of immunosuppression will be enough as 15% of low-risk patients develop DSA and disappear spont. without causing any graft harm.
but if there is no explanation for her dearranged kidney functions or some proteinuria started to develop, a kidney biopsy should be considered and treatment of the underlying cause.
proteinuria and the serial of her s.creatinine
This patient received a living donor 111 mismatch kidney.
No pre-transplant DSA.
On Tacrolimus based triple drug immunosuppression.
Post-transplant creatinine 101 micromol/L, increased by 10% to 112 micromol/L.
For any increase in post-transplant creatinine, we should evaluate the patient:
1) History of any hypovolemia (loose stools, poor intake), any non-adherence, recent fever, dysuria or oliguria.
2) Examination to look for any signs of hypovolemia, blood pressure, abdominal distension, tenderness over graft etc.
3) USG graft kidney and doppler: to look for any obstruction/ fluid collection.
4) Tacrolimus trough level should be tested
5) Urine examination: to look for proteinuria, RBC, WBC
6) DSA levels.
This patient has no proteinuria and a new onset DSA (DQ4, MFI: 1400)
This patient is a low-risk patient (non-sensitized, first time transplanted).
de novo DSA can develop in 15% of low-risk patients. A large proportion of these de novo DSA disappear spontaneously.
First and foremost, the serum creatinine should be repeated, and we need to see whether there is a recent trend of increase in serum creatinine.
At this moment, as the DSA MFI is low, trend of DSA levels can be monitored in addition to the serum creatinine.
In cases with setting of graft dysfunction with presence of a new onset DSA which is increasing, a graft biopsy should be done (due to data showing association between DSA and clinical or subclinical rejection). If the biopsy shows AMR, it should be treated. The efficacy of treatment can be assessed with the in DSA levels and improvement of graft function.
If the biopsy does not show AMR, serial monitoring of DSA is recommended.
The prognosis in this case will depend on:
a) Serial graft function: Higher degree of graft dysfunction is associated with poorer outcomes.
b) Serial DSA level: Increasing DSA levels (MFI>3000), in presence of a biopsy proven acute rejection, have a poorer prognosis. In absence of BPAR, DSA levels are not associated with increased risk of graft failure. (3) DSA subclass IgG3 have increased microvascular injury and graft failure.
c) Presence of proteinuria
It has been seen that eGFR<30 and urine protein creatinine ratio >0.3 g/g is a poor prognostic factor for the graft kidney. (4)
So, the most important prognostic factor at this moment would be presence of proteinuria.
References:
1) Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013 Jan 15;95(1):19-47. doi: 10.1097/TP.0b013e31827a19cc. PMID: 23238534.
Management:
Living donor 111 mismatch
No DSA .before Tr with Tac based triple therapy..
For increase of creatinine, patient must be evaluated :for hypovolemia, drug non adherence, or infection and tenderness over graft. Also, US for graft, Tac level, DSA level and urine analysis.
In this patient, no proteinuria bu new onset DSA (DQ4, MFI: 1400)
This patient is a low-risk patient being not-sensitized, and first time transplanted.
Serum creatinine should be repeated to see whether there is trend of increase in serum creatinine and DSA levels.
Considering graft dysfunction with presence of increasing new onset DSA , a graft biopsy should be done with necessary AMR treatment if found. with DSA monitoring..
If no AMR, serial monitoring of DSA is recommended.
The prognosis is determined by:
_ Trend of graft function.
_ Increasing DSA levels (MFI>3000), with biopsy proven acute rejection, have a poorer prognosis. If no BPAR, DSA levels are not associated with increased risk of graft failure; DSA subclass IgG3 has increased microvascular injury and graft failure.
_ proteinuria
eGFR<30 and urine protein creatinine ratio >0.3 g/g have poor prognosis of graft .
References:
Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013 Jan 15;95(1):19-47. doi: 10.1097/TP.0b013e31827a19cc. PMID: 23238534.
Valenzuela NM, Reed EF. Antibodies in transplantation: the effects of HLA and non-HLA antibody binding and mechanisms of injury. Methods Mol Biol. 2013;1034:41-70. doi: 10.1007/978-1-62703-493-7_2. PMID: 23775730; PMCID: PMC3879955. ) Parajuli S, Joachim E, Alagusundaramoorthy S, Aziz F, Blazel J, Garg N, Muth B, Mohamed M, Redfield RR, Mandelbrot DA, Zhong W, Djamali A. Donor-Specific Antibodies in the Absence of Rejection Are Not a Risk Factor for Allograft Failure. Kidney Int Rep. 2019 Apr 18;4(8):1057-1065. doi: 10.1016/j.ekir.2019.04.011. PMID: 31440696; PMCID: PMC6698321.
Aubert O, Loupy A, Hidalgo L, Duong van Huyen JP, Higgins S, Viglietti D, Jouven X, Glotz D, Legendre C, Lefaucheur C, Halloran PF. Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients. J Am Soc Nephrol. 2017 Jun;28(6):1912-1923. doi: 10.1681/ASN.2016070797. Epub 2017 Mar 2. PMID: 28255002
· What is your management plan?
· No history of hypovolemia or non-adherence the MFI value at which the graft is rejected generally happens to be >4000. The DQ antibodies in this case had an MFI of around 1400. It has also been proved that the strength of the MFI is directly proportional to the graft loss and the outcome. This patient has increase in serum creatinine of only10% after 6 months. He has no protein-uria. His DSA MFI is not high (1400)there for I will monitor the level of DSA ,TAC trough level intensification of immunosuppression .
What is the most significant prognostic factor in this case?
Presence of protien uria and MFI level of DQ DSA
Management plan
Monitor DSA and RFT. Augment immunosuppression and monitor graft function.
The patient does not require treatment at this stage as the findings given do not satisfy the criteria for graft dysfunction.
Criteria for graft dysfunction include
Increase in serum creatinine above 25% from baseline
Significant proteinuria more than 1 gm per day
I would not biopsy in this case since there is no evidence of significant renal damage. Biopsy would be needed to identify interstitial fibrosis or tubular atrophy.
Most significant prognostic factor
No history of sensitization, no proteinuria, low level of DSA are all significant factors for prognosis of this patient.
Management plan :
Having a modest rise in creatinine level ( from the index level ) ,, no proteinuria , low MFI De novo DSA ; then I might consider a non immunologic cause besides rejection ( which can be slow and even subclinical here ) . So first I shall check the adherence to IS , Tac trough level with dose adjustment , pre/intra/post renal causes , viral infection , keep monitoring kidney function and DSA regularly , consider biopsy if things are going worse ( eGFR decline , increasing DSA , emergence of proteinuria ).
prognostic factors :
1- absence of proteinuria
2- No major decline in eGFR
regarding the prognosis , having class 2 DSA , which is more to be associated with chronic histological changes and later graft loss
as his graft function is stable with no proteinuria, and the MFI level is low so no need for graft biopsy. he will need follow-up with urine protein: creatinine ratio, e GFR, s.cr, Tac level and DSA after 3 months or if there is evidence of proteinuria.
review with the patient’s drug compliance.
low DSA MFI level < 5000, no sign of proteinuria, no history of sensitization (blood transfusion), a living donor with acceptable mismatch
This patient received a living donor with acceptable HLA match, with no sensitization pretransplant. On Tacrolimus based triple drug immunosuppression.
Post-transplant creatinine 101 micromole/L, increased by 10%.
Just monitoring for DSA titer and graft function renal biopsy should be considered if there is an increase in renal function associated with increase in DSA titer
Prognostic factor
1- presence or absence of graft dysfunction
2-degree of proteinuria
For any increase in post-transplant creatinine, we should evaluate the patient:
1. Immunosuppression adherence which is the most common cause for denovo DSA occurrence
1) History of any hypovolemia (loose stools, poor intake), , recent fever, dysuria or oliguria.
2) Examination to look for any signs of hypovolemia, , tenderness over graft etc..
3) Tacrolimus trough level .
4) DSA levels.
In This scenario, a young patient has 111 mismatches, no DSA , received a kidney from his brother, with stable graft function postoperatively, on triple immunosuppressive meds, he developed DnDSA DQ with low MFI , did not meet the criteria of acute allograft dysfunction, as there is no increase in s Cr above 25 % & nor proteinuria, so just follow up the therapeutic level of TAC and adjust the meds accordingly & follow up the DSA level if increased above 5000, he needs a renal biopsy.
to continue same immunosuppression with close monitoring of DSA level as the MFI is low, no graft dysfunction and absent proteinuria.
The low MFI is a prognostic factor also absent proteinuria
A multicenter study showed that biopsy performed for dnDSA in absence of graft dysfunction leaded to diagnosis of subclinical AMR in 40% of cases. In this study the mean MFI of de novo DSA considered was 6247 ±24016 and mean sum of all de novo DSA was 7786 ± 5562
The higher the MFI (>4000 at time of biopsy), the higher the incidence of subclinical AMR
Bertrand D, Gatault P, Jauréguy M, Garrouste C, Sayegh J, Bouvier N, Caillard S, Lanfranco L, Galinier A, Laurent C, Etienne I. Protocol biopsies in patients with subclinical de novo donor-specific antibodies after kidney transplantation: a multicentric study. Transplantation. 2020 Aug 1;104(8):1726-37.
This scenario is about a relative living donor kidney transplantation with 111 HLA mismatches. Six months after transplantation, de novo DSA was detected that was class II (anti DQ antibody) with MFI 1400. Common MFI cutoffs for HLA class II DSAs and HLA class I DSAs are 5000 and 3000 respectively, although there is difference between laboratories in MFI cutoffs. In addition, recipients’ creatinine level had any significant rise and there was no proteinuria. The patient was on triple agent maintenance therapy consisting of tacrolimus.
Evaluation for the reasons of de novo DSA formation such as noncompliance or insufficient dose of maintenance therapy and serial monitoring of DSA and kidney function is suggested.
Optimizing maintenance immunosuppressive therapy and protocol biopsy may be helpful. The absence of proteinuria in the presence of stable kidney function is the most prognostic factor.
The majority of de novo DSAs after kidney transplant are class 2 antibodies, especially DQ. Class 2 de novo DSAs appear later, tend to be persistent and are associated with chronic antibody-mediated rejection and transplant glomerulopathy. Trying aggressively to eliminate class 2 DSA, especially the DQ, may not be successful, and it can put patients at great risk of excessive immunosuppression without much benefit.
What is your management plan?
Patients with Denovo DSA can be classified according to the clinical. Syndrome they present at the time of detection
The patient had rise of creat about 10%, no proteinuria and developed DSA in 6 months
DSA that developed is anti-HLA DQ4 with MFI 1400
Patient who had mismatched at HLA DR locus were at significant risk of developing DQ DSA
I would asses the adherence of the IS that given to medication as non adherence to meds is one of the risk factor for DnDSA
Then, if patient adhere to meds, I would intensify IS therapy:
Maintain higher Tac through level >6ng/ml and MMF at 2g / day
Some study advocate proteasome inhibitor, bortezomib as a desensitization therapy in DnDSA but need further evaluation
will continuee monitoring DSA, monthly for 3 months then at 6,9,12 month
I would not do Biopsy unless there is significant renal impairment- to asses interstitial fibrosis and tubular atrophy- to avoid treating patient who unlikely benefit from advancement of IS
What is the most significant prognostic factor in this case?
Reference
Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation by Sophia Lionaki
Dear all.
Going through your answers which are mostly correct and sufficient
Decision Taking to manage this real case.we agree upon:
These are de novo DSAs 6 months after Tx ,DQ4 with a comfortable MFI of 1400.
There is always a window time lapse between their detection and appearance of their effects.
Being DQ4 which can cause cABMR and TG.
Your answers were either
Group 1(majority)
after studying the immune history to rule out history of sensitizing events and factors causing ischemia.
Also Tac trough levels
Viral infections BK
History of TCMR
Decided to follow up both titre level which could be stable, or on the rise or even disappearing, alongside with kidney function.
And biopsy when in doubt
Question: How frequent do you measure the titre and which modality?
Can there be a change in type of DSA alongside with titre?
GROUP 2
They are a skeptical few who decided to go for a biopsy straight away.
With this kidney function they will be expecting a Subclinical rejection:
Question. How will you manage that?
Management plan:
Immunosuppressive protocol as scheduled (triple therapy tacrolimus, MMF, prednisolone)
Adjusted by drug level monitoring, and protocol biopsy to be considered.
Revision for DSA titer as scheduled 9 and 12 months after,
No intervention would be needed at this stage.
Desensitization may be required later on if antibody titer exceeded 5000 for DQ or anti HLA A,B,or DR exceeded 3000.Monoclonal antibodies can be used as rituximab or eculizumab according to cost, protocol and availability of the transplant center.
Most significant prognostic factor:
In my opinion would be rise of DQ DSA, or development of other DSA denovo subtypes.
Biopsy changes indicative of antibody mediated rejection.
Proteinuria may be a sign of transplant glomerulopathy indicative of chronic ABMR which is not applied to this case.
Dear All
Remember that
anti HLA C antibodies will roughly treat as class II, particularly DP and DQ. I agree that 2000 for HLA A and HLA B DSAs are causes of concern, while HLA C, DP and DQ of MFI 5000 and above are causes of concern.
Some centres
consider MFI > 10000 for HLA C, HLA DP and HLA DQ is a cause of concern
Check for Immunosuppression non -adherence which is considered as the most common cause for denovo DSA formation
Check for TAG level
S.creatinin slightly increased and MFI less than 5000
At time being need monitoring for DSA titer and considered renal biopsy if there is increaseing in renal function associated with increase DSA titer
Prognostic factor
1-degree of graft dysfunction
2-degree of proteinurea
Very good
Titre follow up and not wait for kidney function to start rising
I will manage this patient conservatively, by follow-up of DSA and renal function tests. I will keep the TAC level between 7-10 for the first year at least. I may prefer to take biopsi in case of steadily increasing levels of DSA and or little increase of DSA. If the patient accepts I will even consşder biopsy at this time
I need to know the level of creatinin at discharge and on monthly followup visits
Management plan:
This is a case of stable renal function with no proteinuria and low level HLA DSA against HLA-DQ that needs only close follow up for DSA, renal function and proteinuria.
The most significant prognostic factor is allograft function, and the clinical picture and rapidity of onset of graft dysfunction. In addition, history of immunosuppressive non-adherence on IS reduction are important. In addition, serial measurement of the DSA level is important.
What would be your management if you diagnose a subclinical rejection.
i will just monitor his DSA levels and suggesting protocol bibsies for him but for now , no aggresive tretment of rejection.
Very good
What is your management plan?
Important facts to consider-
Live related donor
111 HLA mismatch
No DSA at the time of transplant
Slight increase in creatinine- 101 micromol/L to 112 micromol/L
No proteinuria
Denovo DSA against HLA DQ-(HLA class 11) – MFI 1400
I will like to take pertinent history and focussed examination to rule out hypo volemia, assess drug compliance and recent infection. Urine result and DSA levels are available. I will like to Doppler scan to check resistive index and will repeat serum creatinine levels.
I will make sure that patient is adequately hydrated and will optimize immunosuppressant levels and then follow creatinine levels. I will not consider biopsy at this stage , however if there is further deterioration in renal function, then will do graft biopsy
What is the most significant prognostic factor in this case?
Renal functions
Proteinuria
DSA titres
Very good but do you think in this situation maybe with possible subclinical rejection resistivity index would show any change?
# In this patient with stable graft function 10% increase from basal creatinine, 6 months after transplantation and absence of protinuria
# The presence of three of six HLA mismatches (1-1-1) is an important factor in the development of de novo DSA.
anti HLA -DQ antibody of low MFI, ( there was no DSA at the time of ransplantation)
# This patient need posttransplant follow up time, implementation of protocol biopsy, different techniques to detect HLA-DQ and non DQ anibody because
the time taken for the de novo antibody to develop differs from patient to patient but generally is formed 6-mont posttransplant. Studies showed there is a delay in detection if antibodies other than DQ are also present some times it takes around 11 – 24 months for detection and comprised of both DQ and non-DQ antibodies. The development of DSA happens before the actual renal dysfunction sets in, (de novo antibodies formed much earlier)
# What is the most significant prognostic factor in this case?
Presence of anti HLA- DQ antibodies
# The HLA-DQ antigen is a α and β heterodimer of the HLA Class II type.
Both α and β chains in DQ molecules express polymorphism unlike HLA-DR antigens, and therefore, de novo DSA antibodies could be formed against both α and β chains. Although it is apparent that alloimmunization is usually and dominantly directed to the β chain, both chains contribute to the complete structure and can induce an immunologic response. Mostly, the β chains are identified and interpreted, and α chain is neglected.
multiple antibody detection assays and techniques and extended high-resolution DQA1/DQB1 typing for both donor and recipient may be required.
Halloran PF. The clinical importance of alloantibody-mediated rejection. Am J Transplant. 2003;3:639–40. [PubMed] [Google Scholar]
Terasaki PI, Cai J. Humoral theory of transplantation: Further evidence. Curr Opin Immunol. 2005;17:541–5. [PubMed] [Google Scholar]
The most important prognostic factor, in this case, is the presence or absence of graft dysfunction
OK, THANKS
What is your management plan?
-The risk factors for de novo DSA include the following: (1) high HLA mismatches (especially DQ mismatches), (2) inadequate immunosuppression and nonadherence, and (3) graft inflammation, such as viral infection, cellular rejection, or ischemia injury, which can increase graft immunogenicity .
-The common cutoffs of 3000 for class 1 DSAs and 5000 for class 2 DSAs as clinically significant mean fluorescence intensity ,So this recipient had low level of DSA (DQ 4 with MFI 1400) which need follow-up and according to follow-up we can take decision about allograft biopsy ,but I need to check :
1.Symptoms and signs of infections.
2. adherence to maintance immuosupression.
3.Tac level
4.Allograft U/S.
What is the most significant prognostic factor in this case?
-DSA titre :High titer of DSA has been correlated with complement binding capability and more severe tissue injuries .
-Proteinuria
-RFT
Reference:
-Rubin Zhang .Donor-Specific Antibodies in Kidney Transplant Recipients
CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
The common cut-offs of 3000 for class 1 DSAs and 5000 for class 2 DSAs as clinically significant mean fluorescence intensity, So this recipient had a low level of DSA (DQ 4 with MFI 1400) which needs follow-up and according to follow-up we can take a decision about allograft biopsy
*What is your management plan?
This is a living donor transplantation with 111 mismatch,No DSA at time of transplantation.
DSA DQ4, MFI: 1400 which is not significant and usually doesn’t cause AMR
There is very minor increase in s creatinine level less than 25 % of the base line.
With no proteinuria.
We need to check the following :
1 Adherence to immunosuppression.
2 tacrolimus trough level.
3 signs of infection especially viral infection.
4 us of the graft with doppler for RI.
Follow-up of s creatinine level to see if there is further rise or not
If it stabilizing no need to do biposy just Follow-up of kidney function ,tacrolimus trough level, and DSA.
If further rise occurs more than 25% of the baseline biposy should be considered .
*What is the most significant prognostic factor in this case?
-more rise of s creatinine
– appearance of proteinuria
– DSA level monitor.
Very good but what would RI show at this stage of function ?
What is your management plan? First we should Check adherence to immunosuppressant medication Check tacrolimus level & adjust dose as appropriate graft biopsy as part of protocol biopsy DSA monitoring
FU of graft function
Exclude any pre and post renal conditions
What is the most significant prognostic factor in this case? De novo DQ DSAs MFI level
And appearance of proteinuria
You can simply follow that with A/C ratio
Mild graft dysfunction at 6 mnth-
1.pre-renal conditions to be ruled out.
2.usg of graft to rule out post renal causes.
3.Rejection (very likely) in presence of denovo DSA,so graft biopsy will help in confirming the diagnosis which will help in elevating maintenance immunesuppression with rescue therapy. But sometimes a watchfull monitoring of dsa with graft function is also a resonable approach as the dsa level is not so high but it is a sign of future chronic subclinical rejection.so in a nutshell never harbour a doubt when biopsy is feasible which is gold standard.
4.recurrence of old disease (less likely due to absence of proteinuria)
5.infection-must be ruled out like bkv nephropathy which require completely different approach than rejection.
6.Tac toxicity-last but not the least, must be ruled out with tac level.
Most significant risk factor is development of DSA against DQ.
What makes rejection UNLIKELY in this scenario at this point:
DSA is DQ
MFI is 1400 and you wisely follow the titre.
Creatinine is less than 10% rise which also needs follow up.
Proteinuria is a very strong prognostic sign which can be followed by A/C ratio in urine.
This is a case of kidney transplantation after 6 months presented with denove DSA formation against HLA _II which is can occur in late period post transplant and responsible for chronic ABMR and transplant glomerulopathy.
As there is no proteinuria and no significant renal function test detorioration and DSA level is not so high so management plan will be monitoring of the patient,check tacrolimus level,exclude any infection,keep him on the same drug regimen,DSA level monitoring and graft biopsy .
Prognostic factor is MFI titer with RFT and proteinuria.
Very good
This patient received a living donor 111 mismatch kidney.
No pre-transplant DSA.
On Tacrolimus based triple drug immunosuppression.
Details regarding induction and pre-transplant crossmatch not given.
Post-transplant creatinine 101 micromol/L, increased by 10% to 112 micromol/L.
For any increase in post-transplant creatinine, we should evaluate the patient:
1) History of any hypovolemia (loose stools, poor intake), any non-adherence, recent fever, dysuria or oliguria.
2) Examination to look for any signs of hypovolemia, blood pressure, abdominal distension, tenderness over graft etc.
3) USG graft kidney and doppler: to look for any obstruction/ fluid collection.
4) Tacrolimus trough level should be tested
5) Urine examination: to look for proteinuria, RBC, WBC
6) DSA levels.
This patient has no proteinuria and a new onset DSA (DQ4, MFI: 1400)
This patient is a low-risk patient (non-sensitized, first time transplanted). (1)
de novo DSA can develop in 15% of low-risk patients. A large proportion of these de novo DSA disappear spontaneously.(2)
First and foremost, the serum creatinine should be repeated, and we need to see whether there is a recent trend of increase in serum creatinine.
At this moment, as the DSA MFI is low, trend of DSA levels can be monitored in addition to the serum creatinine.
In cases with setting of graft dysfunction with presence of a new onset DSA which is increasing, a graft biopsy should be done (due to data showing association between DSA and clinical or subclinical rejection). If the biopsy shows AMR, it should be treated. The efficacy of treatment can be assessed with the in DSA levels and improvement of graft function.(10
If the biopsy does not show AMR, serial monitoring of DSA is recommended.
The prognosis in this case will depend on:
a) Serial graft function: Higher degree of graft dysfunction is associated with poorer outcomes.
b) Serial DSA level: Increasing DSA levels (MFI>3000), in presence of a biopsy proven acute rejection, have a poorer prognosis. In absence of BPAR, DSA levels are not associated with increased risk of graft failure. (3) DSA subclass IgG3 have increased microvascular injury and graft failure.
c) Presence of proteinuria
It has been seen that eGFR<30 and urine protein creatinine ratio >0.3 g/g is a poor prognostic factor for the graft kidney. (4)
So, the most important prognostic factor at this moment would be presence of proteinuria.
References:
1) Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013 Jan 15;95(1):19-47. doi: 10.1097/TP.0b013e31827a19cc. PMID: 23238534.
2) Valenzuela NM, Reed EF. Antibodies in transplantation: the effects of HLA and non-HLA antibody binding and mechanisms of injury. Methods Mol Biol. 2013;1034:41-70. doi: 10.1007/978-1-62703-493-7_2. PMID: 23775730; PMCID: PMC3879955.
3) Parajuli S, Joachim E, Alagusundaramoorthy S, Aziz F, Blazel J, Garg N, Muth B, Mohamed M, Redfield RR, Mandelbrot DA, Zhong W, Djamali A. Donor-Specific Antibodies in the Absence of Rejection Are Not a Risk Factor for Allograft Failure. Kidney Int Rep. 2019 Apr 18;4(8):1057-1065. doi: 10.1016/j.ekir.2019.04.011. PMID: 31440696; PMCID: PMC6698321.
4) Aubert O, Loupy A, Hidalgo L, Duong van Huyen JP, Higgins S, Viglietti D, Jouven X, Glotz D, Legendre C, Lefaucheur C, Halloran PF. Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients. J Am Soc Nephrol. 2017 Jun;28(6):1912-1923. doi: 10.1681/ASN.2016070797. Epub 2017 Mar 2. PMID: 28255002; PMCID: PMC5461792.
Excellent
☆What is your management plan?
_______________________________
-Check adherence to immunosuppressive drugs
-Check trough level of tacrolimus and adjust the dose accordingly.
– Graft biopsy: for evidence of AMR
– Follow Renal functions regularly.
– Serial measurements of DSA levels.
☆What is the most significant prognostic factor in this case?
___________________
– MFI less than 2000
– No proteinuria
NOTES:
_______
▪︎The de novo DSAs are associated with AMR and allograft failure, with a higher impact of HLA Class II DSA than Class I.
▪︎ Most of the studies have evaluated the role of DR antibodies, and only a few reports have elaborated the role of DQ antibodies [1].
▪︎ Both α and β chains in DQ molecules express polymorphism unlike HLA-DR antigens, and therefore, de novo DSA antibodies could be formed against both α and β chains.
▪︎Donor-specific HLA-DQ contributes toward inferior graft outcome[2].
________________
Ref:
[1] Mihaylova A, et al. Clinical relevance of anti-HLA antibodies detected by flow-cytometry bead-based assays – Single-center experience.Hum Immunol. 2006;67:787–94.
[2] DeVos JM, et al. Donor-specific HLA-DQ antibodies may contribute to poor graft outcome after renal transplantation. Kidney Int. 2012;82:598–604
True but graft biopsy comes if your serial follow up indicates that it is needed
OK. Thanks
1. The management plan for such patient with postive DSA (anti DQ) with low titer less than 5000 MFI, and nearly stable graft function (about 10% increase from basal creatinine) with onset 6 months after transplantation,absence of protinuria all seems to be assuring prognostic factors.
_ not every DSA means acute rejection, it depends on nature and type of DSA, MFI may give an idea about its seriousness however it is dynamic state and depends on technique and amount if added fluroscence labelling material.
_ However, it may indicate poor adherence to immunosupressives regimen so Chech trough level of tacrolimus and revision of pills uptake may be wise with follow up of titer of DSA is it is rising may need biopsy.
So management plan just to review immunosupressives treatment prescribed doses and adherence in addition to FU of DSA titer, creatinine and A/c ratio.
_ if rising titer of DSA, graft biopsy must be done. Although, no consensus exist about treating subclinical rejection,
there is a concern to treat it to prevent chronic AMR and TG which eventually leads to graft loss
2. I don’t know the most important prognostic factor …may be being anti DQ . However, low MFI, late onset 6 months after transplant, mild increase in creatinine, absence of protinuria all are assuring prognostic criteria.
Knowing that there is a time lapse between the detection of DSA and their effect can you arrange the prognostic factors chronologically:
Titre would be earlier than urine A/C ratio and creatinine level follow up.
What is your management plan?
The presence of anti DQ is expected in this case as there is an enhanced immunogenicity with mismatching at both the HLA-DR and HLA-DQ loci, which is associated with increased production of de novo anti-HLA DQ DSA .Our patient has mismatch at both loci. The high incidence of anti HLA DQ DSA is probably related to the high number of polymorphic epitopes that are expressed on both α and β chains of the HLA-DQ molecule(1)
The MFI value at which the graft is rejected generally happens to be >4000. The DQ antibodies in the present case had an MFI of around 1400. It has also been proved that the strength of the MFI is directly proportional to the graft loss and the outcome. It has also been reported that these DQ antibodies are more resistant to antirejection or desensitization protocols, and therefore should be detected early. This patient has increase in serum creatinine of only10% after 6 months. He has no protein-uria. His DSA MFI is not high (1400). So I will only monitor him with serial DSA in regular interval should be employed as a strategy. The more the MFI levels, the greater the chance of developing rejection and resistance to desensitization. The DQ antibodies either alone or along with other antibodies have an inferior cumulative effect on the graft survival, especially when expressing high MFI.(2)
What is the most significant prognostic factor in this case?
The MFI of DQ DSA
What do you think about kidney function in the index case?
It can be considered stable(only 10% increase above the base line )
1- Sophia Lionaki, Konstantinos Panagiotellis, Aliki Iniotaki, and John N. Boletis, Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation,Journal of Immunology Research / 2013 2- Chowdhry, M., Patel, M., Thakur, Y., & Sharma, V. (2019). Role of de novo DQ donor-specific antibody in antibody-mediated rejection in renal transplant recipient: A case study. Asian journal of transfusion science, 13(2), 136–139. https://doi.org/10.4103/ajts.AJTS_1_18
Very good but prognosis is also affected by proteinuria and kidney function.
What is your management plan?
1-Perform allograft biopsy;
The majority of patients with de novo DSA present signs of rejection in allograft biopsies, even in the absence of proteinuria or eGFR loss. Since the prognosis of rejection therapy crucially depends on early diagnosis, it appears reasonable to perform an allograft biopsy after the detection of de novo DSA, irrespective of proteinuria or eGFR loss.
2- Patients with de novo formation of DSA after transplantation are treated by the clinical syndrome they present with at the time of detection:
(i) Acute allograft dysfunction with histological evidence of antibody mediated injury, are treated with a combination of pulse methylprednisolone, a course of plasma exchange therapy, 6–8 sessions, IVIG, and one pulse of rituximab, 375 mg/m2.
(ii) Recipients who develop de novo DSA often show pathologic features of indolent and slowly progressive microvascular abnormalities. The appearance of these antibodies results from inadequate immunosuppression and thus prevention is synonymous with sufficient immunoregulation and/or enhancing of the level of as needed.
(iii) Detection of de novo DSA in a routine test in patients with stable allograft function;
A closer monitoring of these patients, in addition to the augmentation of immunosuppressive therapy, which typically includes tacrolimus and mycophenolate mofetil is generally suggested. Maintain higher trough level of tacrolimus in such patients (>6 ng/dL) and usually administer 1.5–2 g of mycophenolate mofetil per day, depending on the body weight.
What is the most significant prognostic factor in this case?
There is an enhanced immunogenicity with mismatching at both the HLA-DR and HLA-DQ loci, which is associated with increased production of de novo anti-HLA DQ DSA .
The high incidence of anti HLA DQ DSA is probably related to the high number of polymorphic epitopes that are expressed on both 𝛼 and 𝛽 chains of the HLA-DQ molecule .
Patients who developed DSA after transplant had increased rate of acute rejection episodes, higher serum creatinine, and worst graft survival. Moreover patients with persistent DSA had increased rates of rejection and worst renal function .
Reference ;
1. Nickerson PW. What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation? Am J Transpl. 2020;20(Suppl 4):12–22. doi: 10.1111/ajt.15859. [PubMed] [CrossRef] [Google Scholar].
2- C. Wiebe, I. W. Gibson, T. D. Blydt-Hansen et al., “Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant,” American Journal of Transplantation, vol. 12, no. 5, pp. 1157–1167, 2012.
3-A. Loupy, G. S. Hill, and S. C. Jordan, “The impact of donor-specific anti-HLA antibodies on late kidney allograft failure,” Nature Reviews Nephrology, vol. 8, no. 6, pp. 348–357, 2012.
4- J. M. DeVos, S. J. Patel, K. M. Burns et al., “De novo donor specific antibodies and patient outcomes in renal transplantation,”Clinical Transplantation, pp. 351–358, 2011.
You gave all the different scenarios
What is your decision in this particular real case
Aim of discussing these case is to help in decision taking.
Your first statement strongly implies that ABMR is unlikely.
So monitoring is mandatory specially with 1400 titre of DQ.
If things get worse then biopsy.
But still opinions are diff . And some would start with a biopsy.
So with this stable graft function and no proteinuria what do you expect in the biopsy?
1- Management plan
Anti HLA DQ DSA detection is common due to the high number of polymorphic epitopes that are expressed on both 𝛼 and 𝛽 chains of the HLA-DQ molecule.
The best therapeutic approach for cases with de novo DSA depends on the clinical picture at the time of detection.
In this case de novo DSA (DQ 4 with MFI 1400 which is not considered high level ) was detected 6 months post transplantation with nearly stable serum creatinine as it was(101 umol/l ) post transplantation reaching 6 months later 112 umol/l with no proteinuria.
It could be 2 possibilities either Indolent allograft dysfunction with slower, gradual decline of renal function, without acute deterioration renal function or significant proteinuria and after excluding of other causes. De novo DSA bind to allogenic targets expressed by graft endothelium activating complement system and evoking rejection. De novo DSA detection can be attributed to insufficient immunosuppression , and it is prevented by enhancing adequate doses of immunosuppression.
The other possibility could be continuation of the history of acute AMR. It is unknown how to treat such cases but they need closer monitoring as well as maintain higher trough level of tacrolimus in such patients (>6 ng/dL) and administer 1.5–2 g/kg of mycophenolate mofetil per day, also bortezomib was introduced as one cycle (1.3 mg/m2 × 4 doses) but it’s results as monotherapy was not promising.(1)
2-The most significant prognostic factor is frequent monitoring of DSA level with titer MFI along with renal function and protienuria level as well as protocol allograft biopsy .
A study done by Waldecker C . B. et al concluded that most of the cases with de novo DSA have histological signs of rejection, even in the absence of proteinuria and deterioration of graft function. Therefore it is reasonable to undergo an allograft protocol biopsy after the detection of de novo DSA. (2)
Mean while this was a single center trial .
Reference
1- Lionaki S et al .Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation, Clinical and Developmental Immunology Volume 2013, Article ID 849835, 9 pages.
2- Waldecker C B etal . Biopsy fndings after detection of de novo donor‑specifc antibodies in renal transplant recipients: a single center experience. Journal of Nephrology (2021) 34:2017–2026
HLA DQ is the de novo antibody that develops most often after transplantation, which may be owing to the prevalence of this HLA antigen in the body. This would definitely incline the generation of DSAs against HLA DQ4 due to the fact that they are 111 mismatched. The condition has been linked to a negative allograft result over the long term, as well as a significant risk of chronic AMR. However, for this patient.
-I would recommend that the DSAs MFI and proteinuria be closely monitored
-Review the compliance of the patient with the medications.
-If proteinuria starts to increase will proceed for renal biopsy.
-optimise the immunosuppressive medication(keep tacrolimus on the higher limit).
the prognostic factors: derangement of renal function, the appearance of proteinuria and titration of DSA level.
1- Patient has stable kidney function, no proteinuria, maintained on triple immunosuppression tacrolimus based.
The question is why DSA were measured, as there is clinical indication ( acute rise in creatinine or proteinuria).
DSA anti HLA DQ with MFI 1600 is not associated with AMR, as anti HLA class II are associated with chronic allograft failure and not AMR.
plan:
measurement of CNI to ensure compliance
serial measurement of DSA
Biopsy is the standard of care for the diagnosis of underlying pathology especially in the settings of subclinical rejection.
What is your management plan?
DQ- DSA is the most commonly detected DSA of class II HLA antigens , usually appear later, commonly non-complement fixing, and are usually of IgG2 or IgG4 subclass and is associated with more chances of chronic ABMR and transplant glomerulopathy. In this case ,there is no proteinuria and no significant deterioration of renal function(25% of baseline) ,so close follow up of the DSAs MFI ,proteinuria and also creatinine level on weekly basis needed ,if MFI increasing significantly to more than 5000 MFI or creatinine rising , Flow cross match and biopsy needed to check for histological features of chronic ABMR or MVI. This patient is already on optimal protocol, so no modification needed at present ,however , would check Tacrolimus trough level (keep around 8-10ng/ml)and to adjust accordingly.
What is the most significant prognostic factor in this case?
The most significant prognostic factor is the presence of detectable antiHLA antibodies and its titer which predict the risk of graft loss.
REFERENCE:
1- Fehr T, Gaspert A. Antibody-mediated kidney allograft rejection: therapeutic options and their experimental rationale. Transpl Int 2012; 25:623
2- DeVos JM, Gaber AO, Knight RJ, et al. Donor‑specific HLA‑DQ antibodies may contribute to poor graft outcome after renal transplantation. Kidney Int 2012;82:598‑604
De novo DSA can occur in 13-30% of non sensitized patients, & risk factors of DSA formation include:
Both alpha & beta chains in DQ molecule express polymorphism so de novo DSA can be against both chains & this may be responsible for high prevalence & strength of DQ DSA.
Aggressive removal of DQ DSA may be not successful & this put the recipients on risk of high dose of immunosuppression without much benefit.
Management plan include:
References:
Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J AM Soc Nephrol, 2018; 13: 182-192.
Chowdhry M., Patel M., Thakur Y. and Sharma V. Role of de novo DQ donor-specific antibody in antibody-mediated rejection in renal transplant recipients: A case study. Asian J Transfu Sci, 2019:136-9.
Dq4 de novo DSA with preserved renal function and no proteinuria carry a good prognosis with graft failure , However management same his immunosuppressive agents and serial monitoring of De novo DSA level and scheduling for renal biopsy to avoid graft loss
Prognostic factors de novo DSA level and maintained eGFR and absence of proteinuria
Patient developed De novo DSA 6month with no proteinuria and stable renal
function(less than 25%) .
Ascertain of compliance of medication is important.
Follow up of DSA needed ,even titer is low, as de novo production DSA of any specificity
found to be associated with AMR and transplant glomerulopathy. Only HLA-CW DSA
were found not to be associated with graft failure.(1).
Presence of detectable antiHLA antibodies is important prognostic factor , predict the risk of graft loss.
References :
Sophia Lionaki et al. Incidence and clinical Significance of De Novo DSA after Kidney
Transplantation. open access .Volume 2014/Article ID849835.