III. Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
This is a prospective single center study at University of Pittsburgh Medical Center from January 2013 until November 2014. The objectives of this study is to assess the association of DSA with post transplant renal graft rejection outcome in correlation with T cell mediated rejection and poor compliant to medications.
A total of 67 ( 22.8% ) out of 294 patients developed DSA in the first year after kidney transplantation. The risk factors triggering the DSA are young age, non-Caucasian, numbers of HLA mismatches and delayed graft function. DSA attributed 1.8-fold higher incidence of TCMR among kidney transplant recipients. Both DSA and TCMR associated with severe IFTA lead to allograft failure and poor outcome in 1 year. Nonadherence to immunosuppressants associated with poor renal allograft outcome especially in the presence of both DSA and TCMR. In conclusion, kidney transplant recipients with DSA and TCMR is associated with tubulointerstitial inflammation, which led to subsequent poor allograft outcomes compared with those with DSA or TCMR alone. Furthermore, nonadherence to immunosuppressants markedly contributed to poor renal allograft outcomes in recipients with DSA and TCMR. Thus, it is important to identify kidney transplant recipients with DSA and TCMR and early assessment of their compliant to immunosuppressants.
Ramy Elshahat
2 years ago
Donor-specific antibodies (DSAs) can be classified according to the time of operation into: a preformed DSA which already presents preoperative and de novo DSA which appears after transplantation due to sensitization. Preformed DSA can cause hyperacute and acute rejection post-transplant and this can be avoided by crossmatching screening pre-transplant but de-novo DSA detection post-transplantation is associated with poor graft survival. In this retrospective single-center study including 378 patients who underwent kidney transplantation between January 2013 and November 2014, DSA has screened at 0,1,3,6,9,12 months. protocol biopsies at 3 and 12 months in addition to for-cause biopsy. This study showed that patients with de-novo DSA are more exposed to developing TCMR more frequent, more severe, and more resistant to treatment, and as a sequel, they develop a higher chronicity indexwith a 3-fold increase in the risk of graft loss. On the other hand, pure ABMR is rare and less common than mixed TCMR and ABMR. The relation between DSA and TCMR may be explained by T cell and B cells crosstalk and the 3 signals stimulation of naive T cells which are crucial before forming TFh which is responsible for B cell stimulation and DSA production and tissue injury induced by DSA stimulate T cell response that’s why in this study, 80% of the patients who develop TCMR has DSA either preformed or de novo. Risk factors for developing de-novo DSA · HLA mismatch · cadaveric kidney and delayed graft function · Younger age · subtherapeutic immunosuppression · Noncompliance on immunosuppressive medication · Infections · TCMR One of the most important causes of the development of de-novo DSA is non-adherence to medications In conclusion, Non-adherence was associated with DSA+ TCMR+ and poor graft outcomes.
Wael Jebur
2 years ago
To study the incidence , time of onset and allograft survival of transplant patients who developed TCMR in the context of de novo DSAs, furthermore, the incidence of TCMR vs ABMR in patients with DSAs was observed in this study.
276 patients from single center enrolled in prospective study wherein DSAs level was monitored post transplantation and correlated to the incidence of acute rejection, its type TCMR vs ABMR, severity of rejection , outcome of rejection, correlation of TCMR and ABMR to no DSAs , or presence of DSAs and relation to adherence . Non adherence was identified by intra-patient variation of CNI trough level in the first year post transplantation
DSAs detection and monitoring:
1-De novo DSAs
2-All patient were negative for DSAs at transplantation time as assessed by luminex test and FCXM.
3-67/294 patients tested positive for DSAs during the first year,40% were transient and persistent in the rest of the patients .
3- Risk factors for De novo DSAs are high cPRA, delayed graft function and HLA mismatches.
4-Most important risk factor was those patients with De novo DSAs exhibited much CNi intra-patient variability IPV which is a surrogate marker for non adherence. DSAs andTCMR:
108/294 experienced TCMR in the first year, (with more than 50% sub-clinical detected by protocol biopsy done on 3rd and 12th months post transplantation).
ABMR was discovered in 11/294 patients always in the context of TCMR
(mixed ABMR+TCMR).
DSAs positive Patients had 1.8 higher incidence of TCMR. In 82% the DSAs were present before the diagnosis of TCMR, in 18 % it was detected afterwards.
TCMR+ABMR incidence is higher in DSAs positive patients.
The higher incidence and higher-grade Banff lesions were reported with DSAs positive patients reflected in peak Banff acute inflammation i, g, t, ptc scores. Importantly DSAs positive patients with TCMR featured resistant /late recurrent TCMR than DSAs negative TCMR patients.
DSAs positive patients have higher incidence of IFTA at the one year post transplant and IFTA+i (inflammation) then DSAs negative patients.
Nandita Sugumar
2 years ago
Summary
The focus of this paper is the outcome of a kidney transplant recipient with respect to DSA and TCMR. The theme identifies that patients with DSA and TCMR have worse graft outcomes (almost 3 times higher risk) than patients with DSA alone or TCMR alone.
DSA is associated more with TCMR than AMR. Modifiable risk factor for this is non-adherence. Non-adherence can be measured through the variability in CNI levels between different patients on the same regimen. Patients who were adherent had better graft outcomes even with DSA and TCMR.
DSA in the early post transplant phase is dangerous for the graft, and especially more so in patients who are not regular with their IS regimen. They are more at risk for TCMR than patients with DSA who were adherent.
Jamila Elamouri
2 years ago
III- post-transplant DSA is associated with poor kidney transplant outcomes only when combined with both T-cell-mediated rejection and non-adherence.
Development of de novo DSA post-transplantation is associated with ABMR leading to poor outcomes. Suboptimal control of the humoral immunity by immunosuppressive drugs is the main cause. Mostly, these antibodies are detected at the time of impending graft loss. However, de novo DSA is also associated with subclinical rejection. Therefore, its exact pathologic role remains unclear. In addition, the presence of the DSAs also indicates the presence of a mature cellular alloimmune response, because the development of DSA requires T cell help. Many studies show a relationship between DSA and TCMR. Wiebe et al. TCMR was higher and precede the development of DSA. There is conflict in the literature about the effect of DSA according to the time of their appearance, incidence, and the role of TCMR. Moreover, the incidence of ABMR versus TCMR in patients with post-transplant DSA remains unclear.
The study is prospective in which DSA was screened serially post-transplantation and correlated with acute rejection diagnosed by biopsy either protocol or for cause, at 3 and 12 months. They compare the severity of the rejection and graft outcome according to the presence or absence of DSA, or TCMR, either alone or with DSA. Also, they correlate DSA and TCMR to nonadherence, measured by intrapatient variability of CNI trough levels during the first post-transplant year. Results:
Most patients underwent allograft biopsy either protocol or for the cause. Some in the early period (0 – 5 months), others late between 6 – 12 months, and others had paired biopsies at both early and late times.
Posttransplant DSA detection:
At the time of transplantation (time 0), DSA were negative in all patients assessed by Luminex and negative flow crossmatch. 22.8% of the patients developed DSA during the first year, of which 40% were transient DSA and in 60% were persistent. The mean time to detect DSA was 3.4 months. 39% of patients with DSA had historical DSA up to 2 years and the remaining 60% had de novo DSA.
Patients who developed DSA during the first year were younger, non-Caucasian, had higher PRA, more HLA mismatches, and tends to have delayed graft function than those without DSA. Also, they exhibited greater CNI variability during the first year post-transplant, and the baseline renal function was similar between those with and without DSA. DSA is associated with increased incidence and severity of TCMR:
Patients with DSA gad a higher incidence of TCMR than those without DSA. DSA was also associated with an increased incidence of both clinical and subclinical TCMR.
Patients with either transient or persistent DSA had an increased incidence of clinical TCMR, while patients with persistent DSA had a much higher incidence of subclinical TCMR. In addition, the presence of DSA is associated with TCMR in concomitant with ABMR, compared with those without DSA. DSA correlate with the incidence and severity of TCMR. Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year:
Patients with both DSA and TCMR have the highest mean IFTA score (file:///C:/Users/DRB7C5~1.JAM/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png and high IF + Inflammation, which suggests that these patients are at high risk of early chronicity within one-year posttransplant. Considering the time of detection of DSA, patients whose DSA was detected with or before TCMR had worse IFTA compared with those whose DSA was detected after TCMR. DSA plus TCMR is associated with worse renal allograft outcomes
Patients with DSA+TCMR+ had significantly higher serum creatinine and are at risk of poor outcomes. The timing of DSA to TCMR makes no significant differences. Risk factors for concomitant DSA and TCMR:
Patients with DSA+TCMR represent a high-risk group, young age, HLA class I, and delayed graft function were independently associated with DSA+TCMR+. Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
DSA+TCMR patients had greater CNI-intrapatient variability (CNI-IPV) as defined by cutoff ≥35%). Nonadherence was associated with an increased rate of TCMR either persistent or recurrent and increased IFTA at one year. In fact, patients with DSA+TCMR+ who were adherent had significantly similar graft survival to adherent patients who do not develop either DSA or TCMR or both. But, nonadherent patients who are negative for DSA and TCMR still have an increased risk of graft loss/impending graft loss compared with adherent patients. Therefore, nonadherence as assessed by a high CNI-IPV is a risk for poor outcomes in patients with DSA+TCMR+, and emphasising this problem represents a key therapeutic opportunity.
Discussion:
Any clinical or subclinical rejection, leading to chronic damage, is the major cause of late allograft loss, so early identification of patients at increased risk for chronic damage and graft loss, allowing timely therapeutic intervention, is of paramount importance.
With the development of the DSA test, DSA can be monitored and it adds more understanding to the pathogenesis of ABMR so, it added to the Banff classification of ABMR. DSA assay allows the physician to identify patients at increased risk for subsequent allograft loss.
DSA developed at any time post-transplantation is associated with poorer graft survival, although 50% have stable long-term graft function. They are associated with greater incidence and severity of TCMR that can be mixed with ABMR, although isolated TCMR was more frequent. Indeed, this indicates that the major component of allograft injury in patients with DSA is T cell-mediated, supporting the need for T cell response to develop these antibodies. The present study reveals that the TCMR (i, and t scores) and not the ABMR parameters were associated with graft loss in DSA patients. DSA is associated with increased frequency and severity of TCMR in the first year and this was associated with increased chronic damage and inferior long-term graft survival compared with DSA or TCMR alone.
In the present study, all patients lack preformed DSA at the time of transplant, which can explain the low incidence of ABMR in this study. This finding supports the fact that exposure of the allograft to preformed antibody, even in low titers, is more injurious
and supports other studies that show that presensitized patients are at higher risk of ABMR, and pre-sensitized antibodies are more injurious than the exposure that occurs after accommodation might have occurred. Graft outcome correlated with DSA in the presence or absence of TCMR.
As some of the DSA+ patients have transient DSA, and these so they are unlikely to significantly contribute to antibody-mediated damage. Thus, DSA development likely indicates a mature effector T-cell response.
Nonadherence is of particular importance in the development of DSA. And nonadherent patients with DSA and TCMR show bad allograft outcomes. In contrast, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
The present study is the first to link DSA, TCMR, and nonadherence as a trial that occurs in the first year, provides an opportunity for targeted intervention. Conclusion:
DSA development with TCMR carries bad outcomes as it is associated with chronic damage. Therefore, prompt identification of patients with DSA and TCMR and early assessment of their adherence to medication after transplantation would allow targeted intervention with close follow-up, monitoring, and consideration of long-acting immunosuppressive drugs as belatacept.
ahmed saleeh
3 years ago
the association and clinical significance of TCMR and DSA arising after transplantation is not well understood. As development of antibodies requires T cell help .
the literature is discrepant as to the incidence, timing, and impact in terms of graft survival of TCMR in patients who develop posttransplant DSA.
Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA
The increased incidence of acute rejection and higher-grade Banff lesions in subjects with DSA was also reflected in higher peak Banff acute inflammation (“t,”“i,”“g,”“ptc”)score
DSA+ TCMR+ patients are at high risk for developing chronic allograft nephropathy within 1 year after transplant .
patients whose DSAwas detected with or before TCMR had worse IFTA compared with those whose DSAwas detected after TCMR
although patients who develop DSA anytime in their posttransplant course have poorer graft survival, approximately 50% exhibit stable long-term function
DSA was associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy
Both clinical and subclinical TCMR with Banff 1A and 1B were treated with 3 doses of methylprednisolone (250 mg each) and maintenance prednisolone at 5 mg/d. TCMR with Banff >2A and those resistant to steroids were were treated with Thymoglobulin (maximum6mg/kg) over 4 to 5 days.Acute ABMR was treated with 4 to 6 treatments of plasmapheresis plus IVIG.
Manal Malik
3 years ago
Summary of Post-transplant DSA is associated with poor kidney transplant outcomes only when combined with both TCMR and non-adherence Introduction:
· The study design to determined factors associated with poor four years outcome in desensitized patients who develop post transplant DSA
· De novo anti donor HLA (DSA)is associated with poor graft outcome
· The clinical implication of de novo DSA and the pathogenic role of DSA itself remain unclear
· Antibody production usually require T cell helper so presence of DSA molecule means presence of mature cellular alloimmune response
· Literature is descript as to the incidence ,timing ,and impact in term of graft survival of TCMR in patients with DSA +ve
· Incidence of ABMR versus TCMR in post transplant DSA+ve patients remain unclear
· Prospective study DSA was screened serially from the time of transplantation and correlated with acute rejection, severity of rejection in 4 groups of patients:
a)TCMR +ve , DSA+ve
b) TCMR -ve,DSA -ve
c) TCMR +ve,DSA-ve
d)TCMR -ve, DSA+ve
· TCMR and DSA +ve groups correlate to nonadherence of immunosuppression therapy (CNI)
Results:
· Among 378 patients kidney transplant between JAN 2011-Nov 2014
· 15 patients excluded (death, graft loss within 3 months)
· 363 patients 294 of them had at least 1 allograft biopsy within first year of transplant were include in the study
· 270 renal biopsy taken early from 0 to 5 months
· 244 renal biopsy taken late 6 to 12 months
· Total 209 of 294 had paired biopsy (early+late) and this group of patients were used to analyse histological progression
Posttransplant DSA detection
· All patients were -ve at the time of transplant determined by luminx and negative flow cross-match
· 294 patients 67 develop DSA in the first year so 40% transient DSA and 60%presistent DSA
· 61% of these has de novo DSA
· DSA associated with high incidence of sever TCMR.
· Patents with DSA+ve had 1.8 folder highe incidence of TCMR than those without DSA.
· The incidence of acute rejection and high graft Banff acute inflammation(t,I,g,ptc)
· De novo DSA had a much higher rate of TCMR with persistent TCMR compared with those without DSA
DSA is associated with increased incidence and severity of TCMR
· TCMR with DSA positive have greater interstrial fibrosis and tubular atrophy(IFTA) at one year and poor long term graft out come(graft dysfunction)
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
· Study shows that DSA+ve and TCMR had significs high risk of allograft loss compared with the other patients group 50% versus <20 or less
· Poor graft out come in DSA ve+ TCMR remain signifenciy even after elimination pateints with ABMR or those with early DSA (1month) from analysis so that mean the risk is not due to high incidence of ABMR .
· Transit DSA has poor long term out come as persistent DSA.
Risk factors for concomitant DSA and TCMR
Risk factor DSA+ev plus TCMR include:
· 1) HLA class 1mismatch,
· 2) thymoglobulin induction
· 3) cold ischemia times.
· 4) delay graft function.
· 5) CNI level, cPRA ,living donor or not
· 6) other factors such as age, gender ,ethnicity, chronic disease (DM/HTN )and primary renal disease Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
· .Non adherence to immunosuppression therapy(CNI) increase the rate of TCMR and persist/recurrent TCMR and increase IFA at 1 year and subsequent graft loss (at 48 months) in patients group TCMR +DSA+ve than the other group TCMR with DSA-ve
Discussion:
· Despite 1 year kidney allograft survival improvement graft survival beyond the first year remain unchanged for decades
· Chronic damage and graft loss result from persistent clinical and subclinical rejection
· Early diagnosed of chronic damage allowed proper therapeutic intervention
· Early detection of DSA will offer prevention for patients at risk for allograft loss
· 50% of patients who develop DSA still have stable long term functioning graft
· DSA and rejection relationship with other factors affect allograft survival in patients who develop post transplant DSA are poor understood
· Understanding history of DSA and allograft biology will help to detect risk factors for poor outcome allowing change in therapy before irreversible damage occur
· In this study serially examine DSA in patients not require desensitization starting one month after transplant and examine it relationship with allograft inflammation (protocol biopsy) and 4 year graft outcome
Results:
· DSA associated HLA incident and severely of TCMR and graft loss despite standard of care immunosuppression therapy and antirejection therapy
· TCMR DSA+ve in first year post transplant poor long term allograft survival compare with patients with either DSA or TCMR alone
· Isolated ABMR was not observe in DSA +ve patients only mixed TCMR and ABMR compare patients without DSA
· De novo Antibody require T cell help for B cell maturation
· Both ABMR and TCMR associated with graft loss in patients with DSA
· Limitation of this study lack of direct comparison between patients group stratified by both TCMR and DSA
· 40% of DSA patients was transient so significance to cause ABMR
· TCMR +DSA +ve and nonadherent had bad allograft outcome 70% impending graft loss by 4 years
CONCLUSION:
· Study showed recipient with DSA and TCMR has worse tubulointerstitial inflammation and worse graft outcome compare with those DSA or TCMR alone
· Nonadherence in first year in DSA +ve and TCMR patients has poor graft out come
Ahmed Omran
3 years ago
Post-transplant DSA have been associated with poor outcomes. This study aiming to evaluate effect of DSA on patients having T cell mediated rejection post transplant. 294 transplant recipients between January 2013 and November 2014 were selected. DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies implemented at 3 and 12 months, and any for original cause biopsies.
22.8% patients showed DSA in the first year, 40% of whom developed transient DSA. 39% of them had historical DSA while 61% showed de-novo DSA. Patients who developed DSA were younger, non-Caucasian, had increased HLA mismatches especially class I, with more PRA and higher incidence of delayed graft function in comparison with those who did not develop DSA. Risk factors for developing De Novo DSA include:
HLA mismatch, delayed graft function, younger age, non -living related; deceased donor kidney ,planned subtherapeutic immunosuppression ;due to malignancy, infection or change to CNI free or CS free protocols non compliance on immunosuppressive medication inflammation-induced by infections ,in addition to surgery or TCMR.
Patients with DSA and TCMR shad 1.35-fold greater CNI-IPV than the other patients. Non-compliant patients with DSA and TCMR showed worse allograft outcomes, with graft loss at 4 years in 70% of patients. Adherent patients who developed DSA plus TCMR showed graft survival like those without TCMR and DSA.
The three items of DSA, TCMR and non-compliance to medications are linked to worse graft survival. Hence, identification of patients with these items could help early therapeutic intervention, avoiding early graft loss.
Mohamed Essmat
3 years ago
The article addresses a prospective, single center study involving non-desensitized transplant recipients regarding the effect of post-transplant DSA’s over the kidney transplant outcomes. The study was done to evaluate the effect of DSA on patients having TCMR post-transplant. 294 transplant recipients were included in the study. The DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies were performed at 3 and 12 months. 22.8% patients developed DSA in the first year, 40% of whom had transient DSA. 39% of these patients had historical DSA while 61% developed de-novo DSA. Patients who developed DSA were of younger age, non-caucasian, had more HLA mismatches (especially class I), higher PRA and higher incidence of delayed graft function as compared to those who did not develop DSA. DSA positive patients with TCMR had higher prevalence of chronic allograft damage at 1 year and worse graft outcomes at 4 years. High CNI intrapatient variability (IPV), as a marker of non-adherence, was associated with increased TCMR rate and severity. 46% of patients with DSA and TCMR had high CNI IPV. Graft survival in adherent DSA positive patients with TCMR was similar to those without DSA or TCMR, or both. 75% of non-adherent patients with DSA and TCMR developed graft failure. Thus , DSA leads to increased incidence and severity of TCMR along with poor long-term graft results, which increases in the presence of non-adherence.
Abdullah Raoof
3 years ago
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated
rejection and non-adherence
Post transplant DSA is associated with poor outcome .
Comared to those not exhibit DSA, those with DSA are associated more with clinical and subclinical TCMR.
Combination of +ve DSA and TCMR lead to 3 fold increase in graft loss compared to either DSA or TCMR alone.
ABMR was uncommon and always associated with TCMR.
75% of patients with non adherence and DSA and TCMR has impending graft loss at 4 years.
Insufficient control of humoral immunity by immune suppressant medication is associated graft dysfunction and loss.
DSA is traditionally been shown to be associated with ABMR.
50% of patient has good graft functioning despite of having +ve DSA.
Because the development of antibodies requires T cell help, the presence of DSA also indicates the presence of a more mature cellular allo immune response. Indeed, several studies have shown a relationship between DSA and T-cell–mediated rejection (TCMR).
DSA +ve patients at 4.5 years has higher incidence in TCMR in first year than those who has no DSA . Thesestudies showed that the increased graft loss associated with DSAwas limited to patients who had acute rejection. DSA +VE pt has 1.8 fold higher incidence of TCMR than those without DSA . Interestingly, patientswith de novo DSA had a much higher rate of TCMR with morepersistent or recurrent TCMR when compared with thosewithout DSA or anamnestic DSA Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year. Risk factors for concomitant DSA and TCMR . 1- Young age recipient. 2- Class 1 HLA mismatch. 3- Delayed graft function. Are independently associated with DSA + ve , TCMR + ve .
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA Non adherence (more than 35% variability in intra patient CNI trough level) associated with increase in TCMR AND +VE DSA and increased IFTA the presence of DSA is indicative of a more mature immune response with contributions from both humoral and cellular immunity. Some study found that, In the absence of acute rejection DSA alone has no effect on graft survival. Preformed DSA is more injurious than denovo DSA. In 40% of patient, the DSA is transient and is unlikely contribut to AB mediated damage .
Mohammed Sobair
3 years ago
Post-transplant donor specific antibody (DSA) is associated with poor renal allograft
outcomes.
Prospectively nonsensitized patients STUDIES to determine factors associated with
poor four-year outcomes in patients who developed post transplant DSA. Using serial
monitoring, 67 of 294 patients were found to develop DSA by one year.
Introduction:
In number of studies, DSA was detected at the time of impending graft loss, suggesting a
possible causative role. Moreover, DSA has traditionally been shown to be strongly
associated with ABMR.
Many of these studies retrospective and small sample size and inclusion of presensitized
patients. Several studies have shown a relationship between DSA andTCMR. Moreover,
the incidence of ABMR versus TCMR in patients with post transplant DSA remains
unclear.
To address these issues, a prospective single center study is done, where DSA was
screened serially from the time of transplantation and correlated with acute rejection
(detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months),
severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR,
DSA alone, TCMR alone, or DSA plus TCMR.
In addition, DSA correlated and TCMR to nonadherence, measured by intrapatient
variability of Calcineurin inhibitor (CNI) trough levels during the first post transplant year.
RESULTS Study:
Amongst 378 patients who underwent kidney transplantation between January 2013 and
November 2014.
294 (81%) had at least 1 allograft biopsy within the first post transplant year and were
included in the study.
Of these, 276 patients had a biopsy between 0 and 5 months (early histology) and 224
patients had a biopsy between 6 and 12 months (late histology).
A total of 209 of 294 patients (71%) had paired biopsies at both early and late time point.
Post transplant DSA detection:
Determined by luminex and a negative flow cross-match.
Patients who developed DSA within the first post transplant year were:
Younger.
Non-Caucasian.
Higher Pretransplant panel reactive antibody.
More human leucocyte antigen mismatches.
Greater CNI intrapatient variable.
DSA is associated with increased incidence and severity of TCMR:
36.7% experienced TCMR in the first post transplant year,
47% being clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at
3 months or at 12 months.
Importantly, ABMR in 10.2% of all rejections and was always detected in the presence of
concomitant TCMR.
DSAþ patients were twice as likely to have persistent/ recurrent late TCMR (6–12
months) compared with those without DSA (P ¼ 0.08). This suggests that DSA may
identify a subgroup of patients whose rejection is relatively resistant to standard
treatment.
Patients with DSA and TCMR have increased chronic renal allograft damage at 1
year:
Combination of DSA and TCMR was associated with early chronic histological damage.
DSA plus TCMR is associated with worse renal allograft outcomes:
patients with DSAþ+ TCMRþ had significantly higher serum creatinine at the last follow-
up when compared with all the other groups, Furthermore, DSAþTCMRþ was associated
with significantly worse graft survival at 4 years compared with all other patient groups
(23% vs. approximately 10%).
Immunosuppression adherence markedly affects clinical outcomes in patients with
TCMR plus DSA:
Nonadherence assessed by a high CNI-IPV accounts for the particularly poor outcomes
noted in patients with DSAþTCMRþ, and addressing this problem may represent an
important therapeutic opportunity.
nawaf yehia
3 years ago
The development of de novo anti donor human Leukocyte antigen specific antibody DSA is associated with poor outcomes in kidney transplantation. DSA was detected at time of impending graft loss suggesting a possible causative role. Moreover, DSA has traditionally been shown to be strongly associated with antibody mediated rejection ABMR.
Because the development of antibodies requires T Cell help , The presence of DSA also indicates the presence of a more mature cellular allo immune response. Indeed, several Studies have shown a relationship between DSA and T-cell mediated rejection TCMR ,Yet the association and clinical significance of TCMR and dies arising after transplantation is not well understood.
In a comprehensive prospective analysis It was shown that de novo DSA occurred late (Mean 4.6 years) And was associated with twofold higher incidence of TCMR occurring within the first year as compared with patients without DSA. This suggested that TCMR precedes the development of alloantibodies and antibody-mediated rejection.
In this study , DSA was screened serially from the time of transplantation and correlated with acute rejection. Which, Is detected by for- cause biopsies as well as protocol biopsies at three and 12 months. Also severity of rejection and grafts outcomes, comparing patients exhibiting no DSA nor TCMR Versus those with DSA alone ,Those with TCMR alone or DSA plus TCMR.
In addition to collerating DSA and TCMR to non-adherence measured by intra patient variability of calcineurin inhibitor trough levels during the first post transplant year .
In this study , biopsies done either as Protocol biopsy or for-cause biopsy Between zero and five months(early histology ),or between the 6th and 12th months (late histology)
All patients In this study where – for DSA a time of transplantation.( time 0 )as determined by luminex and a negative flow cross-match.
DSA is associated with increased incidence and severity of TCMR. In this study, 36.7 percent of patients experienced TCM are in the first post transplant year. With 47% being clinical TCM are and 53% being subclinical TCM are diagnosed on a biopsy. Importantly, ABMR was seen in about 10% of all rejections. And was always detected in the presence of concomitant TCMR. Among those patients with DSA+ TCMR+ , DSA was detected concomitant with or before the diagnosis of TCM are in 82 percent of patients. Whereas only 18 percent of patients developed DSA after the diagnosis of TCMR .Also patients with DSA had more TCMR with concomitant ABMR as compared with those without DSA.
The increased incidence of acute rejection and higher grade bannf Lesions in subjects with DSA was also reflected in higher Peak bannf acute inflammation Scores.
Another Finding. Is that despite standard of care treatment of TCMR,DSA positive patients were twice as likely to have persistent or recurrent late TCMR that’s between 6 and 12 months compared with those without DSA. This suggests that DSA May identify a subgroup of patients whose rejection is relatively resistant to standard therapy.
Patients with DSA and TCMR have increased, chronic renal allograft damage at one year ,It was found that DSA was associated with significantly greater interstitial fibrosis and tubular atrophy IFTA at one year. And a greater proportion of patients with DSA had an, an IFTA score that is equal or more than 3. DSA was associated with increased interstitial fibrosis with inflammation. IF + I .So patients with DSA + TCMR+ had the highest mean IFTAscore.
Also, it was found that patients whose DSA was detected with or before TCMR had a worse IFTA compared with those whose DSA was developed afterTCMR.
So in conclusion, DSA + TCMR + is associated with worse renal allograft outcome. DSA+ TC MR+ was associated with significantly worse graft survival at 4 years.
Patients with DSA +. TCMR+ had a significantly higher risk of allograft loss and impending allograft loss (s 50 percent versus less than 20%). Furthermore, DSA detected prior to TCMR was associated with significantly greater risk of graft loss, plus impending graft loss in comparison to DSA alone. In those whose DSA was detected after TCMR , they exhibited as that Statistically nonsignificant Trend toward increased graft loss or impending graft loss compared with the DSA alone. However, regardless of whether DSA precedes or follows TCMR , the combination of DSA & TCMR carries a worse prognosis than having DSA without TCMR .
Risk factors for concomitant, DSA and TCMR : factors associated with this phenotype compared with all remaining patients.
. younger recipient age.
.class. 1 HLA mismatches.
. Third delayed graft function.
.non-adherence to immune suppressive medications
For non-adherent patients. Especially those with a high CNI-IPV. That is equal or more than 35%. With both DSA+TCMR+. Those had significantly higher graft loss or impending graft loss at 48 months as compared to those DSA+TCMR + adherent to treatment. In fact, patients DSA+TCMR+ who were adherent had statistically similar graft survival to adherent patient Who lacked either DSA or TCMR or both.
So in conclusion, DSA is associated with increased incidence of higher Banff grade and recurrent T-cell mediated rejection. The incidence of TCMR was higher in DSA positive. As compared to those who are DSA negative (about 60 % vs 30% )
Comparing between clinical TCM are and subclinical TCMR, which the latter is detected on biopsy ,
It’s found that patients with DSA +had more TCMR whether it’s a clinical or subclinical, then those who are DSA –
regarding the temple relationship between DSA & TCMR ,DSA that is detected before the diagnosis of TCMR Was about thirty percent.DSA detected concomitant with diagnosis of TCMR Is 17%. ,While TCM are diagnosed before the detection of TSA is 10%. So, the most common type is DSA That’s prior to detection of TCMR.
Ben Lomatayo
3 years ago
The presence of DSA is associated adverse outcomes in kidney allograft (1-6). DSA increases the risk of the TCMR either clinical and sub-clinical forms. Non-adherence isan important risk factor for development of both DSA and TCMR.
Methodoolgy ;
Study population;
DSA screening was done at 0,1,3,6,9 & 12 months, and protocol biopsies at 3 and 12 months. indication biopsies was considered when neccessary Early biopsies was 0-5 months and late biopsies was 6-12 months All were DSA negative and non-sensitised This was prospective study of 378 ( 15 excluded due to graft loss at 3 months, another 69 were excluded because no biopsy was done) for development of DSA within one year post-transplant between Jan 2013 and Nov 2014 and followed up to may 2018. Patients were divided into 4 groups ; 1) DSA+ plus TCMR+ 2) DSA- plus TCMR+ 3) DSA+ plus TCMR- 4) DSA- plus TCMR- .
DSA monitorning and testing ; Cut off >= 1000 by single antigen bead Histortical DSA was checked for 2 years before transplants
Renal allograft histology ; Definition of TCMR & IFTA and IF+i was based on 2013 Banff criteria
Immunosuppression ;
Thymoglobulin 6mg/kg + single dose methylpred 500 mg followed by dual therapy = CNI + MPA Few got basilliximab + methylpred Triple therapy ( MPA + CNI + Pred) only if cPRA > 90%
Assessment of non-adherence ;
This measured by CNI-intrapatient variability, where tac levels for 1 year( highest + lowsest level considered) was calculated
Treatment of clinical and sub-clinical TCMR ; 3 days iv 250 methypred for Banff 1A & 1B 4 days of iv Thymoglobulin 6mg/kg for Banff >2A
Study end point ; Graft loss and impending graft loss( eGFR< 30 ml/min and change in eGFR> 30% from 3 to 40 months
Statistical analysis ; Mann-White U test, Chi-squared test, uni-and multivariate analysis plus Kaplan-Meier were used.
Results ;
Posttransplant DSA ; In 67 patients DSA was transient in 40% and 60% of patients The average time for detection of DSA was 3.4 months
DSA is associated with increased incidence and severity of TCMR ; ABMR accounted for 10.2% of all rejections and usually coexisted with TCMR Those with DSA had 1.8 fold increased rates of TCMR than those without TCMR
Patients with DSA and TCMR have increased Chronic renal allograft damage at 1 year; TCMR+ TCMR+ patients are at risk for developing chronic allograft dysfunction within 1 year after transplant. DSA before or at time of TCMR is associated with more chronic IFTA than DSA after TCMR
DSA plus TCMR is associated with worse renal allograft outcomes ; Worse allograft survival at 4 years were seen those with DSA+ plus TCMR (= high risk group for poor outcomes)
Risk factors for con-cominant DSA and TCMR ;
Younger recipient age
HLA-1 mis-matches
Delyaed Graft Function(DGF)
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA ; Non-adherence measured by CNI-IPV is associated high rates of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year. CNI-IPV >= 35% is independent risk factor for both DSA+ TCMR+ status
Discussion ; Despite the presence of DSA, 50% of patients may have stable allograft function over long-term. Detection of DSA indicates more mature immune response including both humoral & cellular immune response. Wiebe et al. reported that half of the patients with de-novo DSA had previous TCMR at 4.6 years(30) Cooper et al. and Devos et al. showed that DSA had no effect on allograft dysfunction in absence of acute rejection(12) ABMR potentiate TCMR by enhancing tissue damage and inflammation, opsonising target antigens Non-adherenc was important association with TCMR+ and DSA+ confounders may include free steriod regiments and re-transplant patients
Conclusion; DSA+TCMR+ associated with worse transplant outcomes. Non-adherence is a risk factors for both DSA+ TCMR+ Early identifications of DSA+TCMR+ and early assessment of adherence status are of para mount importance for good transplant outcomes.
Alaa eddin salamah
3 years ago
This is a single center prospective study on DSA negative renal transplant patients to study the correlation between posttransplant DSA level, TCMR and effect of immunosuppressant adherence with graft survival. The information in available literature still debatable about incidence, timing and impact of TCMR on graft survival on patients who develop post-transplant DSA.
The study measured various variables including age, ethnic group, mismatches, CNI intrapatient variability (CNIIPV,a measure of adherence to immunosuppressive medications) over the course of the first year and kidney biopsies (early -first 6 months, late-after 6 months till 1 year)
The studied recruited 209 patients, only 67 of them developed DSA in first year. These patients’ characteristics include: they were younger, more likely to be non-Caucasian, had a higher pretransplant panel reactive antibody, more human leucocyte antigen mismatches, and a trend toward more delayed graft function than those without DSA and greater CNI intrapatient variability over the course of the first year.
The detection of DSA was associated with 2 folds increased risk of early TCMR, 2 folds increased risk of late TCMR despite the treatment of TCMR and grater IFTA at 1 year follow up. Concomitant tubulitis and transplant glomerulopathy were independent
risk factors for subsequent allograft failure in patients with late de novo DSA.
DSA and TCMR positive patients were considered a high risk of poor outcome group associated high mean IFTA score, severe IFTA, IF with inflammation on 1-year biopsy and early chronic histological damage with worse 4-year graft survival.
Independent risk factors for concomitant DSA and TCMR include: younger age, class I HLA mismatch and delayed graft function
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
Patients with no DSA nor TCMR and patients with DSA+TCMR+ who were adherent to immunosuppressant have similar graft survival. Nonadherence was associated with increased risk of TCMR, recurrent TCMR and IFTA at 1 year follow up.
Patients with DSA have increased risk of both TCMR and ABMR compared to non-DSA patients. Patients with DSA has increased risk of graft loss and severe TCMR even with no ABMR
Theepa Mariamutu
3 years ago
Development of DSA post-transplant has been shown to be associated with poor outcomes. The study was done to evaluate the effect of DSA on patients having T cell mediated rejection (TCMR) post transplant. 294 transplant recipients between January 2013 and November 2014 were included in the study. The DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies were performed at 3 and 12 months, in addition to any for-cause biopsies.
22.8% patients developed DSA in the first year, 40% of whom had transient DSA. 39% of these patients had historical DSA while 61% developed de-novo DSA. Patients who developed DSA were of younger age, non-Caucasian, had more HLA mismatches (especially class I), higher PRA and higher incidence of delayed graft function as compared to those who did not develop DSA.
Risk factors for developing De Novo DSA
1. HLA mismatch
2. Delayed graft function
3. Younger age
4. Non living related (deceased) donor kidney
5. Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
6. Non compliance on immunosuppressive medication
7. Inflammation-induced by infections, surgery or TCMR
DSA and TCMR patients had 1.35-fold greater CNI-IPV than the other patient groups. Non-compliant patients with DSA and TCMR exhibit particularly worse allograft outcomes, with graft loss by 4 years in 70% of the cases.. Importantly, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
The triad of DSA, TCMR and non-compliance to medications ,all linked to worse graft survival. So prompt identification of patients with DSA , TCMR and non-compliance to medications would allow timely therapeutic intervention, thus, preventing early graft loss.
Dalia Ali
3 years ago
Introduction
Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes.
Insufficient control of humoral immunity by current immunosuppressive regimens is increasingly felt to be an important factor underlying allograft dysfunction and loss
Study design
a prospective singlecenter study on 378 patients who underwent kidney transplantation between January 2013 and November 2014 (15 were excluded)
DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR. In addition correlated DSA and TCMR to nonadherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first posttransplant year.
Result
the remaining 363 patients, 294 (81%) had at least 1 allograft biopsy within the first posttransplant year and were included in the study. Of these, 276 patients had a biopsy (either protocol or for-cause) between 0 and 5 months (early histology) and 224 patients had a biopsy between 6 and 12 months (late histology)
A total of 209 of 294 patients (71%) had paired biopsies at both early and late time points, and these patients were used to analyze histological progression.
Posttransplant DSA detection
Of the 294 patients analyzed, 67 (22.8%) developed DSA in the first year. DSA was transient (detected only once during the first year) in 40% of the 67 patients with DSA and was persistent in the remaining 60%
DSA is associated with increased incidence and severity of TCMR
108 of 294 patients (36.7%) experienced TCMR in the first posttransplant year, with 47% being clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at 3 months or at 12 months (data not shown). Importantly, ABMR was seen in 11 patients (10.2% of all rejections) and was always detected in the presence of concomitant TCMR. Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
DSA associated with significant interstitial fibrosis and tubular atrophy (IFTA) at 1 year Importantly, a greater proportion of patients with DSA had IFTA score $3 andfewer patients had no chronic damage onthe1-year biopsy
DSA plus TCMR is associated with worse renal allograft outcomes
patientswithDSAþTCMRþ had significantly higher serum creatinine at the last follow-up when compared with all the other groups. Furthermore, DSAþTCMRþ was associated with significantly worse graft survival at 4 years compared with all other patient groups (23% vs. approximately 10%)
RiskfactorsforconcomitantDSAandTCMR
Adherence to immunosuppressive medications is increasingly recognized as an important risk factor for renal allograft outcomes
Nonadherence was associated with an increased rate of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year
Conclusion
DSA are associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy. Importantly, patients who developed both DSA and TCMRinthe first posttransplant year are at high risk for poor long-term allograft survival compared with patients with either DSA or TCMR alone or lacking either diagnosis.
Although both TCMR and mixed TCMR plus ABMR were increased in DSA patients, isolated TCM was4.6-fold more frequent than mixed rejection.Moreover, TCMR severity and graft loss remained increased inDSA patients,even when those with concomitant ABMR were eliminated from the analysis.
Thus,although amajority of studies on DSA have focused onABMR ,weshowthatamajor component ofallograf tinjury I npatients with DSA is indeed Tcellmediated.
MICHAEL Farag
3 years ago
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
Yet, the association and clinical significance of TCMR and DSA arising after transplantation is not well understood. In a comprehensive prospective analysis, Wiebe et al. showed that de novo DSA occurred late (mean 4.6 years) and was associated with 2-fold higher incidence
(54%) of TCMR occurring within the first year, compared with patients without DSA This suggested that TCMR precedes the development of alloantibodies and antibody.
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA. Early identification of patients at increased risk for chronic damage and graft loss, allowing timely therapeutic intervention, is of paramount importance. Accurate testing
for DSA, developed within the past decade, has helped revamp the diagnostic criteria for ABMR.
Weam Elnazer
3 years ago
When it comes to kidney transplantation, it is well established that de novo DSA is linked with poor renal outcomes.
DSA has been shown to be significantly linked with antibody-mediated rejection. Given that T cell activation is required for antibody formation, the development of DSA also suggests the existence of cellular stimulation and an active T cell response. There has been much research that has indicated a link between ABMR and the existence of preformed or de novo DSA, but more recent studies have revealed a relationship between DSA and T-cell–mediated rejection.
For the purpose of determining the relationship between DSA, total cell mononuclear response (TCMR), and renal outcomes, a prospective single-centre study was conducted in which DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at three and twelve months), the severity of rejection, and graft outcomes.
Consequently, in this investigation, non-desensitized patients who acquired posttransplant DSA were prospectively investigated to identify variables linked with poor four-year outcomes. Before transplantation, all patients were checked for DSA using the Luminex approach, which included a negative flow cross-match negative as a control.
Using serial monitoring, it was discovered that 67 out of 294 patients had DSA within one year. DSA was temporary in 40% of the 67 individuals who had DSA, but it was chronic in the other 60% of the patients who had DSA.
36.7 per cent of patients exhibited TCMR in the first post-transplant year, with 47 per cent experiencing clinical TCMR and 53 per cent experiencing subclinical TCMR, as determined by a protocol biopsy performed at 3 months or 12 months after transplantation. It was shown that just 10.2 per cent of all rejections were due to ABMR and that it was always recognized in the context of concurrent TCMR.
patients who develop both DSA and TCMR in the first year after transplantation is at increased risk for poor long-term allograft survival when compared to patients who acquire either DSA or TCMR alone, or patients who do not develop either DSA or TCMR at all. A more developed immune response, with activation of both humoral and cellular immunity, is characterized by the presence of DSA. In DSA patients, however, there was a rise in both total and mixed total plus ABMR. Patients’ nonadherence, as defined by interpatient variability of calcineurin inhibitor (CNI) trough levels during the first year after transplantation, was likewise linked to DSA and TCMR, according to the research team.
Patients who acquired DSA during the first posttransplant year were younger, had a higher PRA prior to transplant, had more HLA mismatches, and had a tendency toward delayed graft function compared to those who did not develop DSA within the first posttransplant year. A further finding was that these patients had higher CNI interpatient variability, which is a measure of adherence to immunosuppressive drugs throughout a one-year period after transplantation. Patients who acquire both TCMR and DSA within one year of transplantation are at increased risk for poor graft outcomes, according to the study.
The present research was the first to establish a relationship between DSA, TCMR, and nonadherence as a trio of factors associated with significantly reduced allograft survival.
Amit Sharma
3 years ago
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
This was a prospective, single center study involving non-desensitized transplant recipients which dealt with the effect of post-transplant donor specific antibodies (DSA) over the kidney transplant outcomes.
Development of DSA post-transplant has been shown to be associated with poor outcomes. The study was done to evaluate the effect of DSA on patients having T cell mediated rejection (TCMR) post transplant. 294 transplant recipients between January 2013 and November 2014 were included in the study. The DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies were performed at 3 and 12 months, in addition to any for-cause biopsies.
22.8% patients developed DSA in the first year, 40% of whom had transient DSA. 39% of these patients had historical DSA while 61% developed de-novo DSA. Patients who developed DSA were of younger age, non-caucasian, had more HLA mismatches (especially class I), higher PRA and higher incidence of delayed graft function as compared to those who did not develop DSA.
DSA positive patients had 1.8 times higher incidence of TCMR and 2 times higher incidence of early as well as recurrent TCMR which was relatively more resistant to steroid treatment. DSA positive patients with TCMR had higher prevalence of chronic allograft damage at 1 year and worse graft outcomes at 4 years (23% ). High CNI intrapatient variability (IPV), as a marker of non-adherence, was associated with increased TCMR rate and severity. 46% of patients with DSA and TCMR had high CNI IPV. Graft survival in adherent DSA positive patients with TCMR was similar to those without DSA or TCMR, or both. 75% of non-adherent patients with DSA and TCMR developed graft failure.
So, DSA leads to increased incidence and severity of TCMR and poor long-term graft results, which gets worse in presence of non-adherence.
amiri elaf
3 years ago
*The development of de novo anti-donor human leucocyte antigen specific antibody (DSA) is associated with poor outcomes in kidney transplantation.
* This prospective studied non desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post transplant DSA.
* combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone
* Amongst factors independently associated with DSA plus TCMR, nonadherence is potentially modifiable.
* Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post transplant year, further risk stratified patients with DSA plus TCMR about 75% of these patients had impending graft loss by four years.
* Early post-transplant DSA, especially in non-adherent patients is associated with increased incidence of TCMR and
represents a high-risk group of patients who might benefit from targeted therapeutic interventions.
* Insufficient control of humoral immunity by current immunosuppressive regimens is increasingly felt to be an important factor underlying allograft dysfunction and loss.
* The clinical implications of de novo DSA and the pathogenic role of DSA itself remain unclear.
* Because the development of antibodies requires T cell help, the presence of DSA also indicates the presence of a more mature cellular alloimmune response.
* The association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
*Study showed de novo DSA occurred late and was associated with 2-fold higher incidence of TCMR occurring within the first year, compared with patients without DSA, suggested that TCMR precedes the development of alloantibodies and antibody mediated injury.
* Although DSA was associated with poor
graft outcomes, the effect of prior TCMR on long-term outcomes in patients with DSA was not examined.
* In other studies where DSA was serially assessed, DSA occurred much earlier and frequently preceded or was concomitant with TCMR and showed that the increased graft loss associated with DSA was limited to patients who had acute rejection.
* Other studies showed that DSA arising in the first year was associated with stable long-term allograft function irrespective of TCMR.
* The incidence of ABMR versus TCMR in patients with posttransplant DSA unclear.
* prospective single center study where DSA was screened serially from the time
of transplantation and correlated with acute rejection, severity of rejection and graft outcomes comparing patients with: # No DSA or TCMR
# DSA alone
# TCMR alone
# DSA plus TCMR.
# Correlated DSA and TCMR to nonadherence, measured by (CNI) trough levels duringthe first posttransplant year.
** RESULTS **
#Study population
– Amongst 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 were excluded because of patient death or allograft loss within 3 months.
– 294 (81%) had at least 1 allograft
biopsy within the first post transplant year and were included in the study.
– 276 patients had a biopsy between 0 and 5 months (early histology)
– 224 patients had a biopsy between 6 and 12 months (late histology)
– A total of 209 of 294 patients (71%) had paired biopsies at both early and late time points, and these patients were used to analyze histological progression.
**Posttransplant DSA detection**
– All patients were negative for DSA at the time of transplantation, as determined by luminex and a negative flow cross-match. – Of the 294 patients analyzed, 67 (22.8%)
developed DSA in the first year.
– DSA was transient in 40% of the 67 patients with DSA and was persistent in the remaining 60% .
— A total of 24 of 67 patients (36%) had persistent DSA detected 1month after transplant.
– A total of 26 of 67 (39%) patients
with DSA had historical DSA up to 2 years before transplantation.
The remaining patients (61%) had de novo DSA.
# The clinical characteristics of Patients
who developed DSA within the first post transplant year were :
younger, more likely to be non-Caucasian, had a higher pretransplant panel reactive antibody, more human leucocyte antigen mismatches, trend toward more delayed graft function than those without DSA
and exhibited greater CNI intrapatient variability over the course of the first year. Importantly, the baseline renal transplant function measured at 1 and 3
months after transplant was similar between those with andwithout DSA.
** DSA is associated with increased incidence and severity of TCMR **
– (36.7%) of patients experienced TCMR in the first posttransplant year.
– 47% being clinical TCMR.
– 53% subclinical TCMR diagnosed on a protocol biopsy.
– ABMR was seen in (10.2% of all rejections) and was always detected in the presence of concomitant TCMR.
– Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA .
– The increased risk of TCMR in DSA
patients persisted when concomitant ABMR patients or those with early DSA (1 month) were excluded
– Was associated with increased incidence of both clinical and
subclinical TCMR .
-Patients with DSA had more TCMR with concomitant ABMR, compared with those without DSA .
** Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
– DSA was associated with significantly greater interstitial fibrosis and tubular atrophy at 1 year.
– DSA and TCMR patients are at high risk for developing allograft chronicity within 1 year after transplant.
– The combination of DSA and TCMR was
associated with early chronic histological damage.
– DSA and TCMR hads ignificantly higher serum creatinine at the last follow-up when compared with all the other groups.
DSA and TCMR was associated with significantly worse graft survival at 4 years compared with all other patient groups (23% vs10%).
** Risk factors for concomitant DSA and TCMR
Because patients with DSA and TCMR constitute a high-risk group, we examined the factors associated with this:
younger recipient age
Class I human leucocyte antigen mismatches
Delayed graft function
Serum creatinine
CNI, calcineurin inhibitor
** Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
– Adherence to immunosuppressive medications is increasingly recognized as an important risk factor for renal allograft
outcomes.
– Used CNI intrapatient variability as a measure, patients with DSA and TCMR had 1.35-fold greater CNI-IPV than the other patient groups
– Nonadherence was associated with an
increased rate of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year.
# DISCUSSION
– Early identification of patients at increased risk for chronic damage and graft loss, allowing timely therapeutic
intervention.
– Accurate testing for DSA, developed within the past decade has helped
revamp the diagnostic criteria for ABMR. – Early detection of DSA promised to better define the natural history of ABMR and allow us to identify patients at increased risk for subsequent allograft loss.
– Posttransplant DSA in non presensitized patients, in terms of both ABMR and allograft survival, remains uncertain. although patients who develop
DSA anytime in their posttransplant course have poorer graftsurvival.
– Although both TCMR and mixed TCMR
plus ABMR were increased in DSA patients, isolated TCMRwas 4.6-fold more frequent than mixed rejection
** In conclusion, this single center prospective study showed that recipients with DSA who develop TCMR have worse
tubulointerstitial inflammation, which was frequently recurrent and led to subsequent worse outcomes compared with those with DSA or TCMR alone. -Nonadherence, markedly contributed to poor graftoutcomes in patients with DSA and TCMR.
– Identification of patients with DSA and TCMR and early assessment of their adherence status after transplantation would allow targeted intervention with close follow-up, visiting nurses, and consideration of long-actingfollow-up,
immunosuppressive agents such as belatacept.
Innocent lule segamwenge
3 years ago
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
This was a prospective observational study to describe the relationship between the development HLA-DSA and transplant outcomes.
Background
The relationship between HLA-DSA and poor allograft outcomes is well known.
It is possible that current immunosuppression regimens are not able to adequately switch off the production of DSA.
We know that T helper cells are needed to stimulate antibody production.
Therefore, the presence of DSA is likely a process of an active cellular immune response.
There are mixed findings showing T cell mediated rejection (TCMR) precedes antibody mediated rejection (AMR), other studies have shown TCMR may preceed DSA.
Objectives
To determine the incidence, timing and impact on graft survival of TCMR among patients who develop DSA.
To described the incidence of AMR vs TCMR in post-transplant patients
Methods
Single centre prospective study between January 2013 and November 2014.
378 patients were screened
15 excluded due to death or graft loss
all patients had serial DSA screening from the time of transplant and protocol biopsies at 3 and 12 months.
294/363 had biopsy either per protocol or for-cause.
Adherence was assessed by measuring CNI trough levels and estimated the intrapatient variability of calcineurin inhibitor levels (CNI-IPV).
Results
294 had atleast 1 biopsy.
209 had biopsy between 0 and 5 month (early) and between 6 and 12 month(late).
67/294 (22.8%) developed DSA in the first year. 60% DSA persisted, while 40% had transient DSA.
26/67(39%) had historical DSA vs 61% denovo DSA
DSA developed more in younger patients, non-Caucasian, more HLA mismatches and non-adherent to medications.
108/294(36.7%) had TCMR in year 1; with 47% clinical TCMR vs 53% subclinical diagnosed on biopsy.
10.2% had AMR and always associated with TCMR.
Patients with DSA had 1.8-fold higher incidence of TCMR than those without DSA.
DSA was associated with increased higher incidence of clinic and subclinical TCMR.
In DSA + TCMR, 82% DSA was detected with or before diagnosis of TCMR
DSA subjects had high-grade Banff lesions.
De novo DSA more associated TCMR.
DSA patients had twice more early TCMR vs those without DSA.
DSA was more associated with chronic allograft damage and IFTA+i.
DSA + TCMR had higher serum creatinine and worse graft survival vs other groups.
On Multivariate analysis
DSA+ TCMR was independently associated with impending graft loss (p=0.003)
and poor graft outcomes.
Younger recipient age, class I HLA mismatch, and delayed graft function were independently associated with DSA+TCMR.
DSA+TCMR group were more likely to be non-adherent to their immunosuppression treatment as measure by CNI-IPV.
In conclusion, this paper has demonstrated the strong association between the development of HLA-donor specific antibodies and T cell mediated rejection, and how this combination is associated with poor graft outcomes. In addition patients who are non-adherent are more likely to develop DSA and TCMR.
Reem Younis
3 years ago
– De novo DSA is associated with poor outcomes in kidney transplantation.
-DSA is strongly associated with antibody-mediated rejection (ABMR).
– Approximately 50% of patients exhibit good long-term graft function despite developing DSA.
-The development of antibodies requires T cell help, so the presence of DSA also indicates the presence of a more mature cellular alloimmune response.
-Some studies have shown DSA occurred much earlier (3-9 months), and frequently preceded or was concomitant with TCMR.
-One study, showed that de novo DSA occurred late associated with a 2-fold higher incidence of TCMR occurring within the first year, compared with patients without DSA.
– This is a prospective single-center study.
-363 patients, not requiring desensitization, were involved in the study.
-All patients were negative for DSA by Luminex and a negative flow cross-match at the time of transplantation.
-Protocol biopsies were done to detect early rejection, DSA was detected at or before the onset of TCMR in 82% of patients.
-DSA is associated with increased incidence and severity of TCMR
-Some patients experienced TCMR that was associated with ABMR.
-Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA.
-DSA was associated with increased incidence of both clinical and subclinical TCMR.
– patients with transient DSA had an increase in clinical TCMR, whereas patients with persistent DSA had a much higher incidence of subclinical TCMR.
-Patients with de novo DSA had a much higher rate of TCMR with more persistent or recurrent TCMR when compared with those without DSA.
-Patients with DSA and TCMR have increased chronic renal allograft damage.
– DSA was associated with significantly greater interstitial fibrosis with inflammation and tubular atrophy.
-DSA and TCMR patients represent a high-risk group for poor outcomes and graft loss. Regardless of whether DSA precedes or follows TCMR, the combination of DSA and TCMR carries a worse prognosis than having DSA without TCMR.
Risk factors for concomitant DSA and TCMR:
1. younger recipient age.
2. Class I human leucocyte antigen mismatches.
3. Delayed graft function.
-Nonadherent patients with DSA and TCMR exhibit particularly bad allograft outcomes, with 70% impending graft loss by 4 years. Adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA. Conclusion: Identification of patients with DSA and TCMR andearly assessment of their adherence status after transplantationwould allow good interventions and outcomes.
mai shawky
3 years ago
· Detection of denovo DSA after transplantation in non-sensitized recipient (with no preformed DSA or negative cross match) is associated with poor graft outcome on long term follow up.
· Denovo DSA was frequently linked to AMR. However, it is associated with TCMR and mixed rejection by poorly understood mechanism.
· Taking into consideration that acute rejection, whether clinical (rising creatinine) or subclinical (detected in protocol biopsy) have detrimental effects on long term graft and patient outcomes, monitoring of denovo DSA has been implemented for early detection or prediction of AR for early and timely intervention to treat rejection and save the graft.
· DSA can be detected before or at time of TCMR in 50% of recipients.
· Presence of DSA together with biopsy proven TCMR carry worse prognosis and 3 folds increase in graft loss than DSA or TCMR alone.
· Also, those with denovo DSA can have increased IFTA on long term biopsy follow up.
· Those with detected DSA without proven rejection can have stable graft function in nearly 50% of cases. However, the rest may be at risk of acute rejection and worse outcome especially in the context of non-adherence to immunosuppressive therapy.
· Presence of DSA itself can indicate poor adherence to treatment. In addition, non adherence that can be detected by marked intra-personal variability in CNI trough levels > 30 %, is associated with higher risk of graft damage from circulating DSA which can turn into actual DSA mediated graft damage and rejection if not well addressed and managed.
· The timing and titer of DSA affect their impact. Their early detection post-transplant is more serious than late detection after relative accommodation.
Q. I would like to ask what about management of isolated finding positive denvo DSA with stable graft function?
I think I will check for adherence to treatment and trough level, if subtherapeutic , I will mange and discuss the problem seriously with patient.
if accepted target trough level, I will proceed to biopsy to detect subclinical rejection. if detected I will proceed to treatment.
Treatment of subclinical rejection is still a matter of debate, but I think here in the context of combined DSA and subclinical rejection, treatment is essential to preserve the graft.
If no evidence of rejection, I think no need for treatment modification rather than CNI adjusted dose and close monitoring of our patient.
Heba Wagdy
3 years ago
DSA is associated with AMR and poor graft outcome, however its pathogenic effect is not clear and 50% of patients with DSA have good long-term graft survival.
The association between TCMR and post transplant DSA is unclear and their effect on long term outcome is understudied.
A prospective single center study included 363 kidney transplant recipients, negative for DSA at time of transplant without requiring desensitization
DSA was screened serially post transplant an was correlated with acute rejection (detected by for cause biopsy and protocol biopsies at 3&12 months) and 4 year graft outcome
The severity of rejection and graft outcomes are compared in patients with no DSA or TCMR, DSA alone , TCMR alone and DSA plus TCMR.
Also, DSA and TCMR were correlated to non adherence (was determined by intra-patient variability of CNI (CNI-IPV) trough levels during first year post transplant.
DSA was associated with increased incidence and severity of TCMR
DSA was detected at or before onset of TCMR in most cases suggesting temporal relationship
Patients with DSA and TCMR had increased chronic allograft damage at one year.
DSA plus TCMR was associated with worse long-term outcome compared with other groups
Risk factors for concomitant DSA and TCMR were younger age, class I HLA mismatches, delayed graft function.
Adherence to immunosuppression markedly affect clinical outcomes in patients with TCMR and DSA
CNI-IPV was independently associated with DSA and TCMR
patients with DSA and TCMR who were adherent had statistically similar graft survival as adherent patients without DSA or TCMR or both, so adherence is an important therapeutic opportunity
Identification of patients with DSA, TCMR and assessment of adherence allow targeted intervention with consideration of long acting immunosuppression as Belatacept
Batool Butt
3 years ago
DSA is one of the major immunological factors that affect graft outcome.1 Literature review revealed strong association of preformed or de novo DSA with antibody mediated rejection but recently studies have been conducted demonstrating a link between DSA and T cell mediated rejection due to the requirement of T cell activation for antibody production. In some cases, TCMR precedes the development of alloantibodies and antibody mediated injury.2In order to extrapolate this linkage , a prospective single center study was carried out from January 2013-November 2014 ,in which non-desensitized patients were enrolled and DSA was done serially from time of transplantation (0, 1, 3, 6, 9, and 12 months) with protocol biopsies (3 and 12 months)and for cause biopsies to detect acute rejection and also to determine factors associated with four-year outcomes in 4 groups DSA+.TCMR+, DSA+.TCMR-,DSA-,TCMR+,DSA-,TCMR-. Further categorization as early (0–5 months) or late (6–12 months)to assess the persistence/recurrence of TCMR inpatients with and without DSA was being done. All patients were screened for DSA before transplantation using luminex technique with a negative flow cross-match. In this study 67of 294 patients (22.8%) developed DSA in the first year. Mean time for detection of DSA was 3.4 months. Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA. 108 of 294 patients (36.7%) experienced TCMR in the first post transplant year, with 47% having clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at 3 or at 12 months. ABMR was seen always in presence of TCMR. Patients with DSA before or at TCMR diagnosis had higher creatinine value at follow up and increased rates of allograft rejection at one year and had worse IFTA in comparison to patients with DSA detected post TCMR.
Risk factors for concomitant DSA & TCMR is younger age , HLA class I mismatch & delayed graft function, planned decreased immunosuppression due to infection or conversion to CNI free or CS free protocols, and patients non adherent to immunosuppressive agents assessed by CNI intrapatient variability (CNI-IPV )-very important risk factor. DSA and TCMR patients had 1.35-fold greater CNI-IPV than the other patient groups. Non-compliant patients with DSA and TCMR exhibit particularly worse allograft outcomes, with graft loss by 4 years in 70% of the cases.. Importantly, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA. CONCLUSION: The triad of DSA, TCMR and non-compliance to medications ,all linked to worse graft survival. So prompt identification of patients with DSA , TCMR and non-compliance to medications would allow timely therapeutic intervention, thus, preventing early graft loss.
REFERENCES:
1. Worthington JE, Martin S, Al-Husseini DM, et al. Post transplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003;75:1034–1040
2. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012;12:1157–1167
Abdul Rahim Khan
3 years ago
Any form of DSA is bad for renal graft, In this paper authors have studied the effect of DSA or other relevant factors in non sensitized patients on 4 year outcome after transplant. About half of the patients achieve better long term graft function in spite of the fact that they have DSAs. It raises the suspicion that there may be factors other than DSA leading to graft dysfunction. The relationship between DSA and T Cell mediated rejection has been suggested in the past, however the exact relationship has not been understood. In this study DSA was checked serially from transplantation and was related to acute rejection, outcomes and severity of rejection in patients showing No DSA, TCMR, TCMR alone, DSA alone, DSA and TCMR Positive. They also correlated TCMR and DSA to non adherence calculated by CNI levels. They concluded that DSA is related with high TCMR with poor outcome at 1 year. Outcome in patients with TCMR and DSA can be affected by immnuosuppression non adherence.
Tahani Ashmaig
3 years ago
● INTRODUCTION:
Donror specific antibodies are associated with antibody-mediated rejection (ABMR) post renal transplant. But, their clinical implications and the pathogenic role remain unclear.
The development of DSA indicates the presence of a more mature cellular allo-immune response. But, the association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
THIS STUDY:
▪︎Is a prospective single center study where DSA was screened serially from the time of transplantation and correlated with acute rejection, severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR.
▪︎It also correlated DSA and TCMR to non adherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first post transplant year.
▪︎RESULTS
▪︎Study population: 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 were excluded.
▪︎Of the remaining 363 patients, 294 had at least 1 allograft biopsy within the first post transplant year and were included in the study. Of these, 276 patients had an early histology biopsy and 224 patients had a late histology biopsy . A total of 209 of 294 patients had paired biopsies at both early and late time points.
*Post transplant DSA detection:
▪︎All patients were negative for DSA at the time of transplantation , as determined by luminex and a negative flow cross-match.
▪︎Of the 294 patients analyzed, 67 (22.8%) developed DSA in the first year.
▪︎The mean time to the detection of the DSA was 3.4 months.
▪︎ A total of 26 of 67 (39%) patients with DSA had historical DSA up to 2 years before transplantation, and the remaining patients (61%) had de novo DSA.
▪︎ Patients who developed DSA within the first post transplant year were younger, more likely to be non-Caucasian, had a higher pretransplant panel reactive antibody, more human leucocyte antigen mismatches, and a trend toward more delayed graft function than those without DSA. also, these patients exhibited greater CNI intrapatient variability.
●DSA is associated with increased incidence and severity of TCMR
▪︎In this study 36.7% of patient experienced TCMR in the first posttransplant year,
▪︎ABMR was seen in 11 patients (10.2% of all rejections) and was always detected in the presence of concomitant TCMR.
☆ Risk factors for concomitant DSA and TCMR:
1. Younger recipient age
2. Class I human leucocyte antigen mismatch
3. Delayed graft function
●Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
▪︎This study used CNI intrapatient variability as a measure of adherence. They found that DSA and TCMR patients had 1.35-fold greater CNI-IPV than the other patient groups
▪︎ Asignificantly greater proportion of patients with both DSA and TCMR had high CNI-IPV (46% vs. 21%) compared with all other patient groups (DSA-alone, TCMR alone, DSATCMR).
●DISCUSSION:
▪︎ Accurate testing for DSA, developed within the past decade, has helped revamp the diagnostic criteria for ABMR
▪︎Few prospective studies have serially monitored DSA.
▪︎Allograft survival in patients who develop posttransplant DSA are poorly understood.
▪︎In this prospective study, DSA was associated with a greater incidence and severity of TCMR and graft loss, despite
standard of care immunosuppression and antirejection therapy.
▪︎Importantly, patients who developed both DSA and TCMR in the first posttransplant year are at high risk for poor
long-term allograft survival compared with patients with either DSA or TCMR alone or lacking either diagnosis.
▪︎Despite the incorporation of protocol biopsies to detect early rejection, DSA was detected at or before the onset of TCMR
in 82% of patients, suggesting a temporal relationship.
▪︎Although isolated ABMR was not observed, patients with DSA also exhibited increased rates of “mixed” TCMR plus
ABMR compared with patients without
●CONCOLUSION:
▪︎Expression of either de novo or anamnestic antibodies requires T cell help for B cells.
▪︎The presence of DSA is indicative of a more mature immune response with contributions from both humoral and
cellular immunity.
▪︎Post-transplant donor specific antibody is associated with T-cell–mediated response
and non-adherence.
Zahid Nabi
3 years ago
Post transplant DSA either denovo or recurrent has negative impact on graft survival.however there are many unanswered questions.
The authors of this paper have tried to atleast answer one question that is what is impact of DSA and associated factors in non desensitized patient on four year graft outcome.
The fact that approximately 50% of patients exhibit good long-term graft function despite developing DSA raises the question that there are associated factors and just DSA is not the only culprit.
The development of antibodies requires T cell help, the presence of DSA also indicates the presence of a more mature cellular alloimmune response.
It has been shown in the past that there is some relationship between DSA and TCMR. Indeed, several studies have shown a relationship between DSA and T-cell–mediated rejection yet the association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
To address this issue this study was conducted . It was a prospective single- center study where DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR. In addition, they correlated DSA and TCMR to nonadherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first post transplant.
Amongst 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 were excluded because of patient death or allograft loss within 3 months. Of the remaining 363 patients, 294 (81%) had at least 1 allograft biopsy within the first posttransplant year and were included in the study. Of these, 276 patients had a biopsy (either protocol or for-cause) between 0 and 5 months (early his- tology) and 224 patients had a biopsy between 6 and 12 months (late histology) (Figure 1). A total of 209 of 294 pa- tients (71%) had paired biopsies at both early and late time points, and these patients were used to analyze histological progression.
The study highlights that DSA is associated with increased incidence and severity of TCMR.
Patients with DSA and TCMR have increased renal allograft damage at 1 yr.
DSA and TCMR is associated with worst renal graft outcomes.
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA.
This was first study which linked triad of DSA TCMR and non adherence with markedly worse renal graft outcomes.
Mohamed Mohamed
3 years ago
Week 1 Journal club
III. Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
Aravind Cherukuri, Rajil Mehta, Akhil Sharma, Puneet Sood, Adriana Zeevi, Amit D. Tevar, David M. Rothstein and Sundaram Hariharan Introduction
Anti-HLA donor specific antibodies occurring following transplantation (de novo DSA) are well known to be associated with development of AMR & poor graft outcome, & possibly have causative role. [1-3] However, many of the studies examining this issue were small & retrospective.
In this prospective study, the authors looked intofactors determining poor 4-year outcome in non-desensitized recipients who developed de novo DSA.
Relationship between DSA & T-cell–mediated rejection (TCMR): Antibody production requires the help of T-cells, so the development of DSA signifies the occurrence of a more mature cellular alloimmune reaction. However little is known about the association between DSA & TCMR & its clinical significance. Although Wiebe et al.[4] suggested that TCMR precedes the development of DSA & antibody-mediated injury, however the effect of prior TCMR on long-termoutcomes in patients with DSA was not examined. Other studies showed that de novo DSA in the 1st year was associated with stable long-term allograft function irrespective of TCMR. [5,6] In this prospective study the DSA was tested serially from the time of transplantation & correlated with: -acute rejection, – severity of rejection & – graft outcomes.
Patients were categorized into 4 groups based on DSA status & TCMR: (i) DSA+TCMR+ (ii) DSA+TCMR- (iii)DSA–TCMR+ (iv)DSA-TCMR- DSA & TCMR were also correlated to non-adherence during the 1st post-transplant year. RESULTS Study population A total of 378 patients underwent renal transplantation from Jan. 2013-Nov 2014, 15 were excluded due death or graft loss within 3 months. Of the remaining 363 patients, 294 (81%) had at least 1 allograft biopsy within the first post-transplant year & were included in the study. Of these, 276 patients had a biopsy (protocol or for-cause) between 0-5 months (early histology) & 224 patients had a biopsy between 6-12 months (late histology). A total 209 of patients (71%) had paired biopsies at both early & late time points, & these patients were used to analyze histological progression. Post-transplant DSA detection DSA was negative in all patients at time 0. A 67 (22.8%) developed DSA in the 1st year. In 40 % of these 67, the DSA was transient, seen only once during the 1st year; it was persistent in the remaining 60% . A total of 26 of 67 (39%) patients with DSA had historical DSA up to 2 years prior to transplantation, & the remaining 61% had de novo DSA. DSA occurring in the 1st post-transplant year was associated with the following: -younger age -non-Caucasian ethnicity -higher pre-transplant PRA -more HLA mismatches -more DGF. -greater CNI intra-patient variability (adherence to medications) The baseline renal transplant function measured at 1 & 3 months after transplant was similar between those with & without DSA. DSA is associated with increased incidence & severity of TCMR: TCMR was seen in 108 out of 294 patients (36.7%) in the 1st post-transplant year; 47% were clinical TCMR & 53% subclinical (protocol biopsy at 3 months or at 12 months). ABMR was seen in 11 patients (10.2% of all rejections) & was always detected in the presence of concomitant TCMR. Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA. The increased risk of TCMR in DSA patients persisted when concomitant ABMR patients or those with early DSA (1 month) were excluded. DSA was also associated with increased incidence of both clinical and subclinical TCMR. Patients with DSA had more TCMR with concomitant ABMR, compared with those without DSA. Evaluation of allograft histology: – early TCMR (0–5 months) was twice as common in patients with DSA – late TCMR (6–12 months) was twice as frequent in DSA patients – DSA may identify a subgroup of patients whose rejection is relatively resistant to standard therapy. -de novo DSA was linked to higher rate, recurrent or more persistent TCMR compared to those without DSA or anamnestic DSA. Patients with DSA & TCMR have increased chronic renal allograft damage at 1 year: DSA was associated with significantly greater IFTA at 1 year. DSA+TCMR+ linked to high risk for allograft chronicity within 1 year & worse graft survival at 4 years compared with all other patient groups (23% vs. 10%). The combination of DSA & TCMR, irrespective to which one comes 1st, has a worse prognosis than having DSA without TCMR. Transient DSA associated with just as poor long-term outcomes as was persistent one. Risk factors for concomitant DSA & TCMR: – younger recipient age – Class I HLA mismatches
– delayed graft function – serum creatinine at 3 months (trend toward statistical significance) Immunosuppression adherence & TCMR plus DSA: DSA+TCMR+ patients had 1.35-fold greater CNI-IPV (surrogate for non-adherence) than the other groups. Non-adherence increased rate of TCMR persistent/recurrent TCMR & IFTA at 1 year. Non-adherent DSAT+CMR+ patients had significantly higher graft loss/impending graft loss at 48 months than other groups. Addressing non-adherence offers an important therapeutic opportunity. DISCUSSION Early detection of DSA will allow timely identification of those at increased risk for graft loss.[7-11] The actual impact of de novo DSA in non-pre-sensitized recipients, in terms of both ABMR & allograft survival, is still uncertain. DSA anytime post-transplant carries poorer graft survival, but still half of these have stable long-term function. [4,12,13] Temporal relationship between DSA & rejection in patients who develop post-transplant DSA are poorly understood. Improvement in understanding the natural history of DSA, the biology of allograft rejection, and risk factors for poor outcomes, will allow timely therapeutic changes before irreversible damage occurs. In this study DSA was associated with a greater incidence & severity of TCMR & graft loss despite standard therapy. Patients with both DSA & TCMR in the 1st post-transplant year are at high risk for poor long-term allograft survival compared with other patients. Suggesting a temporal relationship, DSA was detected at or before the onset of TCMR in 82% of patients. Although both TCMR and mixed TCMR plus ABMR were increased in DSA patients, isolated TCMR was 4.6-fold more frequent than mixed rejection. Although most studies on DSA have focused on ABMR, this study shows that a major component of allograft injury in patients with DSA is indeed T cell mediated. The effect of early TCMR on the clinical course of patients who developed DSA was unclear in the paper by Wiebe et al., however both Cooper et al.[14] & Devos et al.[15] found, that in the absence of ABMR or TCMR, DSA had no effect on graft survival. The triad of DSA, TCMR, & non-adherence showed a markedly worse allograft survival. Timely identification of this triad will permit early intervention & consideration of long-acting agents such as belatacept.
References 1. Susal C, Wettstein D, Dohler B, et al. Association of kidney graft loss with de novo produced donor-specific and non-donor-specific HLA antibodies detected by single antigen testing. Transplantation. 2015;99:1976–1980. 2. Schinstock CA, Cosio F, Cheungpasitporn W, et al. The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am J Transplant. 2017;17: 1574–1584. 3. Sellares J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12:388–399. 4. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012;12:1157–1167. 5. Bartel G, Regele H, Wahrmann M, et al. Posttransplant HLA alloreactivity in stable kidney transplant recipients-incidences and impact on long-term allograft outcomes. Am J Transplant. 2008;8: 2652–2660. 6. Gill JS, Landsberg D, Johnston O, et al. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation. 2010;89: 178–184. 7. Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol. 2012;8:348–357. 8. Loupy A, Vernerey D, Tinel C, et al. Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts. J Am Soc Nephrol. 2015;26:1721–1731. 9. Halloran PF, de Freitas DG, Einecke G, et al. An integrated view of molecular changes, histopathology and outcomes in kidney transplants. Am J Transplant. 2010;10:2223–2230. 10. Lee PC, Terasaki PI, Takemoto SK, et al. All chronic rejection failures of kidney transplants were preceded by the development of HLA antibodies. Transplantation. 2002;74:1192–1194. 11. Terasaki PI. Humoral theory of transplantation. Am J Transplant. 2003;3: 665–673. 12. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369:1215– 1226. 13. Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87:1505–1513. 14. Cooper JE, Gralla J, Cagle L, et al. Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes. Transplantation. 2011;91:1103–1109. 15. Devos JM, Gaber AO, Teeter LD, et al. Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation. 2014;97:534–540.
Huda Al-Taee
3 years ago
A retrospective single-center study including 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 patients were excluded either because of death or graft loss within 3 months. All of the patients have negative DSA testing at the time of transplantation. DSA has screened at 0,1,3,6,9,12 months. protocol biopsies at 3 and 12 months in addition to for-cause biopsy. biopsies were classified into; early biopsies (0-5 months) & late ( 6-12 months). 209 patients had both early and late biopsies and these patients were used to analyze the histological progression. induction IS was: ATG ( 6mk/kg in total)., MP 500mg single dose, some patients received basiliximab. maintenance IS: Tac, MMF, rapidly tapered steroid.
study endpoint is a 4-year allograft outcome.
So the patients are grouped into 4 groups: DSA+ TCMR+, DSA+ TCMR-, DSA- TCMR+, DSA- TCMR-.
Those who have DSA showed an increased incidence of both clinical and subclinical TCMR. Patients with DSA+ TCMR+ were the high-risk group patients as they have greater IFTA at 1 year so worse allograft outcomes, there was 3 fold higher risk of graft loss compared to either DSA or TCMR alone.
Non-adherence was associated with DSA+ TCMR+.
ABMR was associated with concomitant TCMR.
manal jamid
3 years ago
De novo anti-donor human leucocyte antigen–specific antibody (DSA) is one of the major immunological factors that affect graft out come.
comperative studey conducted studied non desensitized patients to determine factors associated with poor four-year outcomes , in patients who developed post transplant DSA.
Using serial monitoring, 67 of 294 patients were found to develop DSA by one year. Compared to patients who do not develop DSA.Patient with DSA have grate incidence in developing TCMR.
The combination of TCMR plus DSA led to three time increase in graft loss. compared to either DSA or TCMR alone.
Another factor also considered in this study , non adherence is potentially modifiably.post-transplant DSA, in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.Immunosppression sub dose may lead to graft dysfunction and loss.
Few studies have examined the early post transplant period, serial testing, or used protocol biopsies to accurately detect subclinical rejection,approximately 50% of patients exhibit good long-term graft function despite developing DSA.Thus, the clinical implications of de novo DSA and the pathogenic role remain unclear.
T helper cells help in antibodies production thus presence of DSA also indicates the presence of
mature cellular alloimmune response.
comprehensive prospective analysis, showed that de novo DSA occurred late (mean 4.6 years) and was associated with 2-fold higher incidence of TCMR occurring within the first year, compared with patients without DSA.
This suggested that TCMR precedes the development of alloantibodies and antibody mediated injury.
In 2 other studies where DSA was serially assessed, DSA occurred much earlier (mean approximately 3-9 months) and frequently preceded or was concomitant with TCMR.
In contrast, 2 small retrospective studies showed that DSA arising in the first year was associated with stable long-term allograft function irrespective of TCMR.
Thus, the literature is discrepant as to the incidence, timing, and impact in terms of graft survival of
TCMR in patients who develop posttransplant DSA. Moreover, the incidence of ABMR versus TCMR in patients with posttransplant DSA remains unclear Yet, the association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
To address these issues, initiated a prospective single center study where DSA was screene serially from the time of transplantation and correlated with acute rejection
(detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes comparing patients without DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR. In addition, the study
correlated DSA and TCMR to nonadherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first posttransplant year. They found that DSA characteristics are found in young patients, non Caucasians ,with high PRA levels pre trasplant, more antigen mismatches trend toward more delayed graft function than those without DSA.
Importantly, ABMR was seen in few patients and
was always detected in the presence of concomitant TCMR
Patients with DSA and TCMR have increased chronic renal allograft damage .DSA+was associated with interstitial fibrosis and tubular atrophy (IFTA) at 1 year.
and fewer patients had no chronic damage on the 1-year biopsy recognized as a marker for poor long-term outcome.
DSA+TCMR not only had the highest mean IFTA score severe IFTA (score $3) and >80% had IFþ“i” on 1-year protocol biopsy. This suggests that DSAþTCMRþ patients are at high risk for developing allograft chronicity within 1 year
after transplant. Thus, the combination of DSA and TCMR was associated with early chronic histological damage.
patients with DSA andTCMR had significantly higher serum creatinine .
Nonadherence was associated with an
increased rate of TCMR persistent/recurrent TCMR .
Mohamad Habli
3 years ago
De novo DSA is known to be associated with poor renal outcomes in kidney transplantation.
DSA is strongly associated with antibody-mediated rejection. However, because the production of antibodies requires T cell activation, the development of DSA also indicates the presence of cellular stimulation and active T cell responce. Several studies demonstrated the relation between ABMR and presence of preformed or de novo DSA, but recent studies have shown a relationship between DSA and T-cell–mediated rejection.
In order to understand the relation between DSA, TCMR and renal outcomes, a prospective single center study was performed where DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes.
So in this study, prospectively studied nondesensitized patients, in patients who developed posttransplant DSA, to determine factors associated with poor four-year outcomes. All patients were screened for DSA before transplanation using luminex technique with a negative flow cross-match negative.
67 of 294 patients were found to develop DSA by one year using serial monitoring. DSA was transient in 40% of the 67 patients with DSA and was persistent in the remaining 60%.
36.7% experienced TCMR in the first posttransplant year, with 47% being clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at 3 months or at 12 months. Only 10.2% of all rejections were ABMR and were always detected in the presence of concomitant TCMR.
Amongst those with DSA+TCMR+, DSA was detected concomitant with or before the diagnosis of TCMR in 82% of patients, whereas only 18% of patients developed DSA after the diagnosis of TCMR.
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
DSA was associated with significantly greater interstitial fibrosis and tubular atrophy at 1 year. Importantly, a greater proportion of patients with DSA had IFTA score $3 and fewer patients had no chronic damage on the 1-year biopsy.
DSA+TCMR+ was associated with significantly worse graft survival at 4 years compared with all other patient groups.
Of the clinical variables examined, younger recipient age,Class I human leucocyte antigen mismatches, and delayed graft function were independently associated with DSA+TCMR+.
Nonadherence was recongnized as independent risk factor associated with the development of both DSA and TCMR. Nonadherent patients with DSA and TCMR exhibit particularly poor allograft outcome, with graft loss by 4 years in 70% of cases. Importantly, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
Mohamed Fouad
3 years ago
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
Despite improved 1-year long term graft survival, still the percentage of declining in renal graft function after 1 year unchanged. It is already known that Previous or ongoing clinical and subclinical rejection leading to chronic histopathological changes and ultimately graft failure. It is paramount to identify patients at increased risk for chronic damage and graft loss, allowing timely therapeutic intervention to save the allografts. Improvement in technical support to detect accurately DSAs give opportunity to manage patients at risk of ABMR and graft loss.
The actual meaning of posttransplant DSA in non presensitized patients, in terms of both ABMR and allograft survival, remains uncertain. Few prospective studies monitored DSA early in post-transplant period to assess the timing and effects of DSA. Despite already documented that Ppatients who develop DSA anytime in their posttransplant course have poorer graft survival, approximately 50% experience stable long-term function.
In a comprehensive prospective analysis, Wiebe et al.5 showed that de novo DSA occurred late (mean 4.6 years) and was associated with 2-fold higher incidence (54%) of TCMR occurring within the first year, compared with patients without DSA. This suggested that TCMR precedes the development of alloantibodies and ABMR.
In this prospective study, they serially examined DSA in patients without history of desensitization, starting 1 month after transplant and examined relation of DSA with graft inflammation (assessed by protocol biopsies at 3 and 12 months) and 4-year graft outcomes. They found that DSA was associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy.
Importantly, patients who developed both DSA and TCMR in the first posttransplant year are at high risk for poor long-term allograft survival compared with patients with either DSA alone or TCMR alone or patients without DSA or TCMR. The presence of DSA is indicative of a more mature immune response with activation of both humoral and cellular immunity. Although both TCMR and mixed TCMR plus ABMR were increased in DSA patients.They also correlated DSA and TCMR to patient nonadherence, measured by interpatient variability of calcineurin inhibitor (CNI) trough levels during the first posttransplant year.
Patients who developed DSA within the first posttransplant year were younger, had a higher PRA pre transplant, more HLA mismatches, and a trend toward more delayed graft function than those without DSA. In addition, these patients had greater CNI interpatient variability which is the measure of adherence to immunosuppressive medications over 1 year post transplant. Indeed patients developing both TCMR and DSA within 1 year after transplant are at risk for poor graft outcomes.
The current study was the first to link DSA, TCMR, and nonadherence as a triad, with markedly worse allograft survival.
In fact,non adherence remains the challenging part in renal transplantation field.
saja Mohammed
3 years ago
Summary of the study:
this is a prospective study included recipients of kidney transplant with the total number of 294(81%) with at least one garft biopsy( 0-3 months ) and about 276patients included have at least one protocol biopsy (0-5months early histology ) and in 224 cases they have their graft biopsy (6-12 months , late histology ) while 209(71%) they had two protocol biopsies (early/late ) where used for histological progression ,patients information collected electronically from the renal transplant data registry and approved by the University of Pittsburgh from the period of jan ,2013-nov ,2014.
All included patients had negative DSAs by Luminex assay at zero-time with negative FCXM ,examined DSA in patients not requiring desensitization, starting 1 month after transplant and examined its temporal relationship with allograft inflammation (aided by protocol biopsies) and assess the graft survival at 4 yeras as hard outcome in 4 groups (DSA+.TCMR+, DSA+.TCMR-,DSA-,TCMR+,DSA-,TCMR-).
67 (22.8%) developed DSA in the first year. DSA was transient (detected only once during the first year) in 40% of the 67 patients with DSA and was persistent in the remaining 60%.
Mean time for detection of DSA was 3.4 months , In 26(39%) of patients have historical DSA+ up to two years prior to TX.
DSAs is associated with increased incidence and severity of TCMR based on two Banff score protocol biopsies finding and the DSA s plus TCMR was found to be strongly associated with poor graft outcomes even after eliminating patients with ABMR, or those with early DSA (in first month )suggesting that the increased risk is not just due to the higher incidence of ABMR, but also to worse cellular rejection and the risk was even higher in younger recipients with DGF and in DSA +/TCMR , more HLA typing mismatch in both for class1, 11 majority received ATG induction followed by tacrolimus based IS , black African more in DSA+VE 33 / 67 cases
patients with
DSA + also increase the rates of “mixed” TCMR plus ABMR compared with DSA – group .
Immunotherapy non-adherence another significant risk factor based on the measurement of the CNI- IPV which is more in DSA+ group as shown in table 1
TCMR is significantly more in DSA+ (57%,) with significantly greater interstitial fibrosis
and tubular atrophy (IFTA) with grade3 score at 1 year and more than that DSA was associated with increased interstitial fibrosis with inflammation (IFþ“i”), increasingly recognized as a marker for poor long-term outcomes and lower graft survival at 4 years as hard outcome .
Ban Mezher
3 years ago
Presence of new DSA that appeared post transplant were associated with graft loss. But the exact role of these antibodies is not well established because it was noticed that 50% of DSA were not associated with poor graft survival.
As the antibodies development need T cell activation, so the development of de novo DSA may depend on T cell activation therefore may be associated with TCMR.
The impact of DSA presence in association with TCMR was differ between studies. Some of these studies show that TCMR occur before development of DSA while others proved the presence of DSA before occurrence of TCMR.
This prospective study include 379 renal transplant recipients through Jan2013-Nov2013 & followed for 4-5 years. The study exclude the recipients who loss their graft or die in first 3 month post transplant. All patients had induction with ATG or basiliximab. DSA measured at 0,1,3,6 & 12 months, protocol graft biopsy done at 0.1,3,6,12 months & for cause biopsy done when needed.
Immunosuppression regime include MFF & CNI with early drawl of steroid ( after 7 days of transplantation), except for recipients with high cPRA>90% who kept on low dose of steroid.
The study results show that the presence of DSA & TCMR was associated with poor graft outcome when compared with presence of DSA alone or TCMR with out DSA. Also it was found that the most common cause for development of de novo DSA & TCMR was poor drug adherence.
Mohamed Saad
3 years ago
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence.
The development of de novo anti-donor human leucocyte antigen–specific antibody (DSA) is associated with poor outcomes in kidney transplantation. Which may be related to non-adherence of immunosuppressive medications.
In this prospective longitudinal study which include non-desensitized patients to determine the factors associated with poor four-year outcomes in patients who developed post kidney transplant DSA in one center.
=Patients who developed DSA within the first post-transplant year characterized by younger age, more likely to be non-Caucasian, had a higher PRA, more HLA mismatches, than those without DSA and high rate of non-adherence to CNI.
=DSA is associated with increased incidence and severity(high Banff severity score) of TCMR as 82% of patients who diagnosed TCMR+DSA, DSA was detected with or before biopsy diagnosed TCMR and also resistant to treatment than those TCMR without DSA.
=Patients who developed TCMR+DSA had more IFTA score and allograft chronicity especially if DSA was detected with or before TCMR diagnosed compared to group developed TCMR without DSA.
=Patients with DSA+TCMR had higher risk of allograft loss than other groups and TCMR+DSA detected later had worse prognosis than those with DSA alone group.
=Non-adherence was associated with an increased rate of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year especially with DSA+TCMR. =Conclusion:
The study showed that recipients with DSA who develop TCMR have worse tubule interstitial inflammation and worse outcomes compared with those with DSA or TCMR alone especially with non-adherence. Comments:
The prospective longitudinal study addressed clear issue that Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence.
Done on accepted number of patients with variable demographics and recruited in acceptable way.
DSA and kidney biopsy are reliable methods for detect the result and also applicable.
Group classification according to DSA result so no bias and follow up complete enough ,time around four-year.
Ethical guidelines and privacy protection are considered.
But Kidney biopsy as a measurement tool is invasive .
Role of non DSA with outcome not mentioned and Adherence to Mycophenolate mofetil was not considered.
Role of rapid steroid tapering versus other not a clear point.
Filipe prohaska Batista
3 years ago
This paper evaluates T lymphocyte-mediated rejection, especially when associated with donor-specific antibodies (DSA). It is a longitudinal, prospective, single-center study that excluded Hyperacute Rejection and sensitized patients.
The collection of DSA in specific months associated with the local protocol of biopsies could diagnose early T lymphocyte-mediated rejection and include the early development of DSA in more than 80% of cases before developing TLMR.
In this study, no patient had ABMR in isolation, and at least one-third of the patients had TLMR in the first year after transplantation. However, high levels of DSA are related to a worse prognosis of TLMR. It is possible that the DSA may identify some patients whose rejection is resistant to classical therapy.
Interestingly, patients with elevated DSA before or at diagnosis of LTMR had worse rates of tubular atrophy and graft interstitial fibrosis. This combination increased serum creatinine levels and worsened graft quality at four years. Renal recovery by immunosuppressive techniques or not was also worse in this group.
The risk factors for this combination are young patients, HLA class I Mismatch, delayed improvement in graft function, and elevated serum creatinine in the third month after transplantation. Another isolated risk factor is not adhering to immunosuppressive treatment, especially calcineurin inhibitors. The study measured individual consumption of this medication and its impact.
Development of DSA at any time after transplantation showed worsening of the graft when compared to its absence, but when associated with TCMR the evolution is much more severe.
Conclusions
Apparently, de novo DSA may be related to chronic T lymphocyte immunomodulation. DSA measurements at different times can help in the early diagnosis of graft rejection.
DSA+TCMR+ individuals have a worse prognosis.
Sahar elkharraz
3 years ago
Presence of DSA post transplant are associated with loss of graft.
This study done to assess risk of rejection by serial check of DSA level in concurrent with TCMR and serial biopsy done 3 & 12 months to assess level of severity and graft outcome and comparing it to the patients without DSA / DSA alone / DSA with TCMR / TCMR alone.
Characteristic DSA: patients who develop DSA within first year post transplant are younger and non caucasian; they have higher pre-transplant panel reactive antibody & HLA mismatch. DSA is associated with increase incidence & severity of clinical and sub clinical TCMR.
They found ABMR always detected in presence of concomitant TCMR. DSA is detected largely with or before TCMR diagnosis. patients with DSA have higher evidence of acute rejection and higher grade of Banff lesions. patients with DSA and TCMR together have increase risk of chronic kidney allograft rejection at one year and in biopsy shows interstitial fibrosis and tubular atrophy (IFTA). Those patients had DSA with or before TCMR had worse IFTA compared with patients DSA detected post TCMR. Also shows increase level of creatinine & decrease eGFR less than 30ml/min within 4 years.
Risk factors for concomitant DSA & TCMR is younger age and HLA class I mismatch & delayed graft function, independent factor for graft loss which develops de novo DSA and concomitant tubulitis and transplant glomerlopathy and patients non adherent to immunosuppressive agents.
immunosuppressive adherence may lead to affects clinical outcome in patients with TCMR plus DSA. Those patients which are not adherent to immunosuppressive agents whether with DSA or not have increase risk of chronic allograft. Those adherent patients to immunosuppressive drug are similar survival rate of graft to the patients without DSA or TCMR or both. This study recommended desensitisation protocol for presensitised patients.
Sherif Yusuf
3 years ago
Donor-specific antibodies (DSAs) can be classified according to the time of detection into a preformed DSA detected in the patient serum before transplantation and de novo DSA, which will be detected post-transplantation as a result of sensitization.
Denovo DSA detection post transplantation is associated with poor 4 – years graft survival
Patients with denovo DSA had increase in the incidence of TCMR, and the occurrence of DSA together with TCMR is associated with increase in the frequency of TCMR episodes during the first year, increase in the severity of TCMR (higher Banff grade), higher chronicity index and a 3 fold increase in the risk of graft loss when compared to TCMR alone. On the other hand pure ABMR is uncommon (most patients had pure TCMR and less commonly mixed TCMR, ABMR)
The relation between DSA and TCMR may be explained by the interplay between T cell and B cells, T cells are crucial in the induction of complete B cell response with subsequent production of DSA, and tissue injury induced by DSA stimulate T cell response, thus in this study it was found that more than 80% of the patients who develop TCMR has DSA either before or at the same time of development of TCMR.
DSA may have a great impact on graft survival in only patients with biopsy proven rejection, on the other hand patients without biopsy- proven rejection DSA dose not correlate well with graft survival
Risk factors for developing denovo DSA
1. HLA mismatch
2. Delayed graft function
3. Younger age
4. Non living related (deceased) donor kidney
5. Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
6. Non compliance on immunosuppressive medication ( very significant risk factor)
7. Inflammation-induced by infections, surgery or TCMR
One of the most important causes of the development of denovo DSA is non-adherence to medications, as it was found that patients developing DSA plus TCMR who were adherent to their immunosuppressive medications had better graft survival than those who were nonadherent
In conclusion, the tirade of TCMR, DSA, and non- adherence is associated with the worst outcome.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated
rejection and non-adherence
Previous or ongoing clinical and subclinical rejection, leading to chronic damage, is a major cause of late allograft loss.
patients who develop DSA anytime in their posttransplant course have poorer graft survival, approximately 50% exhibit stable long-term function.
DSA was associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy.
patients who developed both DSA and TCMR in the first posttransplant year are at high risk for poor long-term allograft survival compared with patients with either DSA or TCMR alone or lacking either diagnosis.
DSA was detected at or before the onset of TCMR in 82% of patients.
patients with DSA also exhibited increased rates of “mixed” TCMR plus ABMR compared with patients without DSA.
major component of allograft injury in patients with DSA is indeed T cell mediated.
TCMR (i and t scores), and not parameters of ABMR, were associated with increased graft loss in patients with DSA.
Of the independent risk factors associated with the development of both DSA and TCMR, nonadherence as assessed by CNI variability is particularly important.
66% of TCMR was subclinical
This is a prospective single center study at University of Pittsburgh Medical Center from January 2013 until November 2014. The objectives of this study is to assess the association of DSA with post transplant renal graft rejection outcome in correlation with T cell mediated rejection and poor compliant to medications.
A total of 67 ( 22.8% ) out of 294 patients developed DSA in the first year after kidney transplantation. The risk factors triggering the DSA are young age, non-Caucasian, numbers of HLA mismatches and delayed graft function. DSA attributed 1.8-fold higher incidence of TCMR among kidney transplant recipients. Both DSA and TCMR associated with severe IFTA lead to allograft failure and poor outcome in 1 year. Nonadherence to immunosuppressants associated with poor renal allograft outcome especially in the presence of both DSA and TCMR. In conclusion, kidney transplant recipients with DSA and TCMR is associated with tubulointerstitial inflammation, which led to subsequent poor allograft outcomes compared with those with DSA or TCMR alone. Furthermore, nonadherence to immunosuppressants markedly contributed to poor renal allograft outcomes in recipients with DSA and TCMR. Thus, it is important to identify kidney transplant recipients with DSA and TCMR and early assessment of their compliant to immunosuppressants.
Donor-specific antibodies (DSAs) can be classified according to the time of operation into:
a preformed DSA which already presents preoperative and de novo DSA which appears after transplantation due to sensitization.
Preformed DSA can cause hyperacute and acute rejection post-transplant and this can be avoided by crossmatching screening pre-transplant but de-novo DSA detection post-transplantation is associated with poor graft survival.
In this retrospective single-center study including 378 patients who underwent kidney transplantation between January 2013 and November 2014, DSA has screened at 0,1,3,6,9,12 months. protocol biopsies at 3 and 12 months in addition to for-cause biopsy. This study showed that patients with de-novo DSA are more exposed to developing TCMR more frequent, more severe, and more resistant to treatment, and as a sequel, they develop a higher chronicity index with a 3-fold increase in the risk of graft loss. On the other hand, pure ABMR is rare and less common than mixed TCMR and ABMR.
The relation between DSA and TCMR may be explained by T cell and B cells crosstalk and the 3 signals stimulation of naive T cells which are crucial before forming TFh which is responsible for B cell stimulation and DSA production and tissue injury induced by DSA stimulate T cell response that’s why in this study, 80% of the patients who develop TCMR has DSA either preformed or de novo.
Risk factors for developing de-novo DSA
· HLA mismatch
· cadaveric kidney and delayed graft function
· Younger age
· subtherapeutic immunosuppression
· Noncompliance on immunosuppressive medication
· Infections
· TCMR
One of the most important causes of the development of de-novo DSA is non-adherence to medications
In conclusion, Non-adherence was associated with DSA+ TCMR+ and poor graft outcomes.
To study the incidence , time of onset and allograft survival of transplant patients who developed TCMR in the context of de novo DSAs, furthermore, the incidence of TCMR vs ABMR in patients with DSAs was observed in this study.
276 patients from single center enrolled in prospective study wherein DSAs level was monitored post transplantation and correlated to the incidence of acute rejection, its type TCMR vs ABMR, severity of rejection , outcome of rejection, correlation of TCMR and ABMR to no DSAs , or presence of DSAs and relation to adherence . Non adherence was identified by intra-patient variation of CNI trough level in the first year post transplantation
DSAs detection and monitoring:
1-De novo DSAs
2-All patient were negative for DSAs at transplantation time as assessed by luminex test and FCXM.
3-67/294 patients tested positive for DSAs during the first year,40% were transient and persistent in the rest of the patients .
3- Risk factors for De novo DSAs are high cPRA, delayed graft function and HLA mismatches.
4-Most important risk factor was those patients with De novo DSAs exhibited much CNi intra-patient variability IPV which is a surrogate marker for non adherence.
DSAs andTCMR:
108/294 experienced TCMR in the first year, (with more than 50% sub-clinical detected by protocol biopsy done on 3rd and 12th months post transplantation).
ABMR was discovered in 11/294 patients always in the context of TCMR
(mixed ABMR+TCMR).
DSAs positive Patients had 1.8 higher incidence of TCMR. In 82% the DSAs were present before the diagnosis of TCMR, in 18 % it was detected afterwards.
TCMR+ABMR incidence is higher in DSAs positive patients.
The higher incidence and higher-grade Banff lesions were reported with DSAs positive patients reflected in peak Banff acute inflammation i, g, t, ptc scores.
Importantly DSAs positive patients with TCMR featured resistant /late recurrent TCMR than DSAs negative TCMR patients.
DSAs positive patients have higher incidence of IFTA at the one year post transplant and IFTA+i (inflammation) then DSAs negative patients.
Summary
The focus of this paper is the outcome of a kidney transplant recipient with respect to DSA and TCMR. The theme identifies that patients with DSA and TCMR have worse graft outcomes (almost 3 times higher risk) than patients with DSA alone or TCMR alone.
DSA is associated more with TCMR than AMR. Modifiable risk factor for this is non-adherence. Non-adherence can be measured through the variability in CNI levels between different patients on the same regimen. Patients who were adherent had better graft outcomes even with DSA and TCMR.
DSA in the early post transplant phase is dangerous for the graft, and especially more so in patients who are not regular with their IS regimen. They are more at risk for TCMR than patients with DSA who were adherent.
III- post-transplant DSA is associated with poor kidney transplant outcomes only when combined with both T-cell-mediated rejection and non-adherence.
Development of de novo DSA post-transplantation is associated with ABMR leading to poor outcomes. Suboptimal control of the humoral immunity by immunosuppressive drugs is the main cause. Mostly, these antibodies are detected at the time of impending graft loss. However, de novo DSA is also associated with subclinical rejection. Therefore, its exact pathologic role remains unclear. In addition, the presence of the DSAs also indicates the presence of a mature cellular alloimmune response, because the development of DSA requires T cell help. Many studies show a relationship between DSA and TCMR. Wiebe et al. TCMR was higher and precede the development of DSA. There is conflict in the literature about the effect of DSA according to the time of their appearance, incidence, and the role of TCMR. Moreover, the incidence of ABMR versus TCMR in patients with post-transplant DSA remains unclear.
The study is prospective in which DSA was screened serially post-transplantation and correlated with acute rejection diagnosed by biopsy either protocol or for cause, at 3 and 12 months. They compare the severity of the rejection and graft outcome according to the presence or absence of DSA, or TCMR, either alone or with DSA. Also, they correlate DSA and TCMR to nonadherence, measured by intrapatient variability of CNI trough levels during the first post-transplant year.
Results:
Most patients underwent allograft biopsy either protocol or for the cause. Some in the early period (0 – 5 months), others late between 6 – 12 months, and others had paired biopsies at both early and late times.
Posttransplant DSA detection:
At the time of transplantation (time 0), DSA were negative in all patients assessed by Luminex and negative flow crossmatch. 22.8% of the patients developed DSA during the first year, of which 40% were transient DSA and in 60% were persistent. The mean time to detect DSA was 3.4 months. 39% of patients with DSA had historical DSA up to 2 years and the remaining 60% had de novo DSA.
Patients who developed DSA during the first year were younger, non-Caucasian, had higher PRA, more HLA mismatches, and tends to have delayed graft function than those without DSA. Also, they exhibited greater CNI variability during the first year post-transplant, and the baseline renal function was similar between those with and without DSA.
DSA is associated with increased incidence and severity of TCMR:
Patients with DSA gad a higher incidence of TCMR than those without DSA. DSA was also associated with an increased incidence of both clinical and subclinical TCMR.
Patients with either transient or persistent DSA had an increased incidence of clinical TCMR, while patients with persistent DSA had a much higher incidence of subclinical TCMR. In addition, the presence of DSA is associated with TCMR in concomitant with ABMR, compared with those without DSA. DSA correlate with the incidence and severity of TCMR.
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year:
Patients with both DSA and TCMR have the highest mean IFTA score (file:///C:/Users/DRB7C5~1.JAM/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png and high IF + Inflammation, which suggests that these patients are at high risk of early chronicity within one-year posttransplant. Considering the time of detection of DSA, patients whose DSA was detected with or before TCMR had worse IFTA compared with those whose DSA was detected after TCMR.
DSA plus TCMR is associated with worse renal allograft outcomes
Patients with DSA+TCMR+ had significantly higher serum creatinine and are at risk of poor outcomes. The timing of DSA to TCMR makes no significant differences.
Risk factors for concomitant DSA and TCMR:
Patients with DSA+TCMR represent a high-risk group, young age, HLA class I, and delayed graft function were independently associated with DSA+TCMR+.
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
DSA+TCMR patients had greater CNI-intrapatient variability (CNI-IPV) as defined by cutoff ≥35%). Nonadherence was associated with an increased rate of TCMR either persistent or recurrent and increased IFTA at one year. In fact, patients with DSA+TCMR+ who were adherent had significantly similar graft survival to adherent patients who do not develop either DSA or TCMR or both. But, nonadherent patients who are negative for DSA and TCMR still have an increased risk of graft loss/impending graft loss compared with adherent patients. Therefore, nonadherence as assessed by a high CNI-IPV is a risk for poor outcomes in patients with DSA+TCMR+, and emphasising this problem represents a key therapeutic opportunity.
Discussion:
Any clinical or subclinical rejection, leading to chronic damage, is the major cause of late allograft loss, so early identification of patients at increased risk for chronic damage and graft loss, allowing timely therapeutic intervention, is of paramount importance.
With the development of the DSA test, DSA can be monitored and it adds more understanding to the pathogenesis of ABMR so, it added to the Banff classification of ABMR. DSA assay allows the physician to identify patients at increased risk for subsequent allograft loss.
DSA developed at any time post-transplantation is associated with poorer graft survival, although 50% have stable long-term graft function. They are associated with greater incidence and severity of TCMR that can be mixed with ABMR, although isolated TCMR was more frequent. Indeed, this indicates that the major component of allograft injury in patients with DSA is T cell-mediated, supporting the need for T cell response to develop these antibodies. The present study reveals that the TCMR (i, and t scores) and not the ABMR parameters were associated with graft loss in DSA patients. DSA is associated with increased frequency and severity of TCMR in the first year and this was associated with increased chronic damage and inferior long-term graft survival compared with DSA or TCMR alone.
In the present study, all patients lack preformed DSA at the time of transplant, which can explain the low incidence of ABMR in this study. This finding supports the fact that exposure of the allograft to preformed antibody, even in low titers, is more injurious
and supports other studies that show that presensitized patients are at higher risk of ABMR, and pre-sensitized antibodies are more injurious than the exposure that occurs after accommodation might have occurred. Graft outcome correlated with DSA in the presence or absence of TCMR.
As some of the DSA+ patients have transient DSA, and these so they are unlikely to significantly contribute to antibody-mediated damage. Thus, DSA development likely indicates a mature effector T-cell response.
Nonadherence is of particular importance in the development of DSA. And nonadherent patients with DSA and TCMR show bad allograft outcomes. In contrast, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
The present study is the first to link DSA, TCMR, and nonadherence as a trial that occurs in the first year, provides an opportunity for targeted intervention.
Conclusion:
DSA development with TCMR carries bad outcomes as it is associated with chronic damage. Therefore, prompt identification of patients with DSA and TCMR and early assessment of their adherence to medication after transplantation would allow targeted intervention with close follow-up, monitoring, and consideration of long-acting immunosuppressive drugs as belatacept.
the association and clinical significance of TCMR and DSA arising after transplantation is not well understood. As development of antibodies requires T cell help .
the literature is discrepant as to the incidence, timing, and impact in terms of graft survival of TCMR in patients who develop posttransplant DSA.
Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA
The increased incidence of acute rejection and higher-grade Banff lesions in subjects with DSA was also reflected in higher peak Banff acute inflammation (“t,”“i,”“g,”“ptc”)score
DSA+ TCMR+ patients are at high risk for developing chronic allograft nephropathy within 1 year after transplant .
patients whose DSAwas detected with or before TCMR had worse IFTA compared with those whose DSAwas detected after TCMR
although patients who develop DSA anytime in their posttransplant course have poorer graft survival, approximately 50% exhibit stable long-term function
DSA was associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy
Both clinical and subclinical TCMR with Banff 1A and 1B were treated with 3 doses of methylprednisolone (250 mg each) and maintenance prednisolone at 5 mg/d. TCMR with Banff >2A and those resistant to steroids were were treated with Thymoglobulin (maximum6mg/kg) over 4 to 5 days.Acute ABMR was treated with 4 to 6 treatments of plasmapheresis plus IVIG.
Summary of Post-transplant DSA is associated with poor kidney transplant outcomes only when combined with both TCMR and non-adherence
Introduction:
a)TCMR +ve , DSA+ve
b) TCMR -ve,DSA -ve
c) TCMR +ve,DSA-ve
d)TCMR -ve, DSA+ve
Results:
Posttransplant DSA detection
DSA is associated with increased incidence and severity of TCMR
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
Risk factors for concomitant DSA and TCMR
Risk factor DSA+ev plus TCMR include:
· 1) HLA class 1mismatch,
· 2) thymoglobulin induction
· 3) cold ischemia times.
· 4) delay graft function.
· 5) CNI level, cPRA ,living donor or not
· 6) other factors such as age, gender ,ethnicity, chronic disease (DM/HTN )and primary renal disease
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
Discussion:
Results:
CONCLUSION:
Post-transplant DSA have been associated with poor outcomes. This study aiming to evaluate effect of DSA on patients having T cell mediated rejection post transplant. 294 transplant recipients between January 2013 and November 2014 were selected. DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies implemented at 3 and 12 months, and any for original cause biopsies.
22.8% patients showed DSA in the first year, 40% of whom developed transient DSA. 39% of them had historical DSA while 61% showed de-novo DSA. Patients who developed DSA were younger, non-Caucasian, had increased HLA mismatches especially class I, with more PRA and higher incidence of delayed graft function in comparison with those who did not develop DSA.
Risk factors for developing De Novo DSA include:
HLA mismatch, delayed graft function, younger age, non -living related; deceased donor kidney ,planned subtherapeutic immunosuppression ;due to malignancy, infection or change to CNI free or CS free protocols non compliance on immunosuppressive medication inflammation-induced by infections ,in addition to surgery or TCMR.
Patients with DSA and TCMR shad 1.35-fold greater CNI-IPV than the other patients. Non-compliant patients with DSA and TCMR showed worse allograft outcomes, with graft loss at 4 years in 70% of patients. Adherent patients who developed DSA plus TCMR showed graft survival like those without TCMR and DSA.
The three items of DSA, TCMR and non-compliance to medications are linked to worse graft survival. Hence, identification of patients with these items could help early therapeutic intervention, avoiding early graft loss.
The article addresses a prospective, single center study involving non-desensitized transplant recipients regarding the effect of post-transplant DSA’s over the kidney transplant outcomes.
The study was done to evaluate the effect of DSA on patients having TCMR post-transplant. 294 transplant recipients were included in the study. The DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies were performed at 3 and 12 months.
22.8% patients developed DSA in the first year, 40% of whom had transient DSA. 39% of these patients had historical DSA while 61% developed de-novo DSA. Patients who developed DSA were of younger age, non-caucasian, had more HLA mismatches (especially class I), higher PRA and higher incidence of delayed graft function as compared to those who did not develop DSA. DSA positive patients with TCMR had higher prevalence of chronic allograft damage at 1 year and worse graft outcomes at 4 years. High CNI intrapatient variability (IPV), as a marker of non-adherence, was associated with increased TCMR rate and severity. 46% of patients with DSA and TCMR had high CNI IPV. Graft survival in adherent DSA positive patients with TCMR was similar to those without DSA or TCMR, or both. 75% of non-adherent patients with DSA and TCMR developed graft failure.
Thus , DSA leads to increased incidence and severity of TCMR along with poor long-term graft results, which increases in the presence of non-adherence.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated
rejection and non-adherence
Post transplant DSA is associated with poor outcome .
Comared to those not exhibit DSA, those with DSA are associated more with clinical and subclinical TCMR.
Combination of +ve DSA and TCMR lead to 3 fold increase in graft loss compared to either DSA or TCMR alone.
ABMR was uncommon and always associated with TCMR.
75% of patients with non adherence and DSA and TCMR has impending graft loss at 4 years.
Insufficient control of humoral immunity by immune suppressant medication is associated graft dysfunction and loss.
DSA is traditionally been shown to be associated with ABMR.
50% of patient has good graft functioning despite of having +ve DSA.
Because the development of antibodies requires T cell help, the presence of DSA also indicates the presence of a more mature cellular allo immune response. Indeed, several studies have shown a relationship between DSA and T-cell–mediated rejection (TCMR).
DSA +ve patients at 4.5 years has higher incidence in TCMR in first year than those who has no DSA .
These studies showed that the increased graft loss associated with DSA was limited to patients who had acute rejection.
DSA +VE pt has 1.8 fold higher incidence of TCMR than those without DSA . Interestingly, patients with de novo DSA had a much higher rate of TCMR with more persistent or recurrent TCMR when compared with those without DSA or anamnestic DSA
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year.
Risk factors for concomitant DSA and TCMR .
1- Young age recipient.
2- Class 1 HLA mismatch.
3- Delayed graft function.
Are independently associated with DSA + ve , TCMR + ve .
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
Non adherence (more than 35% variability in intra patient CNI trough level) associated with increase in TCMR AND +VE DSA and increased IFTA
the presence of DSA is indicative of a more mature immune response with contributions from both humoral and cellular immunity.
Some study found that, In the absence of acute rejection DSA alone has no effect on graft survival.
Preformed DSA is more injurious than denovo DSA.
In 40% of patient, the DSA is transient and is unlikely contribut to AB mediated damage .
Post-transplant donor specific antibody (DSA) is associated with poor renal allograft
outcomes.
Prospectively nonsensitized patients STUDIES to determine factors associated with
poor four-year outcomes in patients who developed post transplant DSA. Using serial
monitoring, 67 of 294 patients were found to develop DSA by one year.
Introduction:
In number of studies, DSA was detected at the time of impending graft loss, suggesting a
possible causative role. Moreover, DSA has traditionally been shown to be strongly
associated with ABMR.
Many of these studies retrospective and small sample size and inclusion of presensitized
patients. Several studies have shown a relationship between DSA andTCMR. Moreover,
the incidence of ABMR versus TCMR in patients with post transplant DSA remains
unclear.
To address these issues, a prospective single center study is done, where DSA was
screened serially from the time of transplantation and correlated with acute rejection
(detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months),
severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR,
DSA alone, TCMR alone, or DSA plus TCMR.
In addition, DSA correlated and TCMR to nonadherence, measured by intrapatient
variability of Calcineurin inhibitor (CNI) trough levels during the first post transplant year.
RESULTS Study:
Amongst 378 patients who underwent kidney transplantation between January 2013 and
November 2014.
294 (81%) had at least 1 allograft biopsy within the first post transplant year and were
included in the study.
Of these, 276 patients had a biopsy between 0 and 5 months (early histology) and 224
patients had a biopsy between 6 and 12 months (late histology).
A total of 209 of 294 patients (71%) had paired biopsies at both early and late time point.
Post transplant DSA detection:
Determined by luminex and a negative flow cross-match.
Patients who developed DSA within the first post transplant year were:
Younger.
Non-Caucasian.
Higher Pretransplant panel reactive antibody.
More human leucocyte antigen mismatches.
Greater CNI intrapatient variable.
DSA is associated with increased incidence and severity of TCMR:
36.7% experienced TCMR in the first post transplant year,
47% being clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at
3 months or at 12 months.
Importantly, ABMR in 10.2% of all rejections and was always detected in the presence of
concomitant TCMR.
DSAþ patients were twice as likely to have persistent/ recurrent late TCMR (6–12
months) compared with those without DSA (P ¼ 0.08). This suggests that DSA may
identify a subgroup of patients whose rejection is relatively resistant to standard
treatment.
Patients with DSA and TCMR have increased chronic renal allograft damage at 1
year:
Combination of DSA and TCMR was associated with early chronic histological damage.
DSA plus TCMR is associated with worse renal allograft outcomes:
patients with DSAþ+ TCMRþ had significantly higher serum creatinine at the last follow-
up when compared with all the other groups, Furthermore, DSAþTCMRþ was associated
with significantly worse graft survival at 4 years compared with all other patient groups
(23% vs. approximately 10%).
Immunosuppression adherence markedly affects clinical outcomes in patients with
TCMR plus DSA:
Nonadherence assessed by a high CNI-IPV accounts for the particularly poor outcomes
noted in patients with DSAþTCMRþ, and addressing this problem may represent an
important therapeutic opportunity.
The development of de novo anti donor human Leukocyte antigen specific antibody DSA is associated with poor outcomes in kidney transplantation. DSA was detected at time of impending graft loss suggesting a possible causative role. Moreover, DSA has traditionally been shown to be strongly associated with antibody mediated rejection ABMR.
Because the development of antibodies requires T Cell help , The presence of DSA also indicates the presence of a more mature cellular allo immune response. Indeed, several Studies have shown a relationship between DSA and T-cell mediated rejection TCMR ,Yet the association and clinical significance of TCMR and dies arising after transplantation is not well understood.
In a comprehensive prospective analysis It was shown that de novo DSA occurred late (Mean 4.6 years) And was associated with twofold higher incidence of TCMR occurring within the first year as compared with patients without DSA. This suggested that TCMR precedes the development of alloantibodies and antibody-mediated rejection.
In this study , DSA was screened serially from the time of transplantation and correlated with acute rejection. Which, Is detected by for- cause biopsies as well as protocol biopsies at three and 12 months. Also severity of rejection and grafts outcomes, comparing patients exhibiting no DSA nor TCMR Versus those with DSA alone ,Those with TCMR alone or DSA plus TCMR.
In addition to collerating DSA and TCMR to non-adherence measured by intra patient variability of calcineurin inhibitor trough levels during the first post transplant year .
In this study , biopsies done either as Protocol biopsy or for-cause biopsy Between zero and five months(early histology ),or between the 6th and 12th months (late histology)
All patients In this study where – for DSA a time of transplantation.( time 0 )as determined by luminex and a negative flow cross-match.
DSA is associated with increased incidence and severity of TCMR. In this study, 36.7 percent of patients experienced TCM are in the first post transplant year. With 47% being clinical TCM are and 53% being subclinical TCM are diagnosed on a biopsy. Importantly, ABMR was seen in about 10% of all rejections. And was always detected in the presence of concomitant TCMR. Among those patients with DSA+ TCMR+ , DSA was detected concomitant with or before the diagnosis of TCM are in 82 percent of patients. Whereas only 18 percent of patients developed DSA after the diagnosis of TCMR .Also patients with DSA had more TCMR with concomitant ABMR as compared with those without DSA.
The increased incidence of acute rejection and higher grade bannf Lesions in subjects with DSA was also reflected in higher Peak bannf acute inflammation Scores.
Another Finding. Is that despite standard of care treatment of TCMR,DSA positive patients were twice as likely to have persistent or recurrent late TCMR that’s between 6 and 12 months compared with those without DSA. This suggests that DSA May identify a subgroup of patients whose rejection is relatively resistant to standard therapy.
Patients with DSA and TCMR have increased, chronic renal allograft damage at one year ,It was found that DSA was associated with significantly greater interstitial fibrosis and tubular atrophy IFTA at one year. And a greater proportion of patients with DSA had an, an IFTA score that is equal or more than 3. DSA was associated with increased interstitial fibrosis with inflammation. IF + I .So patients with DSA + TCMR+ had the highest mean IFTAscore.
Also, it was found that patients whose DSA was detected with or before TCMR had a worse IFTA compared with those whose DSA was developed afterTCMR.
So in conclusion, DSA + TCMR + is associated with worse renal allograft outcome. DSA+ TC MR+ was associated with significantly worse graft survival at 4 years.
Patients with DSA +. TCMR+ had a significantly higher risk of allograft loss and impending allograft loss (s 50 percent versus less than 20%). Furthermore, DSA detected prior to TCMR was associated with significantly greater risk of graft loss, plus impending graft loss in comparison to DSA alone. In those whose DSA was detected after TCMR , they exhibited as that Statistically nonsignificant Trend toward increased graft loss or impending graft loss compared with the DSA alone. However, regardless of whether DSA precedes or follows TCMR , the combination of DSA & TCMR carries a worse prognosis than having DSA without TCMR .
Risk factors for concomitant, DSA and TCMR : factors associated with this phenotype compared with all remaining patients.
. younger recipient age.
.class. 1 HLA mismatches.
. Third delayed graft function.
.non-adherence to immune suppressive medications
For non-adherent patients. Especially those with a high CNI-IPV. That is equal or more than 35%. With both DSA+TCMR+. Those had significantly higher graft loss or impending graft loss at 48 months as compared to those DSA+TCMR + adherent to treatment. In fact, patients DSA+TCMR+ who were adherent had statistically similar graft survival to adherent patient Who lacked either DSA or TCMR or both.
So in conclusion, DSA is associated with increased incidence of higher Banff grade and recurrent T-cell mediated rejection. The incidence of TCMR was higher in DSA positive. As compared to those who are DSA negative (about 60 % vs 30% )
Comparing between clinical TCM are and subclinical TCMR, which the latter is detected on biopsy ,
It’s found that patients with DSA +had more TCMR whether it’s a clinical or subclinical, then those who are DSA –
regarding the temple relationship between DSA & TCMR ,DSA that is detected before the diagnosis of TCMR Was about thirty percent.DSA detected concomitant with diagnosis of TCMR Is 17%. ,While TCM are diagnosed before the detection of TSA is 10%. So, the most common type is DSA That’s prior to detection of TCMR.
The presence of DSA is associated adverse outcomes in kidney allograft (1-6). DSA increases the risk of the TCMR either clinical and sub-clinical forms. Non-adherence isan important risk factor for development of both DSA and TCMR.
Methodoolgy ;
Study population;
DSA screening was done at 0,1,3,6,9 & 12 months, and protocol biopsies at 3 and 12 months. indication biopsies was considered when neccessary
Early biopsies was 0-5 months and late biopsies was 6-12 months
All were DSA negative and non-sensitised
This was prospective study of 378 ( 15 excluded due to graft loss at 3 months, another 69 were excluded because no biopsy was done) for development of DSA within one year post-transplant between Jan 2013 and Nov 2014 and followed up to may 2018. Patients were divided into 4 groups ; 1) DSA+ plus TCMR+ 2) DSA- plus TCMR+ 3) DSA+ plus TCMR- 4) DSA- plus TCMR- .
DSA monitorning and testing ;
Cut off >= 1000 by single antigen bead
Histortical DSA was checked for 2 years before transplants
Renal allograft histology ;
Definition of TCMR & IFTA and IF+i was based on 2013 Banff criteria
Immunosuppression ;
Thymoglobulin 6mg/kg + single dose methylpred 500 mg followed by dual therapy = CNI + MPA
Few got basilliximab + methylpred
Triple therapy ( MPA + CNI + Pred) only if cPRA > 90%
Assessment of non-adherence ;
This measured by CNI-intrapatient variability, where tac levels for 1 year( highest + lowsest level considered) was calculated
Treatment of clinical and sub-clinical TCMR ;
3 days iv 250 methypred for Banff 1A & 1B
4 days of iv Thymoglobulin 6mg/kg for Banff >2A
Study end point ;
Graft loss and impending graft loss( eGFR< 30 ml/min and change in eGFR> 30% from 3 to 40 months
Statistical analysis ; Mann-White U test, Chi-squared test, uni-and multivariate analysis plus Kaplan-Meier were used.
Results ;
Posttransplant DSA ;
In 67 patients DSA was transient in 40% and 60% of patients
The average time for detection of DSA was 3.4 months
DSA is associated with increased incidence and severity of TCMR ;
ABMR accounted for 10.2% of all rejections and usually coexisted with TCMR
Those with DSA had 1.8 fold increased rates of TCMR than those without TCMR
Patients with DSA and TCMR have increased Chronic renal allograft damage at 1 year;
TCMR+ TCMR+ patients are at risk for developing chronic allograft dysfunction within 1 year after transplant.
DSA before or at time of TCMR is associated with more chronic IFTA than DSA after TCMR
DSA plus TCMR is associated with worse renal allograft outcomes ;
Worse allograft survival at 4 years were seen those with DSA+ plus TCMR (= high risk group for poor outcomes)
Risk factors for con-cominant DSA and TCMR ;
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA ;
Non-adherence measured by CNI-IPV is associated high rates of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year.
CNI-IPV >= 35% is independent risk factor for both DSA+ TCMR+ status
Discussion ;
Despite the presence of DSA, 50% of patients may have stable allograft function over long-term.
Detection of DSA indicates more mature immune response including both humoral & cellular immune response.
Wiebe et al. reported that half of the patients with de-novo DSA had previous TCMR at 4.6 years(30)
Cooper et al. and Devos et al. showed that DSA had no effect on allograft dysfunction in absence of acute rejection(12)
ABMR potentiate TCMR by enhancing tissue damage and inflammation, opsonising target antigens
Non-adherenc was important association with TCMR+ and DSA+
confounders may include free steriod regiments and re-transplant patients
Conclusion;
DSA+TCMR+ associated with worse transplant outcomes.
Non-adherence is a risk factors for both DSA+ TCMR+
Early identifications of DSA+TCMR+ and early assessment of adherence status are of para mount importance for good transplant outcomes.
This is a single center prospective study on DSA negative renal transplant patients to study the correlation between posttransplant DSA level, TCMR and effect of immunosuppressant adherence with graft survival. The information in available literature still debatable about incidence, timing and impact of TCMR on graft survival on patients who develop post-transplant DSA.
The study measured various variables including age, ethnic group, mismatches, CNI intrapatient variability (CNIIPV,a measure of adherence to immunosuppressive medications) over the course of the first year and kidney biopsies (early -first 6 months, late-after 6 months till 1 year)
The studied recruited 209 patients, only 67 of them developed DSA in first year. These patients’ characteristics include: they were younger, more likely to be non-Caucasian, had a higher pretransplant panel reactive antibody, more human leucocyte antigen mismatches, and a trend toward more delayed graft function than those without DSA and greater CNI intrapatient variability over the course of the first year.
The detection of DSA was associated with 2 folds increased risk of early TCMR, 2 folds increased risk of late TCMR despite the treatment of TCMR and grater IFTA at 1 year follow up. Concomitant tubulitis and transplant glomerulopathy were independent
risk factors for subsequent allograft failure in patients with late de novo DSA.
DSA and TCMR positive patients were considered a high risk of poor outcome group associated high mean IFTA score, severe IFTA, IF with inflammation on 1-year biopsy and early chronic histological damage with worse 4-year graft survival.
Independent risk factors for concomitant DSA and TCMR include: younger age, class I HLA mismatch and delayed graft function
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
Patients with no DSA nor TCMR and patients with DSA+TCMR+ who were adherent to immunosuppressant have similar graft survival. Nonadherence was associated with increased risk of TCMR, recurrent TCMR and IFTA at 1 year follow up.
Patients with DSA have increased risk of both TCMR and ABMR compared to non-DSA patients. Patients with DSA has increased risk of graft loss and severe TCMR even with no ABMR
Development of DSA post-transplant has been shown to be associated with poor outcomes. The study was done to evaluate the effect of DSA on patients having T cell mediated rejection (TCMR) post transplant. 294 transplant recipients between January 2013 and November 2014 were included in the study. The DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies were performed at 3 and 12 months, in addition to any for-cause biopsies.
22.8% patients developed DSA in the first year, 40% of whom had transient DSA. 39% of these patients had historical DSA while 61% developed de-novo DSA. Patients who developed DSA were of younger age, non-Caucasian, had more HLA mismatches (especially class I), higher PRA and higher incidence of delayed graft function as compared to those who did not develop DSA.
Risk factors for developing De Novo DSA
1. HLA mismatch
2. Delayed graft function
3. Younger age
4. Non living related (deceased) donor kidney
5. Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
6. Non compliance on immunosuppressive medication
7. Inflammation-induced by infections, surgery or TCMR
DSA and TCMR patients had 1.35-fold greater CNI-IPV than the other patient groups. Non-compliant patients with DSA and TCMR exhibit particularly worse allograft outcomes, with graft loss by 4 years in 70% of the cases.. Importantly, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
The triad of DSA, TCMR and non-compliance to medications ,all linked to worse graft survival. So prompt identification of patients with DSA , TCMR and non-compliance to medications would allow timely therapeutic intervention, thus, preventing early graft loss.
Introduction
Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes.
Insufficient control of humoral immunity by current immunosuppressive regimens is increasingly felt to be an important factor underlying allograft dysfunction and loss
Study design
a prospective singlecenter study on 378 patients who underwent kidney transplantation between January 2013 and November 2014 (15 were excluded)
DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR. In addition correlated DSA and TCMR to nonadherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first posttransplant year.
Result
the remaining 363 patients, 294 (81%) had at least 1 allograft biopsy within the first posttransplant year and were included in the study. Of these, 276 patients had a biopsy (either protocol or for-cause) between 0 and 5 months (early histology) and 224 patients had a biopsy between 6 and 12 months (late histology)
A total of 209 of 294 patients (71%) had paired biopsies at both early and late time points, and these patients were used to analyze histological progression.
Posttransplant DSA detection
Of the 294 patients analyzed, 67 (22.8%) developed DSA in the first year. DSA was transient (detected only once during the first year) in 40% of the 67 patients with DSA and was persistent in the remaining 60%
DSA is associated with increased incidence and severity of TCMR
108 of 294 patients (36.7%) experienced TCMR in the first posttransplant year, with 47% being clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at 3 months or at 12 months (data not shown). Importantly, ABMR was seen in 11 patients (10.2% of all rejections) and was always detected in the presence of concomitant TCMR. Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
DSA associated with significant interstitial fibrosis and tubular atrophy (IFTA) at 1 year Importantly, a greater proportion of patients with DSA had IFTA score $3 andfewer patients had no chronic damage onthe1-year biopsy
DSA plus TCMR is associated with worse renal allograft outcomes
patientswithDSAþTCMRþ had significantly higher serum creatinine at the last follow-up when compared with all the other groups. Furthermore, DSAþTCMRþ was associated with significantly worse graft survival at 4 years compared with all other patient groups (23% vs. approximately 10%)
RiskfactorsforconcomitantDSAandTCMR
Adherence to immunosuppressive medications is increasingly recognized as an important risk factor for renal allograft outcomes
Nonadherence was associated with an increased rate of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year
Conclusion
DSA are associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy. Importantly, patients who developed both DSA and TCMRinthe first posttransplant year are at high risk for poor long-term allograft survival compared with patients with either DSA or TCMR alone or lacking either diagnosis.
Although both TCMR and mixed TCMR plus ABMR were increased in DSA patients, isolated TCM was4.6-fold more frequent than mixed rejection.Moreover, TCMR severity and graft loss remained increased inDSA patients,even when those with concomitant ABMR were eliminated from the analysis.
Thus,although amajority of studies on DSA have focused onABMR ,weshowthatamajor component ofallograf tinjury I npatients with DSA is indeed Tcellmediated.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
Yet, the association and clinical significance of TCMR and DSA arising after transplantation is not well understood. In a comprehensive prospective analysis, Wiebe et al. showed that de novo DSA occurred late (mean 4.6 years) and was associated with 2-fold higher incidence
(54%) of TCMR occurring within the first year, compared with patients without DSA This suggested that TCMR precedes the development of alloantibodies and antibody.
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA. Early identification of patients at increased risk for chronic damage and graft loss, allowing timely therapeutic intervention, is of paramount importance. Accurate testing
for DSA, developed within the past decade, has helped revamp the diagnostic criteria for ABMR.
When it comes to kidney transplantation, it is well established that de novo DSA is linked with poor renal outcomes.
DSA has been shown to be significantly linked with antibody-mediated rejection. Given that T cell activation is required for antibody formation, the development of DSA also suggests the existence of cellular stimulation and an active T cell response. There has been much research that has indicated a link between ABMR and the existence of preformed or de novo DSA, but more recent studies have revealed a relationship between DSA and T-cell–mediated rejection.
For the purpose of determining the relationship between DSA, total cell mononuclear response (TCMR), and renal outcomes, a prospective single-centre study was conducted in which DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at three and twelve months), the severity of rejection, and graft outcomes.
Consequently, in this investigation, non-desensitized patients who acquired posttransplant DSA were prospectively investigated to identify variables linked with poor four-year outcomes. Before transplantation, all patients were checked for DSA using the Luminex approach, which included a negative flow cross-match negative as a control.
Using serial monitoring, it was discovered that 67 out of 294 patients had DSA within one year. DSA was temporary in 40% of the 67 individuals who had DSA, but it was chronic in the other 60% of the patients who had DSA.
36.7 per cent of patients exhibited TCMR in the first post-transplant year, with 47 per cent experiencing clinical TCMR and 53 per cent experiencing subclinical TCMR, as determined by a protocol biopsy performed at 3 months or 12 months after transplantation. It was shown that just 10.2 per cent of all rejections were due to ABMR and that it was always recognized in the context of concurrent TCMR.
patients who develop both DSA and TCMR in the first year after transplantation is at increased risk for poor long-term allograft survival when compared to patients who acquire either DSA or TCMR alone, or patients who do not develop either DSA or TCMR at all. A more developed immune response, with activation of both humoral and cellular immunity, is characterized by the presence of DSA. In DSA patients, however, there was a rise in both total and mixed total plus ABMR. Patients’ nonadherence, as defined by interpatient variability of calcineurin inhibitor (CNI) trough levels during the first year after transplantation, was likewise linked to DSA and TCMR, according to the research team.
Patients who acquired DSA during the first posttransplant year were younger, had a higher PRA prior to transplant, had more HLA mismatches, and had a tendency toward delayed graft function compared to those who did not develop DSA within the first posttransplant year. A further finding was that these patients had higher CNI interpatient variability, which is a measure of adherence to immunosuppressive drugs throughout a one-year period after transplantation. Patients who acquire both TCMR and DSA within one year of transplantation are at increased risk for poor graft outcomes, according to the study.
The present research was the first to establish a relationship between DSA, TCMR, and nonadherence as a trio of factors associated with significantly reduced allograft survival.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
This was a prospective, single center study involving non-desensitized transplant recipients which dealt with the effect of post-transplant donor specific antibodies (DSA) over the kidney transplant outcomes.
Development of DSA post-transplant has been shown to be associated with poor outcomes. The study was done to evaluate the effect of DSA on patients having T cell mediated rejection (TCMR) post transplant. 294 transplant recipients between January 2013 and November 2014 were included in the study. The DSA levels were checked at 0,1,3,6,9 and 12 months and protocol biopsies were performed at 3 and 12 months, in addition to any for-cause biopsies.
22.8% patients developed DSA in the first year, 40% of whom had transient DSA. 39% of these patients had historical DSA while 61% developed de-novo DSA. Patients who developed DSA were of younger age, non-caucasian, had more HLA mismatches (especially class I), higher PRA and higher incidence of delayed graft function as compared to those who did not develop DSA.
DSA positive patients had 1.8 times higher incidence of TCMR and 2 times higher incidence of early as well as recurrent TCMR which was relatively more resistant to steroid treatment. DSA positive patients with TCMR had higher prevalence of chronic allograft damage at 1 year and worse graft outcomes at 4 years (23% ). High CNI intrapatient variability (IPV), as a marker of non-adherence, was associated with increased TCMR rate and severity. 46% of patients with DSA and TCMR had high CNI IPV. Graft survival in adherent DSA positive patients with TCMR was similar to those without DSA or TCMR, or both. 75% of non-adherent patients with DSA and TCMR developed graft failure.
So, DSA leads to increased incidence and severity of TCMR and poor long-term graft results, which gets worse in presence of non-adherence.
*The development of de novo anti-donor human leucocyte antigen specific antibody (DSA) is associated with poor outcomes in kidney transplantation.
* This prospective studied non desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post transplant DSA.
* combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone
* Amongst factors independently associated with DSA plus TCMR, nonadherence is potentially modifiable.
* Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post transplant year, further risk stratified patients with DSA plus TCMR about 75% of these patients had impending graft loss by four years.
* Early post-transplant DSA, especially in non-adherent patients is associated with increased incidence of TCMR and
represents a high-risk group of patients who might benefit from targeted therapeutic interventions.
* Insufficient control of humoral immunity by current immunosuppressive regimens is increasingly felt to be an important factor underlying allograft dysfunction and loss.
* The clinical implications of de novo DSA and the pathogenic role of DSA itself remain unclear.
* Because the development of antibodies requires T cell help, the presence of DSA also indicates the presence of a more mature cellular alloimmune response.
* The association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
*Study showed de novo DSA occurred late and was associated with 2-fold higher incidence of TCMR occurring within the first year, compared with patients without DSA, suggested that TCMR precedes the development of alloantibodies and antibody mediated injury.
* Although DSA was associated with poor
graft outcomes, the effect of prior TCMR on long-term outcomes in patients with DSA was not examined.
* In other studies where DSA was serially assessed, DSA occurred much earlier and frequently preceded or was concomitant with TCMR and showed that the increased graft loss associated with DSA was limited to patients who had acute rejection.
* Other studies showed that DSA arising in the first year was associated with stable long-term allograft function irrespective of TCMR.
* The incidence of ABMR versus TCMR in patients with posttransplant DSA unclear.
* prospective single center study where DSA was screened serially from the time
of transplantation and correlated with acute rejection, severity of rejection and graft outcomes comparing patients with: # No DSA or TCMR
# DSA alone
# TCMR alone
# DSA plus TCMR.
# Correlated DSA and TCMR to nonadherence, measured by (CNI) trough levels duringthe first posttransplant year.
** RESULTS **
#Study population
– Amongst 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 were excluded because of patient death or allograft loss within 3 months.
– 294 (81%) had at least 1 allograft
biopsy within the first post transplant year and were included in the study.
– 276 patients had a biopsy between 0 and 5 months (early histology)
– 224 patients had a biopsy between 6 and 12 months (late histology)
– A total of 209 of 294 patients (71%) had paired biopsies at both early and late time points, and these patients were used to analyze histological progression.
**Posttransplant DSA detection**
– All patients were negative for DSA at the time of transplantation, as determined by luminex and a negative flow cross-match. – Of the 294 patients analyzed, 67 (22.8%)
developed DSA in the first year.
– DSA was transient in 40% of the 67 patients with DSA and was persistent in the remaining 60% .
— A total of 24 of 67 patients (36%) had persistent DSA detected 1month after transplant.
– A total of 26 of 67 (39%) patients
with DSA had historical DSA up to 2 years before transplantation.
The remaining patients (61%) had de novo DSA.
# The clinical characteristics of Patients
who developed DSA within the first post transplant year were :
younger, more likely to be non-Caucasian, had a higher pretransplant panel reactive antibody, more human leucocyte antigen mismatches, trend toward more delayed graft function than those without DSA
and exhibited greater CNI intrapatient variability over the course of the first year. Importantly, the baseline renal transplant function measured at 1 and 3
months after transplant was similar between those with andwithout DSA.
** DSA is associated with increased incidence and severity of TCMR **
– (36.7%) of patients experienced TCMR in the first posttransplant year.
– 47% being clinical TCMR.
– 53% subclinical TCMR diagnosed on a protocol biopsy.
– ABMR was seen in (10.2% of all rejections) and was always detected in the presence of concomitant TCMR.
– Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA .
– The increased risk of TCMR in DSA
patients persisted when concomitant ABMR patients or those with early DSA (1 month) were excluded
– Was associated with increased incidence of both clinical and
subclinical TCMR .
-Patients with DSA had more TCMR with concomitant ABMR, compared with those without DSA .
** Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
– DSA was associated with significantly greater interstitial fibrosis and tubular atrophy at 1 year.
– DSA and TCMR patients are at high risk for developing allograft chronicity within 1 year after transplant.
– The combination of DSA and TCMR was
associated with early chronic histological damage.
– DSA and TCMR hads ignificantly higher serum creatinine at the last follow-up when compared with all the other groups.
DSA and TCMR was associated with significantly worse graft survival at 4 years compared with all other patient groups (23% vs10%).
** Risk factors for concomitant DSA and TCMR
Because patients with DSA and TCMR constitute a high-risk group, we examined the factors associated with this:
younger recipient age
Class I human leucocyte antigen mismatches
Delayed graft function
Serum creatinine
CNI, calcineurin inhibitor
** Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
– Adherence to immunosuppressive medications is increasingly recognized as an important risk factor for renal allograft
outcomes.
– Used CNI intrapatient variability as a measure, patients with DSA and TCMR had 1.35-fold greater CNI-IPV than the other patient groups
– Nonadherence was associated with an
increased rate of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year.
# DISCUSSION
– Early identification of patients at increased risk for chronic damage and graft loss, allowing timely therapeutic
intervention.
– Accurate testing for DSA, developed within the past decade has helped
revamp the diagnostic criteria for ABMR. – Early detection of DSA promised to better define the natural history of ABMR and allow us to identify patients at increased risk for subsequent allograft loss.
– Posttransplant DSA in non presensitized patients, in terms of both ABMR and allograft survival, remains uncertain. although patients who develop
DSA anytime in their posttransplant course have poorer graftsurvival.
– Although both TCMR and mixed TCMR
plus ABMR were increased in DSA patients, isolated TCMRwas 4.6-fold more frequent than mixed rejection
** In conclusion, this single center prospective study showed that recipients with DSA who develop TCMR have worse
tubulointerstitial inflammation, which was frequently recurrent and led to subsequent worse outcomes compared with those with DSA or TCMR alone. -Nonadherence, markedly contributed to poor graftoutcomes in patients with DSA and TCMR.
– Identification of patients with DSA and TCMR and early assessment of their adherence status after transplantation would allow targeted intervention with close follow-up, visiting nurses, and consideration of long-actingfollow-up,
immunosuppressive agents such as belatacept.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
This was a prospective observational study to describe the relationship between the development HLA-DSA and transplant outcomes.
Background
The relationship between HLA-DSA and poor allograft outcomes is well known.
It is possible that current immunosuppression regimens are not able to adequately switch off the production of DSA.
We know that T helper cells are needed to stimulate antibody production.
Therefore, the presence of DSA is likely a process of an active cellular immune response.
There are mixed findings showing T cell mediated rejection (TCMR) precedes antibody mediated rejection (AMR), other studies have shown TCMR may preceed DSA.
Objectives
To determine the incidence, timing and impact on graft survival of TCMR among patients who develop DSA.
To described the incidence of AMR vs TCMR in post-transplant patients
Methods
Single centre prospective study between January 2013 and November 2014.
378 patients were screened
15 excluded due to death or graft loss
all patients had serial DSA screening from the time of transplant and protocol biopsies at 3 and 12 months.
294/363 had biopsy either per protocol or for-cause.
Adherence was assessed by measuring CNI trough levels and estimated the intrapatient variability of calcineurin inhibitor levels (CNI-IPV).
Results
294 had atleast 1 biopsy.
209 had biopsy between 0 and 5 month (early) and between 6 and 12 month(late).
67/294 (22.8%) developed DSA in the first year. 60% DSA persisted, while 40% had transient DSA.
26/67(39%) had historical DSA vs 61% denovo DSA
DSA developed more in younger patients, non-Caucasian, more HLA mismatches and non-adherent to medications.
108/294(36.7%) had TCMR in year 1; with 47% clinical TCMR vs 53% subclinical diagnosed on biopsy.
10.2% had AMR and always associated with TCMR.
Patients with DSA had 1.8-fold higher incidence of TCMR than those without DSA.
DSA was associated with increased higher incidence of clinic and subclinical TCMR.
In DSA + TCMR, 82% DSA was detected with or before diagnosis of TCMR
DSA subjects had high-grade Banff lesions.
De novo DSA more associated TCMR.
DSA patients had twice more early TCMR vs those without DSA.
DSA was more associated with chronic allograft damage and IFTA+i.
DSA + TCMR had higher serum creatinine and worse graft survival vs other groups.
On Multivariate analysis
DSA+ TCMR was independently associated with impending graft loss (p=0.003)
and poor graft outcomes.
Younger recipient age, class I HLA mismatch, and delayed graft function were independently associated with DSA+TCMR.
DSA+TCMR group were more likely to be non-adherent to their immunosuppression treatment as measure by CNI-IPV.
In conclusion, this paper has demonstrated the strong association between the development of HLA-donor specific antibodies and T cell mediated rejection, and how this combination is associated with poor graft outcomes. In addition patients who are non-adherent are more likely to develop DSA and TCMR.
– De novo DSA is associated with poor outcomes in kidney transplantation.
-DSA is strongly associated with antibody-mediated rejection (ABMR).
– Approximately 50% of patients exhibit good long-term graft function despite developing DSA.
-The development of antibodies requires T cell help, so the presence of DSA also indicates the presence of a more mature cellular alloimmune response.
-Some studies have shown DSA occurred much earlier (3-9 months), and frequently preceded or was concomitant with TCMR.
-One study, showed that de novo DSA occurred late associated with a 2-fold higher incidence of TCMR occurring within the first year, compared with patients without DSA.
– This is a prospective single-center study.
-363 patients, not requiring desensitization, were involved in the study.
-All patients were negative for DSA by Luminex and a negative flow cross-match at the time of transplantation.
-Protocol biopsies were done to detect early rejection, DSA was detected at or before the onset of TCMR in 82% of patients.
-DSA is associated with increased incidence and severity of TCMR
-Some patients experienced TCMR that was associated with ABMR.
-Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA.
-DSA was associated with increased incidence of both clinical and subclinical TCMR.
– patients with transient DSA had an increase in clinical TCMR, whereas patients with persistent DSA had a much higher incidence of subclinical TCMR.
-Patients with de novo DSA had a much higher rate of TCMR with more persistent or recurrent TCMR when compared with those without DSA.
-Patients with DSA and TCMR have increased chronic renal allograft damage.
– DSA was associated with significantly greater interstitial fibrosis with inflammation and tubular atrophy.
-DSA and TCMR patients represent a high-risk group for poor outcomes and graft loss. Regardless of whether DSA precedes or follows TCMR, the combination of DSA and TCMR carries a worse prognosis than having DSA without TCMR.
Risk factors for concomitant DSA and TCMR:
1. younger recipient age.
2. Class I human leucocyte antigen mismatches.
3. Delayed graft function.
-Nonadherent patients with DSA and TCMR exhibit particularly bad allograft outcomes, with 70% impending graft loss by 4 years. Adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
Conclusion: Identification of patients with DSA and TCMR andearly assessment of their adherence status after transplantationwould allow good interventions and outcomes.
· Detection of denovo DSA after transplantation in non-sensitized recipient (with no preformed DSA or negative cross match) is associated with poor graft outcome on long term follow up.
· Denovo DSA was frequently linked to AMR. However, it is associated with TCMR and mixed rejection by poorly understood mechanism.
· Taking into consideration that acute rejection, whether clinical (rising creatinine) or subclinical (detected in protocol biopsy) have detrimental effects on long term graft and patient outcomes, monitoring of denovo DSA has been implemented for early detection or prediction of AR for early and timely intervention to treat rejection and save the graft.
· DSA can be detected before or at time of TCMR in 50% of recipients.
· Presence of DSA together with biopsy proven TCMR carry worse prognosis and 3 folds increase in graft loss than DSA or TCMR alone.
· Also, those with denovo DSA can have increased IFTA on long term biopsy follow up.
· Those with detected DSA without proven rejection can have stable graft function in nearly 50% of cases. However, the rest may be at risk of acute rejection and worse outcome especially in the context of non-adherence to immunosuppressive therapy.
· Presence of DSA itself can indicate poor adherence to treatment. In addition, non adherence that can be detected by marked intra-personal variability in CNI trough levels > 30 %, is associated with higher risk of graft damage from circulating DSA which can turn into actual DSA mediated graft damage and rejection if not well addressed and managed.
· The timing and titer of DSA affect their impact. Their early detection post-transplant is more serious than late detection after relative accommodation.
Q. I would like to ask what about management of isolated finding positive denvo DSA with stable graft function?
DSA is associated with AMR and poor graft outcome, however its pathogenic effect is not clear and 50% of patients with DSA have good long-term graft survival.
The association between TCMR and post transplant DSA is unclear and their effect on long term outcome is understudied.
A prospective single center study included 363 kidney transplant recipients, negative for DSA at time of transplant without requiring desensitization
DSA was screened serially post transplant an was correlated with acute rejection (detected by for cause biopsy and protocol biopsies at 3&12 months) and 4 year graft outcome
The severity of rejection and graft outcomes are compared in patients with no DSA or TCMR, DSA alone , TCMR alone and DSA plus TCMR.
Also, DSA and TCMR were correlated to non adherence (was determined by intra-patient variability of CNI (CNI-IPV) trough levels during first year post transplant.
DSA was detected at or before onset of TCMR in most cases suggesting temporal relationship
CNI-IPV was independently associated with DSA and TCMR
patients with DSA and TCMR who were adherent had statistically similar graft survival as adherent patients without DSA or TCMR or both, so adherence is an important therapeutic opportunity
Identification of patients with DSA, TCMR and assessment of adherence allow targeted intervention with consideration of long acting immunosuppression as Belatacept
DSA is one of the major immunological factors that affect graft outcome.1 Literature review revealed strong association of preformed or de novo DSA with antibody mediated rejection but recently studies have been conducted demonstrating a link between DSA and T cell mediated rejection due to the requirement of T cell activation for antibody production. In some cases, TCMR precedes the development of alloantibodies and antibody mediated injury.2 In order to extrapolate this linkage , a prospective single center study was carried out from January 2013-November 2014 ,in which non-desensitized patients were enrolled and DSA was done serially from time of transplantation (0, 1, 3, 6, 9, and 12 months) with protocol biopsies (3 and 12 months)and for cause biopsies to detect acute rejection and also to determine factors associated with four-year outcomes in 4 groups DSA+.TCMR+, DSA+.TCMR-,DSA-,TCMR+,DSA-,TCMR-. Further categorization as early (0–5 months) or late (6–12 months)to assess the persistence/recurrence of TCMR inpatients with and without DSA was being done. All patients were screened for DSA before transplantation using luminex technique with a negative flow cross-match. In this study 67of 294 patients (22.8%) developed DSA in the first year. Mean time for detection of DSA was 3.4 months. Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA. 108 of 294 patients (36.7%) experienced TCMR in the first post transplant year, with 47% having clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at 3 or at 12 months. ABMR was seen always in presence of TCMR. Patients with DSA before or at TCMR diagnosis had higher creatinine value at follow up and increased rates of allograft rejection at one year and had worse IFTA in comparison to patients with DSA detected post TCMR.
Risk factors for concomitant DSA & TCMR is younger age , HLA class I mismatch & delayed graft function, planned decreased immunosuppression due to infection or conversion to CNI free or CS free protocols, and patients non adherent to immunosuppressive agents assessed by CNI intrapatient variability (CNI-IPV )-very important risk factor. DSA and TCMR patients had 1.35-fold greater CNI-IPV than the other patient groups. Non-compliant patients with DSA and TCMR exhibit particularly worse allograft outcomes, with graft loss by 4 years in 70% of the cases.. Importantly, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
CONCLUSION: The triad of DSA, TCMR and non-compliance to medications ,all linked to worse graft survival. So prompt identification of patients with DSA , TCMR and non-compliance to medications would allow timely therapeutic intervention, thus, preventing early graft loss.
REFERENCES:
1. Worthington JE, Martin S, Al-Husseini DM, et al. Post transplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003;75:1034–1040
2. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012;12:1157–1167
Any form of DSA is bad for renal graft, In this paper authors have studied the effect of DSA or other relevant factors in non sensitized patients on 4 year outcome after transplant. About half of the patients achieve better long term graft function in spite of the fact that they have DSAs. It raises the suspicion that there may be factors other than DSA leading to graft dysfunction. The relationship between DSA and T Cell mediated rejection has been suggested in the past, however the exact relationship has not been understood. In this study DSA was checked serially from transplantation and was related to acute rejection, outcomes and severity of rejection in patients showing No DSA, TCMR, TCMR alone, DSA alone, DSA and TCMR Positive. They also correlated TCMR and DSA to non adherence calculated by CNI levels. They concluded that DSA is related with high TCMR with poor outcome at 1 year. Outcome in patients with TCMR and DSA can be affected by immnuosuppression non adherence.
● INTRODUCTION:
Donror specific antibodies are associated with antibody-mediated rejection (ABMR) post renal transplant. But, their clinical implications and the pathogenic role remain unclear.
The development of DSA indicates the presence of a more mature cellular allo-immune response. But, the association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
THIS STUDY:
▪︎Is a prospective single center study where DSA was screened serially from the time of transplantation and correlated with acute rejection, severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR.
▪︎It also correlated DSA and TCMR to non adherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first post transplant year.
▪︎RESULTS
▪︎Study population: 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 were excluded.
▪︎Of the remaining 363 patients, 294 had at least 1 allograft biopsy within the first post transplant year and were included in the study. Of these, 276 patients had an early histology biopsy and 224 patients had a late histology biopsy . A total of 209 of 294 patients had paired biopsies at both early and late time points.
*Post transplant DSA detection:
▪︎All patients were negative for DSA at the time of transplantation , as determined by luminex and a negative flow cross-match.
▪︎Of the 294 patients analyzed, 67 (22.8%) developed DSA in the first year.
▪︎The mean time to the detection of the DSA was 3.4 months.
▪︎ A total of 26 of 67 (39%) patients with DSA had historical DSA up to 2 years before transplantation, and the remaining patients (61%) had de novo DSA.
▪︎ Patients who developed DSA within the first post transplant year were younger, more likely to be non-Caucasian, had a higher pretransplant panel reactive antibody, more human leucocyte antigen mismatches, and a trend toward more delayed graft function than those without DSA. also, these patients exhibited greater CNI intrapatient variability.
●DSA is associated with increased incidence and severity of TCMR
▪︎In this study 36.7% of patient experienced TCMR in the first posttransplant year,
▪︎ABMR was seen in 11 patients (10.2% of all rejections) and was always detected in the presence of concomitant TCMR.
☆ Risk factors for concomitant DSA and TCMR:
1. Younger recipient age
2. Class I human leucocyte antigen mismatch
3. Delayed graft function
●Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA
▪︎This study used CNI intrapatient variability as a measure of adherence. They found that DSA and TCMR patients had 1.35-fold greater CNI-IPV than the other patient groups
▪︎ Asignificantly greater proportion of patients with both DSA and TCMR had high CNI-IPV (46% vs. 21%) compared with all other patient groups (DSA-alone, TCMR alone, DSATCMR).
●DISCUSSION:
▪︎ Accurate testing for DSA, developed within the past decade, has helped revamp the diagnostic criteria for ABMR
▪︎Few prospective studies have serially monitored DSA.
▪︎Allograft survival in patients who develop posttransplant DSA are poorly understood.
▪︎In this prospective study, DSA was associated with a greater incidence and severity of TCMR and graft loss, despite
standard of care immunosuppression and antirejection therapy.
▪︎Importantly, patients who developed both DSA and TCMR in the first posttransplant year are at high risk for poor
long-term allograft survival compared with patients with either DSA or TCMR alone or lacking either diagnosis.
▪︎Despite the incorporation of protocol biopsies to detect early rejection, DSA was detected at or before the onset of TCMR
in 82% of patients, suggesting a temporal relationship.
▪︎Although isolated ABMR was not observed, patients with DSA also exhibited increased rates of “mixed” TCMR plus
ABMR compared with patients without
●CONCOLUSION:
▪︎Expression of either de novo or anamnestic antibodies requires T cell help for B cells.
▪︎The presence of DSA is indicative of a more mature immune response with contributions from both humoral and
cellular immunity.
▪︎Post-transplant donor specific antibody is associated with T-cell–mediated response
and non-adherence.
Post transplant DSA either denovo or recurrent has negative impact on graft survival.however there are many unanswered questions.
The authors of this paper have tried to atleast answer one question that is what is impact of DSA and associated factors in non desensitized patient on four year graft outcome.
The fact that approximately 50% of patients exhibit good long-term graft function despite developing DSA raises the question that there are associated factors and just DSA is not the only culprit.
The development of antibodies requires T cell help, the presence of DSA also indicates the presence of a more mature cellular alloimmune response.
It has been shown in the past that there is some relationship between DSA and TCMR. Indeed, several studies have shown a relationship between DSA and T-cell–mediated rejection yet the association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
To address this issue this study was conducted . It was a prospective single- center study where DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes comparing patients exhibiting no DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR. In addition, they correlated DSA and TCMR to nonadherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first post transplant.
Amongst 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 were excluded because of patient death or allograft loss within 3 months. Of the remaining 363 patients, 294 (81%) had at least 1 allograft biopsy within the first posttransplant year and were included in the study. Of these, 276 patients had a biopsy (either protocol or for-cause) between 0 and 5 months (early his- tology) and 224 patients had a biopsy between 6 and 12 months (late histology) (Figure 1). A total of 209 of 294 pa- tients (71%) had paired biopsies at both early and late time points, and these patients were used to analyze histological progression.
The study highlights that DSA is associated with increased incidence and severity of TCMR.
Patients with DSA and TCMR have increased renal allograft damage at 1 yr.
DSA and TCMR is associated with worst renal graft outcomes.
Immunosuppression adherence markedly affects clinical outcomes in patients with TCMR plus DSA.
This was first study which linked triad of DSA TCMR and non adherence with markedly worse renal graft outcomes.
Week 1
Journal club
III. Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence
Aravind Cherukuri, Rajil Mehta, Akhil Sharma, Puneet Sood, Adriana Zeevi, Amit D. Tevar, David M. Rothstein and Sundaram Hariharan
Introduction
Anti-HLA donor specific antibodies occurring following transplantation (de novo DSA) are well known to be associated with development of AMR & poor graft outcome, & possibly have causative role. [1-3] However, many of the studies examining this issue were small & retrospective.
In this prospective study, the authors looked into factors determining poor 4-year outcome in non-desensitized recipients who developed de novo DSA.
Relationship between DSA & T-cell–mediated rejection (TCMR):
Antibody production requires the help of T-cells, so the development of DSA signifies the occurrence of a more mature cellular alloimmune reaction. However little is known about the association between DSA & TCMR & its clinical significance.
Although Wiebe et al.[4] suggested that TCMR precedes the development of DSA & antibody-mediated injury, however the effect of prior TCMR on long-term outcomes in patients with DSA was not examined.
Other studies showed that de novo DSA in the 1st year was associated with stable long-term allograft function irrespective of TCMR. [5,6]
In this prospective study the DSA was tested serially from the time
of transplantation & correlated with:
-acute rejection,
– severity of rejection &
– graft outcomes.
Patients were categorized into 4 groups based on DSA status & TCMR:
(i) DSA+TCMR+
(ii) DSA+TCMR-
(iii)DSA–TCMR+
(iv)DSA-TCMR-
DSA & TCMR were also correlated to non-adherence during the 1st post-transplant year.
RESULTS
Study population
A total of 378 patients underwent renal transplantation from Jan. 2013-Nov 2014, 15 were excluded due death or graft loss within 3 months. Of the remaining 363 patients, 294 (81%) had at least 1 allograft biopsy within the first post-transplant year & were included in the study.
Of these, 276 patients had a biopsy (protocol or for-cause) between 0-5 months (early histology) & 224 patients had a biopsy between 6-12 months (late histology).
A total 209 of patients (71%) had paired biopsies at both early & late time points, & these patients were used to analyze histological progression.
Post-transplant DSA detection
DSA was negative in all patients at time 0.
A 67 (22.8%) developed DSA in the 1st year.
In 40 % of these 67, the DSA was transient, seen only once during the 1st year; it was persistent in the remaining 60% .
A total of 26 of 67 (39%) patients with DSA had historical DSA up to 2 years prior to transplantation, & the remaining 61% had de novo DSA.
DSA occurring in the 1st post-transplant year was associated with the following:
-younger age
-non-Caucasian ethnicity
-higher pre-transplant PRA
-more HLA mismatches
-more DGF.
-greater CNI intra-patient variability (adherence to medications)
The baseline renal transplant function measured at 1 & 3 months after transplant was similar between those with & without DSA.
DSA is associated with increased incidence & severity of TCMR:
TCMR was seen in 108 out of 294 patients (36.7%) in the 1st post-transplant year; 47% were clinical TCMR & 53% subclinical (protocol biopsy at 3 months or at 12 months).
ABMR was seen in 11 patients (10.2% of all rejections) & was always detected in the presence of concomitant TCMR.
Patients with DSA had a 1.8-fold higher incidence of TCMR than those without DSA.
The increased risk of TCMR in DSA patients persisted when concomitant ABMR patients or those with early DSA (1 month) were excluded.
DSA was also associated with increased incidence of both clinical and
subclinical TCMR.
Patients with DSA had more TCMR with concomitant ABMR, compared with those without DSA.
Evaluation of allograft histology:
– early TCMR (0–5 months) was twice as common in patients with DSA
– late TCMR (6–12 months) was twice as frequent in DSA patients
– DSA may identify a subgroup of patients whose rejection is relatively resistant to standard therapy.
-de novo DSA was linked to higher rate, recurrent or more persistent TCMR compared to those without DSA or anamnestic DSA.
Patients with DSA & TCMR have increased chronic renal allograft damage at 1 year:
DSA was associated with significantly greater IFTA at 1 year.
DSA+TCMR+ linked to high risk for allograft chronicity within 1 year & worse graft survival at 4 years compared with all other patient groups (23% vs. 10%).
The combination of DSA & TCMR, irrespective to which one comes 1st, has a worse prognosis than having DSA without TCMR.
Transient DSA associated with just as poor long-term outcomes as was
persistent one.
Risk factors for concomitant DSA & TCMR:
– younger recipient age
– Class I HLA mismatches
– delayed graft function
– serum creatinine at 3 months (trend toward statistical significance)
Immunosuppression adherence & TCMR plus DSA:
DSA+TCMR+ patients had 1.35-fold greater CNI-IPV (surrogate for non-adherence) than the other groups.
Non-adherence increased rate of TCMR persistent/recurrent TCMR & IFTA at 1 year.
Non-adherent DSAT+CMR+ patients had significantly higher graft loss/impending graft loss at 48 months than other groups.
Addressing non-adherence offers an important therapeutic opportunity.
DISCUSSION
Early detection of DSA will allow timely identification of those at increased risk for graft loss.[7-11]
The actual impact of de novo DSA in non-pre-sensitized recipients, in terms of both ABMR & allograft survival, is still uncertain.
DSA anytime post-transplant carries poorer graft survival, but still half of these have stable long-term function. [4,12,13]
Temporal relationship between DSA & rejection in patients who develop post-transplant DSA are poorly understood.
Improvement in understanding the natural history of DSA, the biology of allograft rejection, and risk factors for poor outcomes, will allow timely therapeutic changes before irreversible damage occurs.
In this study DSA was associated with a greater incidence & severity of TCMR & graft loss despite standard therapy.
Patients with both DSA & TCMR in the 1st post-transplant year are at high risk for poor long-term allograft survival compared with other patients.
Suggesting a temporal relationship, DSA was detected at or before the onset of TCMR in 82% of patients.
Although both TCMR and mixed TCMR plus ABMR were increased in DSA patients, isolated TCMR was 4.6-fold more frequent than mixed rejection.
Although most studies on DSA have focused on ABMR, this study shows that a major component of allograft injury in patients with DSA is indeed T cell mediated.
The effect of early TCMR on the clinical course of patients who developed DSA was unclear in the paper by Wiebe et al., however both Cooper et al.[14] & Devos et al.[15] found, that in the absence of ABMR or TCMR, DSA had no effect on graft survival.
The triad of DSA, TCMR, & non-adherence showed a markedly worse allograft survival.
Timely identification of this triad will permit early intervention
& consideration of long-acting agents such as belatacept.
References
1. Susal C, Wettstein D, Dohler B, et al. Association of kidney graft loss with de novo produced donor-specific and non-donor-specific HLA antibodies detected by single antigen testing. Transplantation.
2015;99:1976–1980.
2. Schinstock CA, Cosio F, Cheungpasitporn W, et al. The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am J Transplant. 2017;17: 1574–1584.
3. Sellares J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12:388–399.
4. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012;12:1157–1167.
5. Bartel G, Regele H, Wahrmann M, et al. Posttransplant HLA alloreactivity in stable kidney transplant recipients-incidences and impact on long-term allograft outcomes. Am J Transplant. 2008;8: 2652–2660.
6. Gill JS, Landsberg D, Johnston O, et al. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation. 2010;89: 178–184.
7. Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol. 2012;8:348–357.
8. Loupy A, Vernerey D, Tinel C, et al. Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts. J Am Soc Nephrol. 2015;26:1721–1731.
9. Halloran PF, de Freitas DG, Einecke G, et al. An integrated view of molecular changes, histopathology and outcomes in kidney transplants. Am J Transplant. 2010;10:2223–2230.
10. Lee PC, Terasaki PI, Takemoto SK, et al. All chronic rejection failures of kidney transplants were preceded by the development of HLA antibodies. Transplantation. 2002;74:1192–1194.
11. Terasaki PI. Humoral theory of transplantation. Am J Transplant. 2003;3: 665–673.
12. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369:1215– 1226.
13. Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87:1505–1513.
14. Cooper JE, Gralla J, Cagle L, et al. Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes. Transplantation. 2011;91:1103–1109.
15. Devos JM, Gaber AO, Teeter LD, et al. Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation. 2014;97:534–540.
A retrospective single-center study including 378 patients who underwent kidney transplantation between January 2013 and November 2014, 15 patients were excluded either because of death or graft loss within 3 months. All of the patients have negative DSA testing at the time of transplantation. DSA has screened at 0,1,3,6,9,12 months. protocol biopsies at 3 and 12 months in addition to for-cause biopsy. biopsies were classified into; early biopsies (0-5 months) & late ( 6-12 months). 209 patients had both early and late biopsies and these patients were used to analyze the histological progression. induction IS was: ATG ( 6mk/kg in total)., MP 500mg single dose, some patients received basiliximab. maintenance IS: Tac, MMF, rapidly tapered steroid.
study endpoint is a 4-year allograft outcome.
So the patients are grouped into 4 groups: DSA+ TCMR+, DSA+ TCMR-, DSA- TCMR+, DSA- TCMR-.
Those who have DSA showed an increased incidence of both clinical and subclinical TCMR. Patients with DSA+ TCMR+ were the high-risk group patients as they have greater IFTA at 1 year so worse allograft outcomes, there was 3 fold higher risk of graft loss compared to either DSA or TCMR alone.
Non-adherence was associated with DSA+ TCMR+.
ABMR was associated with concomitant TCMR.
De novo anti-donor human leucocyte antigen–specific antibody (DSA) is one of the major immunological factors that affect graft out come.
comperative studey conducted studied non desensitized patients to determine factors associated with poor four-year outcomes , in patients who developed post transplant DSA.
Using serial monitoring, 67 of 294 patients were found to develop DSA by one year. Compared to patients who do not develop DSA.Patient with DSA have grate incidence in developing TCMR.
The combination of TCMR plus DSA led to three time increase in graft loss. compared to either DSA or TCMR alone.
Another factor also considered in this study , non adherence is potentially modifiably.post-transplant DSA, in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.Immunosppression sub dose may lead to graft dysfunction and loss.
Few studies have examined the early post transplant period, serial testing, or used protocol biopsies to accurately detect subclinical rejection,approximately 50% of patients exhibit good long-term graft function despite developing DSA.Thus, the clinical implications of de novo DSA and the pathogenic role remain unclear.
T helper cells help in antibodies production thus presence of DSA also indicates the presence of
mature cellular alloimmune response.
comprehensive prospective analysis, showed that de novo DSA occurred late (mean 4.6 years) and was associated with 2-fold higher incidence of TCMR occurring within the first year, compared with patients without DSA.
This suggested that TCMR precedes the development of alloantibodies and antibody mediated injury.
In 2 other studies where DSA was serially assessed, DSA occurred much earlier (mean approximately 3-9 months) and frequently preceded or was concomitant with TCMR.
In contrast, 2 small retrospective studies showed that DSA arising in the first year was associated with stable long-term allograft function irrespective of TCMR.
Thus, the literature is discrepant as to the incidence, timing, and impact in terms of graft survival of
TCMR in patients who develop posttransplant DSA. Moreover, the incidence of ABMR versus TCMR in patients with posttransplant DSA remains unclear Yet, the association and clinical significance of TCMR and DSA arising after transplantation is not well understood.
To address these issues, initiated a prospective single center study where DSA was screene serially from the time of transplantation and correlated with acute rejection
(detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes comparing patients without DSA or TCMR, DSA alone, TCMR alone, or DSA plus TCMR. In addition, the study
correlated DSA and TCMR to nonadherence, measured by intrapatient variability of calcinuerin inhibitor (CNI) trough levels during the first posttransplant year. They found that DSA characteristics are found in young patients, non Caucasians ,with high PRA levels pre trasplant, more antigen mismatches trend toward more delayed graft function than those without DSA.
Importantly, ABMR was seen in few patients and
was always detected in the presence of concomitant TCMR
Patients with DSA and TCMR have increased chronic renal allograft damage .DSA+was associated with interstitial fibrosis and tubular atrophy (IFTA) at 1 year.
and fewer patients had no chronic damage on the 1-year biopsy recognized as a marker for poor long-term outcome.
DSA+TCMR not only had the highest mean IFTA score severe IFTA (score $3) and >80% had IFþ“i” on 1-year protocol biopsy. This suggests that DSAþTCMRþ patients are at high risk for developing allograft chronicity within 1 year
after transplant. Thus, the combination of DSA and TCMR was associated with early chronic histological damage.
patients with DSA andTCMR had significantly higher serum creatinine .
Nonadherence was associated with an
increased rate of TCMR persistent/recurrent TCMR .
De novo DSA is known to be associated with poor renal outcomes in kidney transplantation.
DSA is strongly associated with antibody-mediated rejection. However, because the production of antibodies requires T cell activation, the development of DSA also indicates the presence of cellular stimulation and active T cell responce. Several studies demonstrated the relation between ABMR and presence of preformed or de novo DSA, but recent studies have shown a relationship between DSA and T-cell–mediated rejection.
In order to understand the relation between DSA, TCMR and renal outcomes, a prospective single center study was performed where DSA was screened serially from the time of transplantation and correlated with acute rejection (detected by for-cause biopsies as well as protocol biopsies at 3 and 12 months), severity of rejection and graft outcomes.
So in this study, prospectively studied nondesensitized patients, in patients who developed posttransplant DSA, to determine factors associated with poor four-year outcomes. All patients were screened for DSA before transplanation using luminex technique with a negative flow cross-match negative.
67 of 294 patients were found to develop DSA by one year using serial monitoring. DSA was transient in 40% of the 67 patients with DSA and was persistent in the remaining 60%.
36.7% experienced TCMR in the first posttransplant year, with 47% being clinical TCMR and 53% subclinical TCMR diagnosed on a protocol biopsy at 3 months or at 12 months. Only 10.2% of all rejections were ABMR and were always detected in the presence of concomitant TCMR.
Amongst those with DSA+TCMR+, DSA was detected concomitant with or before the diagnosis of TCMR in 82% of patients, whereas only 18% of patients developed DSA after the diagnosis of TCMR.
Patients with DSA and TCMR have increased chronic renal allograft damage at 1 year
DSA was associated with significantly greater interstitial fibrosis and tubular atrophy at 1 year. Importantly, a greater proportion of patients with DSA had IFTA score $3 and fewer patients had no chronic damage on the 1-year biopsy.
DSA+TCMR+ was associated with significantly worse graft survival at 4 years compared with all other patient groups.
Of the clinical variables examined, younger recipient age,Class I human leucocyte antigen mismatches, and delayed graft function were independently associated with DSA+TCMR+.
Nonadherence was recongnized as independent risk factor associated with the development of both DSA and TCMR. Nonadherent patients with DSA and TCMR exhibit particularly poor allograft outcome, with graft loss by 4 years in 70% of cases. Importantly, adherent patients who developed DSA plus TCMR exhibited graft survival similar to those without TCMR and DSA.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated
rejection and non-adherence
Despite improved 1-year long term graft survival, still the percentage of declining in renal graft function after 1 year unchanged. It is already known that Previous or ongoing clinical and subclinical rejection leading to chronic histopathological changes and ultimately graft failure. It is paramount to identify patients at increased risk for chronic damage and graft loss, allowing timely therapeutic intervention to save the allografts. Improvement in technical support to detect accurately DSAs give opportunity to manage patients at risk of ABMR and graft loss.
The actual meaning of posttransplant DSA in non presensitized patients, in terms of both ABMR and allograft survival, remains uncertain. Few prospective studies monitored DSA early in post-transplant period to assess the timing and effects of DSA. Despite already documented that Ppatients who develop DSA anytime in their posttransplant course have poorer graft survival, approximately 50% experience stable long-term function.
In a comprehensive prospective analysis, Wiebe et al.5 showed that de novo DSA occurred late (mean 4.6 years) and was associated with 2-fold higher incidence (54%) of TCMR occurring within the first year, compared with patients without DSA. This suggested that TCMR precedes the development of alloantibodies and ABMR.
In this prospective study, they serially examined DSA in patients without history of desensitization, starting 1 month after transplant and examined relation of DSA with graft inflammation (assessed by protocol biopsies at 3 and 12 months) and 4-year graft outcomes. They found that DSA was associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy.
Importantly, patients who developed both DSA and TCMR in the first posttransplant year are at high risk for poor long-term allograft survival compared with patients with either DSA alone or TCMR alone or patients without DSA or TCMR. The presence of DSA is indicative of a more mature immune response with activation of both humoral and cellular immunity. Although both TCMR and mixed TCMR plus ABMR were increased in DSA patients.They also correlated DSA and TCMR to patient nonadherence, measured by interpatient variability of calcineurin inhibitor (CNI) trough levels during the first posttransplant year.
Patients who developed DSA within the first posttransplant year were younger, had a higher PRA pre transplant, more HLA mismatches, and a trend toward more delayed graft function than those without DSA. In addition, these patients had greater CNI interpatient variability which is the measure of adherence to immunosuppressive medications over 1 year post transplant. Indeed patients developing both TCMR and DSA within 1 year after transplant are at risk for poor graft outcomes.
The current study was the first to link DSA, TCMR, and nonadherence as a triad, with markedly worse allograft survival.
In fact,non adherence remains the challenging part in renal transplantation field.
Summary of the study:
this is a prospective study included recipients of kidney transplant with the total number of 294(81%) with at least one garft biopsy( 0-3 months ) and about 276patients included have at least one protocol biopsy (0-5months early histology ) and in 224 cases they have their graft biopsy (6-12 months , late histology ) while 209(71%) they had two protocol biopsies (early/late ) where used for histological progression ,patients information collected electronically from the renal transplant data registry and approved by the University of Pittsburgh from the period of jan ,2013-nov ,2014.
All included patients had negative DSAs by Luminex assay at zero-time with negative FCXM ,examined DSA in patients not requiring desensitization, starting 1 month after transplant and examined its temporal relationship with allograft inflammation (aided by protocol biopsies) and assess the graft survival at 4 yeras as hard outcome in 4 groups (DSA+.TCMR+, DSA+.TCMR-,DSA-,TCMR+,DSA-,TCMR-).
67 (22.8%) developed DSA in the first year. DSA was transient (detected only once during the first year) in 40% of the 67 patients with DSA and was persistent in the remaining 60%.
Mean time for detection of DSA was 3.4 months , In 26(39%) of patients have historical DSA+ up to two years prior to TX.
DSAs is associated with increased incidence and severity of TCMR based on two Banff score protocol biopsies finding and the DSA s plus TCMR was found to be strongly associated with poor graft outcomes even after eliminating patients with ABMR, or those with early DSA (in first month )suggesting that the increased risk is not just due to the higher incidence of ABMR, but also to worse cellular rejection and the risk was even higher in younger recipients with DGF and in DSA +/TCMR , more HLA typing mismatch in both for class1, 11 majority received ATG induction followed by tacrolimus based IS , black African more in DSA+VE 33 / 67 cases
patients with
DSA + also increase the rates of “mixed” TCMR plus ABMR compared with DSA – group .
Immunotherapy non-adherence another significant risk factor based on the measurement of the CNI- IPV which is more in DSA+ group as shown in table 1
TCMR is significantly more in DSA+ (57%,) with significantly greater interstitial fibrosis
and tubular atrophy (IFTA) with grade3 score at 1 year and more than that DSA was associated with increased interstitial fibrosis with inflammation (IFþ“i”), increasingly recognized as a marker for poor long-term outcomes and lower graft survival at 4 years as hard outcome .
Presence of new DSA that appeared post transplant were associated with graft loss. But the exact role of these antibodies is not well established because it was noticed that 50% of DSA were not associated with poor graft survival.
As the antibodies development need T cell activation, so the development of de novo DSA may depend on T cell activation therefore may be associated with TCMR.
The impact of DSA presence in association with TCMR was differ between studies. Some of these studies show that TCMR occur before development of DSA while others proved the presence of DSA before occurrence of TCMR.
This prospective study include 379 renal transplant recipients through Jan2013-Nov2013 & followed for 4-5 years. The study exclude the recipients who loss their graft or die in first 3 month post transplant. All patients had induction with ATG or basiliximab. DSA measured at 0,1,3,6 & 12 months, protocol graft biopsy done at 0.1,3,6,12 months & for cause biopsy done when needed.
Immunosuppression regime include MFF & CNI with early drawl of steroid ( after 7 days of transplantation), except for recipients with high cPRA>90% who kept on low dose of steroid.
The study results show that the presence of DSA & TCMR was associated with poor graft outcome when compared with presence of DSA alone or TCMR with out DSA. Also it was found that the most common cause for development of de novo DSA & TCMR was poor drug adherence.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence.
The development of de novo anti-donor human leucocyte antigen–specific antibody (DSA) is associated with poor outcomes in kidney transplantation. Which may be related to non-adherence of immunosuppressive medications.
In this prospective longitudinal study which include non-desensitized patients to determine the factors associated with poor four-year outcomes in patients who developed post kidney transplant DSA in one center.
=Patients who developed DSA within the first post-transplant year characterized by younger age, more likely to be non-Caucasian, had a higher PRA, more HLA mismatches, than those without DSA and high rate of non-adherence to CNI.
=DSA is associated with increased incidence and severity(high Banff severity score) of TCMR as 82% of patients who diagnosed TCMR+DSA, DSA was detected with or before biopsy diagnosed TCMR and also resistant to treatment than those TCMR without DSA.
=Patients who developed TCMR+DSA had more IFTA score and allograft chronicity especially if DSA was detected with or before TCMR diagnosed compared to group developed TCMR without DSA.
=Patients with DSA+TCMR had higher risk of allograft loss than other groups and TCMR+DSA detected later had worse prognosis than those with DSA alone group.
=Non-adherence was associated with an increased rate of TCMR and persistent/recurrent TCMR and increased IFTA at 1 year especially with DSA+TCMR.
=Conclusion:
The study showed that recipients with DSA who develop TCMR have worse tubule interstitial inflammation and worse outcomes compared with those with DSA or TCMR alone especially with non-adherence.
Comments:
The prospective longitudinal study addressed clear issue that Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence.
Done on accepted number of patients with variable demographics and recruited in acceptable way.
DSA and kidney biopsy are reliable methods for detect the result and also applicable.
Group classification according to DSA result so no bias and follow up complete enough ,time around four-year.
Ethical guidelines and privacy protection are considered.
But Kidney biopsy as a measurement tool is invasive .
Role of non DSA with outcome not mentioned and Adherence to Mycophenolate mofetil was not considered.
Role of rapid steroid tapering versus other not a clear point.
This paper evaluates T lymphocyte-mediated rejection, especially when associated with donor-specific antibodies (DSA). It is a longitudinal, prospective, single-center study that excluded Hyperacute Rejection and sensitized patients.
The collection of DSA in specific months associated with the local protocol of biopsies could diagnose early T lymphocyte-mediated rejection and include the early development of DSA in more than 80% of cases before developing TLMR.
In this study, no patient had ABMR in isolation, and at least one-third of the patients had TLMR in the first year after transplantation. However, high levels of DSA are related to a worse prognosis of TLMR. It is possible that the DSA may identify some patients whose rejection is resistant to classical therapy.
Interestingly, patients with elevated DSA before or at diagnosis of LTMR had worse rates of tubular atrophy and graft interstitial fibrosis. This combination increased serum creatinine levels and worsened graft quality at four years. Renal recovery by immunosuppressive techniques or not was also worse in this group.
The risk factors for this combination are young patients, HLA class I Mismatch, delayed improvement in graft function, and elevated serum creatinine in the third month after transplantation. Another isolated risk factor is not adhering to immunosuppressive treatment, especially calcineurin inhibitors. The study measured individual consumption of this medication and its impact.
Development of DSA at any time after transplantation showed worsening of the graft when compared to its absence, but when associated with TCMR the evolution is much more severe.
Conclusions
Apparently, de novo DSA may be related to chronic T lymphocyte immunomodulation. DSA measurements at different times can help in the early diagnosis of graft rejection.
DSA+TCMR+ individuals have a worse prognosis.
Presence of DSA post transplant are associated with loss of graft.
This study done to assess risk of rejection by serial check of DSA level in concurrent with TCMR and serial biopsy done 3 & 12 months to assess level of severity and graft outcome and comparing it to the patients without DSA / DSA alone / DSA with TCMR / TCMR alone.
Characteristic DSA: patients who develop DSA within first year post transplant are younger and non caucasian; they have higher pre-transplant panel reactive antibody & HLA mismatch. DSA is associated with increase incidence & severity of clinical and sub clinical TCMR.
They found ABMR always detected in presence of concomitant TCMR. DSA is detected largely with or before TCMR diagnosis. patients with DSA have higher evidence of acute rejection and higher grade of Banff lesions. patients with DSA and TCMR together have increase risk of chronic kidney allograft rejection at one year and in biopsy shows interstitial fibrosis and tubular atrophy (IFTA). Those patients had DSA with or before TCMR had worse IFTA compared with patients DSA detected post TCMR. Also shows increase level of creatinine & decrease eGFR less than 30ml/min within 4 years.
Risk factors for concomitant DSA & TCMR is younger age and HLA class I mismatch & delayed graft function, independent factor for graft loss which develops de novo DSA and concomitant tubulitis and transplant glomerlopathy and patients non adherent to immunosuppressive agents.
immunosuppressive adherence may lead to affects clinical outcome in patients with TCMR plus DSA. Those patients which are not adherent to immunosuppressive agents whether with DSA or not have increase risk of chronic allograft. Those adherent patients to immunosuppressive drug are similar survival rate of graft to the patients without DSA or TCMR or both. This study recommended desensitisation protocol for presensitised patients.
Donor-specific antibodies (DSAs) can be classified according to the time of detection into a preformed DSA detected in the patient serum before transplantation and de novo DSA, which will be detected post-transplantation as a result of sensitization.
Denovo DSA detection post transplantation is associated with poor 4 – years graft survival
Patients with denovo DSA had increase in the incidence of TCMR, and the occurrence of DSA together with TCMR is associated with increase in the frequency of TCMR episodes during the first year, increase in the severity of TCMR (higher Banff grade), higher chronicity index and a 3 fold increase in the risk of graft loss when compared to TCMR alone. On the other hand pure ABMR is uncommon (most patients had pure TCMR and less commonly mixed TCMR, ABMR)
The relation between DSA and TCMR may be explained by the interplay between T cell and B cells, T cells are crucial in the induction of complete B cell response with subsequent production of DSA, and tissue injury induced by DSA stimulate T cell response, thus in this study it was found that more than 80% of the patients who develop TCMR has DSA either before or at the same time of development of TCMR.
DSA may have a great impact on graft survival in only patients with biopsy proven rejection, on the other hand patients without biopsy- proven rejection DSA dose not correlate well with graft survival
Risk factors for developing denovo DSA
1. HLA mismatch
2. Delayed graft function
3. Younger age
4. Non living related (deceased) donor kidney
5. Planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols
6. Non compliance on immunosuppressive medication ( very significant risk factor)
7. Inflammation-induced by infections, surgery or TCMR
One of the most important causes of the development of denovo DSA is non-adherence to medications, as it was found that patients developing DSA plus TCMR who were adherent to their immunosuppressive medications had better graft survival than those who were nonadherent
In conclusion, the tirade of TCMR, DSA, and non- adherence is associated with the worst outcome.
Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated
rejection and non-adherence
Previous or ongoing clinical and subclinical rejection, leading to chronic damage, is a major cause of late allograft loss.
patients who develop DSA anytime in their posttransplant course have poorer graft survival, approximately 50% exhibit stable long-term function.
DSA was associated with a greater incidence and severity of TCMR and graft loss, despite standard of care immunosuppression and antirejection therapy.
patients who developed both DSA and TCMR in the first posttransplant year are at high risk for poor long-term allograft survival compared with patients with either DSA or TCMR alone or lacking either diagnosis.
DSA was detected at or before the onset of TCMR in 82% of patients.
patients with DSA also exhibited increased rates of “mixed” TCMR plus ABMR compared with patients without DSA.
major component of allograft injury in patients with DSA is indeed T cell mediated.
TCMR (i and t scores), and not parameters of ABMR, were associated with increased graft loss in patients with DSA.
Of the independent risk factors associated with the development of both DSA and TCMR, nonadherence as assessed by CNI variability is particularly important.
66% of TCMR was subclinical