Cyclosporine was associated with SCR & borderline rejection more when compared with tacrolimus. And it was found that among patient with high immunological risk the using of protocol biopsy has a great value in diagnosis of SCR, & treatment of SCR improve graft outcome.
Fadel F., Elbaky A., Mawla M., et al. Subclinical Rejection & Immunosuppression in Pediatric Kidney Transplantation Recipient: Single Center Study. Biochemical & Pharmacology Journal. 2021, 14(3): 1149-1159.
The incidence of subclinical rejection is variable due to variable inclusion criteria in different studies.
How common in Tacrolimus era compared to Cya era?
The use of Tacrolimus was associated with a subacute rejection prevalence of 4.6% only in comparison to about 30% with the previous immune suppression a decade earlier (1).
2. How common in highly sensitized patient?
The incidence of subacute rejection may reach up to 36% in sensitized patients (2).
3. Would it be better to treat it? why?
The detection of subacute rejection is associated with a worse allograft outcome (1). Therefore, I will proceed with anti-rejection measures once subclinical rejection is detected.
2) Yamanaga S, Watarai Y, Yamamoto T, et al. Frequent development of subclinical chronic antibody-mediated rejection within 1 year after renal transplantation with pre-transplant positive donor-specific antibodies and negative CDC crossmatches. Hum Immunol. 2013 Sep; 74(9):1111-8.
subclinical ABMR at 1 year has 3.5 fold increase in graft loss independent on immunological status high risk or not, DSA de novo or not, presence or absent of comorbidities.
subclinical T cell mediated rejection also associated with poor graft survival at one year but less than subclinical ABMR.
incidence of SCR in tacrolimus based regimen is lower.
treatment of SCR early with steroid has better prognosis
Subclinical acute rejection and chronic allograft nephropathy, in pre-transplant sensitized patients are common at 6 months post-transplant in kidney recipients with stable allograft function.
One study reported subclinical CMR in 39.7% of the biopsies at 1 month and >20% at all other time points. The presence of diffuse C4d on biopsies obtained at each time interval ranged from 20 to 30%, indicative of AMR.
In another study published in 2021, evaluating patients receiving tacrolimus as part of their maintenance therapy, using revised Banff criteria, detected subclinical inflammation in 31%, with the majority (75%) having a subclinical borderline phenotype (at least minimal inflammation with mild tubulitis.
Would it be better to treat it?
There is no RCT comparing SAR receiving immunosuppressive treatment to control groups. however it is known that patient with histologic signs of acute rejection, even with normal allograft function, are at high risk for graft loss. They are also at risk to develop interstitial fibrosis and tubular atrophy, which is independent risk factor for kidney loss.
1/ Subclinical rejection: defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection.
In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%
Subclinical rejection was detected in 2.6% of patients (3/114, 95% confidence interval 0.5-7.5%). Borderline changes were detected in 11% (12/114). Subclinical rejections were treated with bolus methylprednisolone.
{Transplantation.2002 Jun 27;73(12):1965-8. doi: 10.1097/00007890-20020627000023. Subclinical rejection in tacrolimus-treated renal transplant recipients}
2/ DD transplant, presence of DSA and DGF were associated with a higher incidence of SCR
Cya era is more common in causing subclinical rejection
SCR is highly prevalent in sensitized patients
If SCR not treated early will lead to poor graft outcome
Subclinical rejection is less prevalent in immunosuppressive protocols that use tacrolimus compared to CSA.
How common in highly sensitised patient?
It is common in highly sensitized patients( A study found it in 40-50% of patients with positive crossmatching in the first 2 months post transplantation).
Would it be better to treat it? why?
Patients with treated subclinical rejection had better graft outcome.
References:
Rush D.N., Gibson I.W. Subclinical Inflammation in Renal Transplantation. Transplantation.June 2019,Volume 103, Number 6.
Parajuli S., Joachim E., Alagusundaramoorthy S., Blazel J. et al. Subclinical Antibody-mediated Rejection After Kidney Transplantation: Treatment Outcomes. Transplantation .August 2019,Volume 103,Number 8.
1.Subclinical rejection is less seen in tacrolimus era compared to cyclosporine era .Some studies showed up to 30% subclinical rejection with cyclosporine.
2.In sensitised patient, subclinical rejection increases and this reason for protocol biopsy in this group of transplant population.
3.SCR is associated with long-term deterioration of graft function and early intervention may result in better outcome.
.
Subclinical rejection incidence is quiet variable it dependes on the degree of HLA matching , DSAs level , immunsuppressive protocal and the occurance of DGF
the rate is lower in the first six months post KTX due to the improvement of both the sensitivity of the HLA typing , DSA screening assay , in addition to the development in the immunsuppresive therapy.
– the incidence of SCR in tacrolimus based IS in much lower 4.6 % only compared to
> 30% in cyclosporine group(1).
-SCR with ABMR with diffuse and focal C4D staining was found in 2-2.4% in protocal biopies(2). even higher in senesitized patients with SCR-ABMR was up to 36% (1) and its assocaited with worse graft outcome .one study shows one year graft survival of 56% only compared with 885 in patinets with SCR – ACMR.
would you treat SCR :
—————————————————————
as per available evidnece there is no clear aggreament in regards SCR treatment
some centres preferred just to augment the current IS for example if patinet on cyclosprine based IS will modify to tacroimus based and target higher level 6-8 ng , with full dose MMF or some centres give short course steriods espically in ACMR and FU closely by DSA and protocal biopsy.
SCR preferred to be treated espcially in sensitazed patient with ABMR and DSA postive assay or denovo DSAs and the response to therapy depends on some histological fininding like those with less vascular intimal sclerosis, less arteriolar hyalinosis and IFTA likely will have better response to the treatment,
-SCR-TCMR ususlly steriod responsive and had better graft survival up to 90% in the first year which is comparable to non SCR group(1)
-patients with SCR with more chronic histological changes most likely will progress to chronic allograft nephropathy and the treatment will be hampered by the incresed risk of side effects like infection , malignancy .
References:
1-UPTo Date,kideny transplant in adult:Clinical features and diagnosis of acute kidney allograft rejection.2021 .
2-Subclinical rejection in tacrolimus-treated renal transplant recipients
James M Gloor 1, Ari J Cohen, Donna J Lager, Joseph P Grande, Mary E Fidler, Jorge A Velosa, Timothy S Larson, Thomas R Schwab, Matthew D Griffin, Mikel Prieto, Scott L Nyberg, Sylvester Sterioff, Walter K Kremers, Mark D StegallTransplantation2002 Jun 27;73(12):1965-8.
SCR was more common in cyclosporine era comparing tacrolimus era.
It is more common in highly sensitized patients.
It’s better to treat SCR because if left untreated is associated with worse graft outcome.
1. How common in Tacrolimus era compared to CyA era?
The subclinical rejection rates in cyclosporine era was upto 30%. (1) Subclinical rejection rates are lower in tacrolimus era, 4.6%. (2)
2. How common in highly sensitised patient?
In Sensitized patients, the incidence of SCR maybe as high as 36%. (3)
3. Would it be better to treat it? why?
Once a diagnosis of SCR has been made, it is better to treat as it has been shown to decrease early and late acute rejection as well as chronic graft damage. (1)
References:
1) Rush D, Nickerson P, Gough J, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998;9:2129.
2) Rush D, Arlen D, Boucher A, et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study. Am J Transplant 2007;7:2538-2545.
3) Yamanaga S, Watarai Y, Yamamoto T, et al. Frequent development of subclinical chronic antibody-mediated rejection within 1 year after renal transplantation with pre-transplant positive donor-specific antibodies and negative CDC crossmatches. Hum Immunol 2013;74:1111-1118.
1.Sub clinical rejection is less with tacrolimus based immunosuppression.
2.It is more common among highly sensitized patients.
3. Yes .it is better to treat sub clinical infection .
1-Subclinical rejection is much improved in Tac era compared to Cys era(4.6% vs 30% )
2-In sensitized patients, subacute rejection can reach up to 36%
3- Yes, it is better to treat as it is important to improve the graft outcome.
Uptodate,2021
Akram Abdullah
3 years ago
Protocol biopsy it is the biopsy set with intervals without the association of graft dysfunction. Chronic allograft nephropathy (CAN) and acute rejection may be subclinical without a decline in kidney functions leading to delayed diagnosis and delayed start of treatment which may affect graft outcome. Protocol biopsies post-transplant could help in the detection and early treatment of SCR and CAN but this benefit is still unproven. PROS of doing the biopsy –Detection of Subclinical Rejection(SCR) SCR leads to long-term worsening of graft function and early intervention can improve the outcome. Con: The Case Against Use of Protocol Biopsies Variation in Reported Incidence of SCR and CAN The incidence of SCR in the first 6 months after transplantation varies from 1 to 29% and CAN from 0 to 79% .
AMAL Anan
3 years ago
The recent introduction of protocol biopsies in some centers to determine the presence of CAN and SCR in stable renal allograft should be seen as a major step forward in the quest to improve long-term transplant outcomes. Paucity of data has meant that clear proof that protocol biopsies improve long-term graft function and survival is lacking and that the benefits of treating SCR detected by protocol biopsy in particular are not
clearcut. However, available evidence suggests that early detection and treatment of CAN that cannot be diagnosed clinically will benefit long-term graft function. Furthermore, reports indicate that protocol biopsies are safe and that their use is likely to improve the treatment of renal transplant patients. In addition, use of protocol biopsies as a primary efficacy variable could well become a useful tool in the design of future trials
aimed at preventing CAN; power calculations suggest that they may allow an important reduction in the number of patients involved in such trials, as well as reducing the follow-up time.
An additional potential benefit of protocol biopsies may in differentiating chronic loss of renal function caused by immunologic causes from nonimmunologic causes. Nevertheless, future studies must focus on reliable methods to quantify histologic changes in protocol biopsies. Furthermore, large-scale, multicenter, prospective trials of protocol biopsies are required to determine the criteria and optimal timing for such biopsies and assess fully their place in the routine treatment of renal transplant patients.
Mohammed Sobair
3 years ago
There’s studies point that surveillance biopsy is useful in :
SCR.
chronic allograft nephropathy
delayed graft function, by allowing for early intervention for acute rejection.
Nevertheless, paucity of data has meant that clear proof of a benefit of early treatment
of subclinical rejection and chronic allograft nephropathy detected by protocol biopsy is
lacking.
Moreover, the optimal timing of protocol biopsies and reliable methods to quantify the
histologic changes observed in biopsy specimens have yet to be determined.
Detection of Graft Dysfunction as a Result of Nonimmune Factors .(BK nephropathy
,CNi nephropathy).
Safety of Protocol Biopsy:
Safe ,straightforward. Procedure.
Cons:
Protocol Biopsies Variation in Reported Incidence of SCR and CAN .
Reliability of SCR and CAN Diagnosis by Protocol biopsy.
How Should Utility of Protocol Biopsies Be Tested.
Timing of protocol biopsy ,no agreement.
Treatment for SCR and Can, still no agreement. That treatment of biopsy detected will
improve. CAN and reduce graft loss.
Reflection on our practice:
We are not using protocol. Biopsies in out center ,more LRD and triple immunotherapy
base on TAC and MMF.
Nadia Ibrahim
3 years ago
1. In your own words, summarise pros and cons of protocol biopsy.
Protocol Biopsy during the first year postTx was of great value in early detection of subclinical graft lesions and unrecognized inflammatory injury, secondary to a low-grade rejection process that may with time end in long-term graft fibrosis and chronic dysfunction eventually graft loss. Early detection and intervention would offer great benefits to the graft survival.
Shall we consider this procedure in the routine follow up of post Tx patients? Pro Detection of Subclinical Rejection
Some studies suggest that SCR eventually ends in long term deterioration of graft function hence early detection and intervention would help improve outcomes (1). data thus suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function. CAN
Evidence suggest that the development of CAN is preceded by the development of early histological chnges within the graft during the first few months early postTx (2). It thus follows that early detection and treatment of CAN could have a dramatic effect on the outcome of the graft. in High-Risk Recipients
for early intervention and management of acute rejection episodes DGF: delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to prevent adverse long-term graft outcome. However it is hard to diagnose AR in patient with DGF on clinical basis, hence a protocol biopsy in crucial. Positive DSA Recipients: early intervention and detection of subclinical AMR episodes in highly sensitized patients Detecion of graft dysfunction due to nonimmune factors:
CNI nephrotoxicity: One of the most common causes of graft failure, and is reversible if reduction of doses is done early enough.
BK nephropathy: leads to rapid decline in renal function and early detection of subclinical BK virus (BKV) nephritis is vital for early reduction of IS dose and ttt to save the graft. Con: Incidence of SCR and CAN : inconsistant
incidences of SCR and CAN reported in biopsy specimens are inconsistent and widely vary. Reliability of SCR and CAN Diagnosis
There is no available standerd criteria to interpret histologic lesions found in proetocol renal biopsies , using Banff criteria otherwise would be associated with high possibility of misclassification (3). the optimal timing and frequency for biopsies has not been evaluated.
Should intervention be made based on serial biopsies ? then it will be necessary to analyze the results in a standardized manner, which is problematic. Conversely, a single biopsy is likely to result in a high degree of inaccuracy. Treatment for SCR and CAN
the benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown as regard evaluation of pros and cons further studies on a large scale should be conducted . Please reflect on your practice if possible. Would prefer performing Biopsy whenever indicated , aotherise protocol Biopsy would be of great value for high risk patients positive DSA Recipients ,with previous failed transplants, high donor mismatching PLNF patients and who exhibited DGF.
References: (1) Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, Cheung E, Allen RD, O’Connell PJ, Chapman JR: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71: 515–523, 2001 (2) Seron D, Moreso F, Ramon JM, Hueso M, Condom E, Fulladosa X: Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy. Transplantation 69: 1849–1855, 2000 (3) Seron D, Moreso F, Fulladosa X, Hueso M, Carrera M, Grinyo JM: Reliability of chronic allograft nephropathy diagnosis in sequential protocol biopsies. Kidney Int 61: 727–733, 2002
Mahmoud Hamada
3 years ago
Pros:
1- detection of subclinical rejection
which has an incidence about 30% in the 1st 6 months of transplantation
2- Detection of chronic allograft nephropathy, which has an occurrence of about 79% 6 months post transplantation.
3- early screen tool in high risk transplantation, allowing early intervention..
Delayed graft function was detected in protocol biopsy even with clinically undiagnosed graft dysfunction.
Cons:
1- the when and frequency of protocol biopsy still not universally agreed upon.
2- the discrepancy between pathology and clinical status may refer to no need for biopsy as therapy will be provided for those who develop DGF with good outcome.
3- The need of good expertise to avoid post biopsy complications e.g. bleeding
Dalia Ali
3 years ago
*
Pro
Detection of Subclinical Rejection
with reported incidences in protocol biopsies performed in the first 6 mo posttransplantation of up to 30%
subsequent development of CAN has not been proved, some studies suggest that SCR leads to long-term deterioration of graft function and that early intervention may well improve outcomes
protocol biopsies at 1, 2, 3, 6, and 12 mo (biopsy group) was compared with that of patients who received protocol biopsies at months 6 and 12 only
continuous correlation for both acute rejection and borderline rejection, between the degree of functional graft impairment at the time of biopsy (protocol biopsies performed at 6 wk and 3 and 6 mo) and outcome at 1 yr
*Diagnosis of CAN by Protocol Biopsy
The frequency of CAN in early protocol biopsies up to 6 mo posttransplantation has been reported in a number of studies, with incidences of up to 79%
suggests that the first few months after transplantation are critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of chronic allograft damage that have yet to become clinically apparent
CAN diagnosed in protocol biopsies at 3 and 6 mo has been shown to predict renal allograft function at 2 yr posttransplantation . In addition, graft survival was found to be significantly better in patients without CAN versus those with CAN detected in protocol biopsies performed at 4
or14 months
Protocol biopsies have also been reported to be useful in the detection of CAN in pediatric transplant recipients. CAN was observed in 30.4% of protocol biopsies that were taken from stable allografts of pediatric patients approximately 100 d after renal transplantation; creatinine clearance decreased in the following year in patients in whom CANwasdetected,evenwhen renal function had been normal at the time of biopsy
*Protocol Biopsies Are Valuable in High-Risk Recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention. For example, delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to
prevent adverse long-term graft outcome. However, it is extremely difficult to diagnose graft rejection in patients with DGF on purely clinical grounds
*Detection of Graft Dysfunction as a Result of Nonimmune Factors
The appropriate therapy for graft dysfunction as a result of immunologic or nonimmunologic factors differs considerably; consequently, it is crucial to identify early the cause of the dysfunction. One of the most common causes of graft failure as a result of nonimmunologic factors is cyclosporine nephrotoxicity, yet the condition is reversible if immunosuppression is modified early enough, that is, reducing the dosage of cyclosporine while increasing the dose of other immunosuppressants. Use of protocol biopsies in this setting could be valuable by identifying cyclosporine nephrotoxicity in patients with stable renal allografts.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis. Activation of BKV is increasingly common in renal transplant recipients and generally leads to a rapid decline of renal function. BKV nephropathy can be controlled only by reducing the intensity of immunosuppression; thus, early detection and treatment are vital
*Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
Evidence suggests that the natural history of CAN may be modified by pharmacologic intervention, yet results from large, randomized, prospective trials that evaluate therapies to prevent or treat CAN are lacking.
*Safety of Protocol Biopsies
Performing protocol biopsies seems to be relatively straightforward, with the procedure generally taking place in the outpatient clinic and patients being discharged a few hours after the procedure. Indeed, transplant recipients’ compliance with the procedure is high, with the consent jjrate in one center reported to be 90%
*Con:
The Case Against Use of Protocol Biopsies
incidence of SCR in the first 6 moposttransplantation varying from 1 to 29% and CAN from 0 to 79%. Furthermore, it is difficult to draw any firm conclusions on the frequency of SCR and CAN from these studies as methodologic differences between studies make comparisons problematic.
*Reliability of SCR and CAN Diagnosis
The lack of reliable methods to quantify histologic changes in protocol biopsies has led to such specimens’ being evaluated by use of Banff ’97 criteria (34). However, Banff criteria were devised to evaluate diagnostic biopsies for which the findings are likely to be more easily interpretable, not protocol biopsies for which the degree of interstitial fibrosis is mild, particularly in early biopsies (0 to 20%) (19). This leads to a high probability of misclassification of biopsies with borderline changes or grade 1 CAN.
*How Should Utility of Protocol Biopsies Be Tested?
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points. Thus, it could be several years before evidence supporting the benefit of protocol biopsies in renal transplant patients with stable kidney function becomes available (36). An additional problem for general implementation of protocol biopsies is that the optimal timing and frequency for such biopsies has not been evaluated.
*Treatment for SCR and CAN
The presence of mononuclear infiltrates in renal allografts does not necessarily indicate rejection, and some recipients maintain good long-term graft function despite signs of SCR (37). Furthermore, the benefit of treating SCR detected by protocol biopsy has yet to be confirmed.
The appropriate management steps to be taken after detection of CAN in a protocol biopsy may also not be clearcut, because it must be proved that the CAN will respond to therapy . CAN detected at 5 yr is rarely therapy responsive;
Hinda Hassan
3 years ago
Since patients might have sub clinical rejection without obvious clinical findings, protocol biopsies has emerged as a surveillance measure to assess AMR early on. Subclinical rejection was found to be associated with poor graft survival and late AMR. Early treatment of subclinical rejection might help rescuing the graft. Furthermore, CAN was detected in 79% of protocol biopsies . In the early 6 months, detection of tubulointerstitial damage and vascular chronic can be early signs of CAN even in the absence of changes in creatinine clearance. It can also be used to monitor the progression of CAN in the future.In high risk patients like those with DGF and in those with high pre transplant anti HLA antibodies, protocol biopsies can detect early signs of rejection. CNI nephrotoxicity in patients with stable renal allografts and subclinical BK virus nephritis can be detected early protocol biopsies. The procedure of protocol biopsy was considered safe with low percentage of complications .There are different incidences of subclinical rejection and CAN between centers which could be due to differences in HLA matching, DGF, immunosuppressive protocol etc. The varying incidence may raise questions regarding the routine use of protocol biopsies in centers with low incidences. Analysis of histological findings need reproducible and easily interpretable methods ( identification of pro-inflammatory transcripts in tissue or urine by PCR , urine spectroscopy , and measurement of cell activation markers) but these are all experimental and cannot be used to predict long term graft function or used as a basis for initiating acute rejection therapy in patients with stable kidney function. So we still depend on Banff ’97 criteria. In protocol biopsies the findings can be easily misdiagnosed as borderline or inadequate .
So we need to evaluate fully the benefit of protocol biopsies regarding long-term survival and function, outcome parameters .optimal timing , frequency ,number of biopsies whether single or serial and using a standardized manner for serial, need to be determined the decision of treatment of subclinical rejection detected on protocol biopsy is controversial since not treated cases had no difference in outcome .
Ahmed Omran
3 years ago
Protocol biopsy:
pros
1- Easy and safe procedure serving for detection of subclinical rejection ;in 30 % and diagnosis of CAN ;in 79% in first 6 months following transplantation.
2-needed in high risk patents like those of delayed graft function ‘
3- helps in diagnosis of cause of graft dysfunction like CNI toxicity and BK nephropathy.
CONS
-lack of good evidence
-optimal timing not established
-benefit of treating subclinical rejection not confirmed
-Lines of CAN management not clear enough
Patient compliance is an essential factor for protocol implementation.
Mohamed Essmat
3 years ago
CAN is the most common cause of late graft rejection and failure. Subclinical rejection means histologic signs of acute rejection in a stable graft function. Early detection and treatment of both CAN and SCR can favorably affect the long-term graft survival. Protocol biopsy may be a possible mean of identifying early SCR and CAN and so allowing an early and effective treatment however, clear benefits of such approaches are still lacking . Pros: Detection of SCR and CAN in the 1st 6 months post-transplant, SCR was found in up to 30% and CAN was found in up to 80 % of grafts. It was valuable in high risk recipients as it detected SCR in a percent of patients with delayed graft function.Detection of graft dysfunction due to non-immune causes as Cyclosporin toxicity and BK virus. It is an almost safe procedure in more than 90 % of patients and serious complications are rare. in one study, serious hemorrhage occurred in 0.4% Cons: Reliability of diagnosis of SCR and CAN, as all grafts generate an immune response to some degree. Extreme variation in incidence of SCR(1-29%) and CAN(0-79) and consequently difficult explanation and interpretation. A minimum of 5 years is needed for evaluation of the usefulness of these approaches. also there are still some conflicts regarding the optimal timing and frequency of the procedure. No hard evidence of benefits of treatment of SCR and CAN on long-term graft survival. Regarding my practice: In my center , protocol biopsy may be used in the setting of high risk , sensitized recipients ; more than 1 transplant , 1ry glomerular disease , known immunological disease .
Ahmed mehlis
3 years ago
●Pro:
1:Detection of Subclinical Rejection:
acute subclinical rejection detected in protocol biopsies performed in the first 6 months post-transplantation. Protocol biopsies for early detection and treatment of acute rejection may be a major factor in preserving long-term graft function.
2:Diagnosis of CAN by Protocol Biopsy:
The presence of tubule-interstitial fibrosis and vascular –damage, which usually occur in the first 6 months following transplantation, are powerful predictors of allograft survival.
3:Protocol Biopsies Are Valuable in Highly sensitizedpatients :
Delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital. In pretransplant sensitized patients, protocol kidney biopsy is warranted to detect subclinical rejection.
4:Detection of Graft Dysfunction as a Result ofNonimmunFactors: Nonimmune mediated kidney damage could also be cause of kidney injury. For example CNI renal toxicity even in the therapeutic ranges should be suspected. Because CNI nephrotoxicity is reversible protocol biopsies may be a useful. Protocol biopsies could also detect renal diseases such as subclinical BK virus (BKV) nephritis.
●Cons 🙁
1- Variations in the reporting incidence of SCR in the studies and CAN variation may be related to low numbers of studies, low sample size, also presence of other factors like extent of HLA mismatch, immunosuppression protocol used, DGF.
2- No clear reliable method to measure or quantify the degree of CAN , as it depends on Banff 97 criteria which can be used in diagnostic biopsy not for protocol biopsy.
3- Introduction of MMF lower the incidence of SCR, so early biopsy not needed if not indicated clinically.
4- Implementation of protocol biopsy to improve graft survival and outcome should be tested for at least 5 years before general implementation , also timing when to do , and plan of therapy will be based on single biopsy or to wait for serial…so many problems.
5- Some studies showed that there is no difference between treatment of SCR and not to treat SCR on outcome and graft survival.
Amit Sharma
3 years ago
1. In your own words, summarise pros and cons of protocol biopsy.
A protocol biopsy is defined as a graft biopsy performed at a pre-specified interval regardless of the graft function. It has its own pros and cons.
Pros of performing a protocol biopsy: In this era of ultrasound guided real-time biopsies and availability of better biopsy guns, the procedure has become very safe with very low complication rates.
1) Most important reason of performing a protocol biopsy is to diagnose subclinical rejection (SCR) as it has been shown to be associated with increased incidence of acute rejection, interstitial fibrosis and tubular atrophy as well as reduced graft survival.
2) Diagnosis of chronic allograft damage leading to early diagnosis of chronic allograft nephropathy (CAN) which will help in taking countermeasures for the well being of graft and prognosticating about the graft life as CAN on protocol biopsies has been shown to be associated with poor graft survival.
3) In high risk patients, protocol biopsies can detect acute rejection and SCR in patients with delayed graft function (DGF) because timely action can prevent long-term damage. Similarly, diagnosing subclinical antibody mediated rejection in presence of DSAs can lead to early treatment and prevention of graft loss.
4) Sometimes non-immunological causes of graft dysfunction can be diagnosed before clinical signs, like Calcineurin inhibitor nephrotoxicity, BK virus nephropathy. It can help in timely intervention and prolonging the graft life.
5) Protocol biopsy has a role in clinical trials for prevention of CAN.
A the same time, protocol biopsies have some cons also, which include:
1) Although SCR can be diagnosed, there is still inconsistent data regarding the incidence of SCR (especially in tacrolimus era) and CAN. There is lot of variation due to difference in HLA mismatch, DGF incidence and immunosuppression protocols used.
2) Another issue is regarding diagnosis SCR and CAN. No standardized histological parameters have been defined for SCR and CAN, hence there are issues with the reliability of histological diagnosis.
3) There is still no consensus on when to perform a protocol biopsy, how frequently to perform it, and what action needs to be taken on the basis of the biopsy (whether a repeat biopsy to confirm the diagnosis to be performed or take action on basis of a single biopsy). Evidence base to recommend protocol biopsy is very low, as no large multicentre trial has studied this aspect.
4) Further, it is also not clear whether treatment of SCR changes the future course of the graft life as there is no case-control study to validate the assumption that SCR treatment helps in improving graft life.
5) Similarly, the action required after diagnosing CAN is not clear (when to treat and how to treat CAN is not clear). It has been shown that CAN, if diagnosed in first year post-transplant is amenable to treatment, but if diagnosed later, does not respond to treatment.
Hence performing a protocol biopsy in all transplant recipients might not be a good idea. It is better to perform protocol biopsies in sensitized patients, or patients with DGF to prevent missing acute rejection as the cause of graft dysfunction superadded on the underlying DGF.
2. Please reflect on your practice if possible.
Ours is a living related transplant program. We do not perform protocol biopsy in our unit. The reasons are:
Most of our donor-recipient pairs are related with <3/6 mismatch. We use Tacrolimus, MMF and steroid as standard immunosuppression protocol. Most of the patients do not have any history of sensitization, hence the risk of subclinical rejection is low.
Also, the patients do not want to undergo an invasive procedure if the graft function is normal and the transplant team is also hesitant in insisting for a protocol biopsy in view of low rates of subclinical rejection in tacrolimus era.
Nasrin Esfandiar
3 years ago
Protocol biopsies means performance of allograft biopsy without a clinical indication and just based on defined intervals especially during first year after transplantation. These biopsy can detect subclinical rejecting (SCR). People who agree on protocol biopsy believe that up to 30% of these biopsy showed SCR and early corticosteroid treatment was associated with improved outcome and long-term function. The other advantage of protocol biopsy on belief of these group is early detection of chronic allograft nephropathy (CAN) and prediction of graft survival and trials to prevent CAN. Protocols biopsy has great value in high risk patients such as patients with DGF or pre-sensitized recipients to detect subclinical AMR. In addition CNI nephrotoxicity or BK virus nephritis could be detect easily. On contrary opposition group believe that different incidence of SCR and CAN depends on immunosuppression potency and there is few advantage for protocol biopsy in all cases. In addition there are many new markers to diagnose SCR or CAN. Interpretation of protocol biopsy using Banff criteria leads to improper classification. Optimal time and proper frequency of protocol biopsies are not investigated and there is not a unique agreement on it. In our practice we do protocol biopsy only in sensitized patients.
Reem Younis
3 years ago
-Acute rejection (AR) is responsible for up to 12 % of graft loss commonly within the first 6 months after transplantation.AR can be classified into humoral and cellular rejection.
-Cellular rejection develop when donor alloantigen, presented by an antigen-presenting cell (APCs) through class I or class II HLA molecules, activate an immune response against the allograft, resulting in activation of naïve T cell which differentiates into cytotoxic CD8+ and helper CD4+cells (TH1) and TH2 or cytoprotective immunoregulatory T cell (Tregs), also Tregs cell originate from the thymus gland.
-Tregs in CD4+T cell expressing CD25 and T lymphocyte antigen 4 (CTLA-4).
-Treg cells are about 5% of T lymphocytes.
-Tregs maintain T cell homeostasis
-prevent activation of autoreactive immune response
-contribute to maintaining self-tolerance and homeostasis of the microbial gut flora
-promote the immunogenic escape of cancer cells.
-Tregs produce IL- 10 which inhibit, either directly or indirectly effector T cells during infection, autoimmunity, and cancer.
-CTLA-4 –expressing Tregs can down-regulate the expression of costimulatory molecules CD80 and CD86 on dendritic cells of lymphoid tissues resulting in impaired co stimulation via CD 28 and defective T cell stimulation.
-Treg cells can inhibit dendritic cells(DC) by stable Treg-DC contact lead to Tregs- mediated inhibition and also Tregs can induce perforin-dependent cytolysis of DC.
-Foxp3 in the urine analysis was high in patients with acute rejection and associated with better response to steroids and lower risk for graft failure.
-Multivariate analysis revealed that Foxp3/IL-17 ratio was a significant predictor for allograft outcome.
-Patients who maintain high Treg levels at both 6 and 12months display better long-term graft survival at 4qnd 5 years follow up.
-According to Banff classification, higher Foxp3 expression was associated with higher levels of interstitial inflammation and tubulitis.
–
In your own words, summarise pros and cons of protocol biopsy.
Please reflect on your practice if possible.
Summary:
many studies suggest that using protocol biopsies post kidney transplant would help in early detection and promptly timing treatment of both subclinical rejection(SCR) and chronic allograft nephropathy(CAN) and this would impact the graft survival and outcome especially in high risk recipients like sensitized candidate or those at risk of DGF , the procedure is safe however the available data about the true benefit of early treatment of SCR , CAN detected by protocol biopsy is limited to few observational studies . Moreover, the optimal timing of the protocol biopsies and the methods used to quantify the histological lesions is not yet determined. So, this article addresses the advantages and disadvantages of protocol biopsies based on the review of the available studies Pro: The Case for Use of Protocol Biopsies
1-Detection of Subclinical Rejection
SCR indicate histological evidence OF acute rejection in patient with stable graft function, the incidence of SCR was higher in the first 6 months post transplantation, based on protocol biopsy surveillance report the incidence of SCR up to 30%, a clear link between SCR and subsequent development of CAN has not been proved, some studies suggest Corticosteroid treatment of SCR detected in the early postoperative period (1 to 3 mo) was found to be associated with an improved outcome. Another two reports suggest early protocol biopsies 1-3 months with SCR diagnosis and left untreated SCR was found to be progressed to CAN with increased interstitial fibrosis andtubular atrophy in FU biopsies in both studies (9,12).
2-Diagnosis of CAN by Protocol Biopsy
The available evidence supports the use of protocol biopsy for detection of CAN as it can impact the graft survival with early pharmacological intervention, but need more studies with better design and longer Fu. CAN detected by protocol biopsy had significant increased incidence of acute rejection before the biopsy .
CAN diagnosed in early protocol biopsy samples is an independent predictor of long-term outcome.
protocol biopsies could well become a useful primary efficacy variable in trials aimed at preventing CAN (7,15). but need further studies with good sample size and longer FU period.
3-Protocol Biopsies for High-Risk Recipient
is preferred tool for the diagnosis of acute rejection like in one study showed SCR was detected in 7-d protocol biopsy specimens in 18% of patients with DGF versus 4% of patients with normal early graft function. Also, humoral/vascular acute rejection was detected in 17% of biopsies performed 10 to 30 d post transplantation, 53% of which were in recipients with antibodies to class I HLA antigens, 25% in recipients with class II antigens, so protocol graft biopsies effective tool for detection of SCR in both high risks sensitized patients and those with DGF post-transplant.
4-Detection of Graft Dysfunction as a Result of Nonimmune Factors
Post-transplant protocol biopsies useful for the early diagnosis of CNI toxicity, one report reached 42% at 12-month post-transplant in protocol biopsies surveillance also found useful in early detection of BKV nephropathy which found in the range of 2-5% based on available studies. Safety of the protocol biopsies;
Based on available evidence the protocol biopsies found to be safe with minimal complications in the range of 0.2, o.7, 1% for major bleed (27,28,29) can be done as OP procedure with good patient’s compliance reported up to 90%.
Con: The Case Against Use of Protocol Biopsies
Due to the heterogenicity of the reviewed studies by methodology and also the different timing of the protocol biopsies we can see the results are very variables as showed in table 1 the frequency of the SCR from different studies based on protocol biopsies vary from1% in mon3 to 43% in first months, the same for the frequency of mild CAN it vary from 0% in mon1 to 79% in mon3in two studies. This can be explained by the heterogenicity of the inclusion and exclusion criteria in regard s to HLA Matching, the frequency of DGF, the type of immunosuppressive medications and the early timing and frequency of protocol biopsies all these variables can affect the frequency of SCR , also age related chronic changes can interpreted as CAN , was missing in 4 studies This suggests that donor-related changes may explain a large proportion of the variability in the reported incidence of CAN.
Reliability of SCR and CAN Diagnosis
The large number of inadequate by adopting the Banff criteria This leads to a high probability
of misclassification of biopsies with borderline changes orgrade 1 CAN. Especially in early protocol biopsies
introduction of MMF in the IS Protocol help in reduction of the frequency of SCR in early biopsy protocol and according to this observation some centers stop doing the protocol biopsies.
One of the problems that affect the adopting the protocol biopsies is the difference in the timing and frequency, a single biopsy is likely to result in a high degree of inaccuracy. Treatment for SCR and CAN:
still therre is no consensus regarding the benefit from the treatment of SCR from the available evidence ,also no difference in outcome (measured by graft survival and mean serum creatinine) at 1 and 6 yr post-transplantation were found between patients with SCR or borderline changes and those with no rejection or borderline changes.
Conclusion:
The protocol biopsies that adopted by many centers for screening of SCR and CAN still important despites the limited data from the current available studies, still needed especially for high risk group of kidney transplant patients ,protocol biopsies are safe and that their use likley improve the treatment especially early diagnosis and treatment of CAN ,in order to address their real advantage and effect on transplant outcome we need for large randomised control trails with longer follow up with the use of protocol biopsies as a primary efficacy variable with standardization of the histopathological criteria, timing and frequency of the biopsies ,and standardized immunosuppressive therapy .
In our center we do the graft biopsy based on indication and in regards to protocal biopies we individualized their use case by case with many limitation including the patient acceptance and compliance.
Last edited 3 years ago by saja Mohammed
Reem Younis
3 years ago
-Chronic allograft nephropathy (CAN)is the most common cause of late graft rejection and is strongly correlated with several acute rejection episodes during the first year after renal transplantation.
-Acute rejection and CAN can be subclinical without causing a measurable decrease in graft function.
-Persistent, unrecognized inflammatory injury due to a low–grade rejection process raises the possibility that surveillance or protocol biopsies, which are performed during the first post-transplantation year irrespective of graft function, may be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are treatable.
-used of protocol biopsies has been limited in some centers by concern over their safety but several studies suggest that the procedure is safe. Pros of protocol biopsies :
1-Detection of subclinical rejection (SCR): SCR leads to long-term deterioration of graft function and early detection and intervention may be improved outcome. Corticosteroid treatment was found to be associated with an improved outcome.
2. Diagnosis of CAN: The first few months after transplantation is critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of CAN that have yet to become clinically apparent.CAN increase during the first 6 months after transplantation, then slowly thereafter.
3. High-risk recipient: Protocol biopsies have great value in detection DGF and acute rejection that lead to reduced graft survival in high- risk recipient
4. Detection of graft dysfunction as a result of nonimmune factors: non-immunological factors like cyclosporine nephrotoxicity and subclinical BKV nephritis can affect graft survival.
5. Used in clinical trial designed to prevent CAN.
Cons of protocol biopsies :
1. Variation in the reported incidence of CAN and SCR.
2. Reliability of SCR and CAN diagnosis is difficult to be assessed.
– To date, there is no good evidence supporting the general implementation of protocol biopsies into clinical practice.
-In our practice in Sudan, we donot do protocol biopsies. if the recipient after transplantation develops complications we do diagnostic allograft biopsy.
MICHAEL Farag
3 years ago
Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment. Although the benefit of this approach has yet to be evaluated in large, multicentre, prospective trials, numerous studies suggest that implementation of protocol biopsies may improve long-term graft function.
Chronic allograft nephropathy (CAN) is the most common cause of late graft rejection and is strongly correlated with the number of acute rejection episodes during the first year after renal transplantation.
Recent reports have suggested that acute rejection episodes and CAN may be subclinical without causing a measurable decrease in graft function. Moreover, persistent, unrecognized inflammatory injury, secondary to a low-grade rejection process, may result in long-term graft fibrosis and chronic dysfunction in the absence of episodes of overt clinical rejection. This
raises the possibility that surveillance or protocol biopsies, which are performed during the first post-transplantation year irrespective of graft function, may be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are amenable to treatment.
Pro: The Case for Use of Protocol Biopsies 1- Detection of Subclinical Rejection
Although a clear link between SCR and subsequent development of CAN has not been proved, some studies suggest that SCR leads to long-term deterioration of graft function and that early intervention may well improve outcomes. The use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
2-Diagnosis of CAN by Protocol Biopsy
Protocol biopsies have also been reported to be useful in the detection of CAN
3- Protocol Biopsies Are Valuable in High-Risk Recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention as in delayed graft function (DGF).
4- Detection of Graft Dysfunction as a Result of Nonimmune Factors
The appropriate therapy for graft dysfunction as a result of immunologic or nonimmunologic factors differs considerably; consequently, it is crucial to identify early the cause of the
dysfunction. One of the most common causes of graft failure as a result of nonimmunologic factors is cyclosporine nephrotoxicity, yet the condition is reversible if immunosuppression is
modified early enough, that is, reducing the dosage of cyclosporine while increasing the dose of other immunosuppressants. Use of protocol biopsies in this setting could be valuable by identifying cyclosporine nephrotoxicity.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis.
5- Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
protocol biopsies from patients with stable grafts may be useful to monitor the progression of CAN and may be a valuable tool in the design of future trials aimed at modifying its natural history.
Con: The Case Against Use of Protocol Biopsies 1- Variation in Reported Incidence of SCR and CAN
The incidences of SCR and CAN reported in biopsy specimens thus far have differed widely, with the incidence of SCR in the first 6 ms post-transplantation varying from 1 to 29% and CAN from 0 to 79%. Furthermore, it is difficult to draw any firm conclusions on the frequency of SCR and CAN as methodologic differences between studies make comparisons problematic
2- Reliability of SCR and CAN Diagnosis
The lack of reliable methods to quantify histologic changes in protocol biopsies has led to such specimens’ being evaluated by use of Banff ’97 criteria (34). However, Banff criteria were
devised to evaluate diagnostic biopsies for which the findings are likely to be more easily interpretable, not protocol biopsies for which the degree of interstitial fibrosis is mild, particularly in early biopsies (0 to 20%) (19). This leads to a high probability
of misclassification of biopsies with borderline changes or grade 1 CAN
3-How Should Utility of Protocol Biopsies Be Tested?
the optimal timing and frequency for such biopsies has not been evaluated. Furthermore, it is unclear whether decisions for intervention should be made on serial biopsies or based on a single biopsy result.
4-Treatment for SCR and CAN
the benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown, as most studies give anti-rejection treatment for SCR as soon as it is detected.
Radwa Ellisy
3 years ago
protocol biopsy: The more rejection episodes occur in the first year, the more CAN incidence. Even if these episodes may not be clinically overt but they are still injurious to the graft leading to fibrosis and malfunction. So it looks wise to perform protocol biopsy in the early post-transplant year hoping for early detection and better management
pros
1- Detection of subclinical rejection which found to occur in 30% of the first 6 months post-transplant
Early detection and management were found to be associated with a better outcome, less fibrosis and atrophy, and better 2-year survival especially with protocol biopsies performed in the first 3 month
Untreated borderline rejection and borderline rejection were associated with more acute rejection episodes after 10 years
2- Early diagnosis of CAN
The presence of CAN early in the protocol biopsy was associated with the risk of acute rejection episodes.
3- For high-risk patients
a. Patients with delayed graft function distinguishing subacute rejection and early management so a better prognosis.
b. Patients with anti HLA antibodies.
4- Early diagnosis and management of other non-immunological causes of graft dysfunction
a. BK virus early signs of infection combined with urine investigations led to marked reduction in the incidence of BK virus nephropathy
b. Identification of histological alarms of CNI induced toxicity so the dose can be modulated with better graft survival Cons
1. Diagnosis of CAN:
no definite criteria differentiate CAN vs early or borderline changes
2. Absence of definite criteria histopathological classification of protocol biopsies Reflection on the practice:
In our practice, we don’t use protocol biopsies as a routine (only indication biopsy).
I think protocol biopsy should be adopted in our center especially for sensitized patients and those with slowly declining serum creatinine (not meeting the criteria of DGF)
But yet I could not preclude which time may be better (first week, first month, or 3-month)
Tahani Hadi
3 years ago
Protocol graft biopsy is known as doing frequent graft biopsy within different intervals regardless the level of graft function ,it has advantages and disadvantages.
Advantages
Early detection of subclinical rejection SCR which means normal renal function but there is a change in histological features, early detection, early management and better outcome.
Diagnosis of CAN
By determining the high risk groups and doing protocol biopsy this help to detect any rejection and improve graft survival. High risk groups like patients with DGF and highly sensitived patients .
Detect silent other non immunological factors like BK virus and CNI toxicity.
Help to decrease rate of hospitalization post operative.
Disadvantages
Difficulties in interpretation of the histological changes as most of the transplanted kidneys show some degree of changes.
Variation reported incidence of SCR and CAN.
Nazik Mahmoud
3 years ago
In summary this article tried to compare between the pros and cons of protocol biopsy; so it is useful in detecting early histological changes in the graft ,it has role in diagnose subclinical rejection (SCR) and chronic allograft nephropathy (CAN) ; also it has great benefit in improving graft survival after delay graft function (DGF) ,it positively affect graft and patient survival. It can also detect non immune graft dysfunction like viral infections (BK nephropathy) and it is a safe procedure. In contrast there’s some cons like over diagnosis of SCR and CAN,difficulty in interpretation of the histological Changes because it almost borderline , the most challenged part which is to treating this subclinical changes or not.
In our transplant centers in Sudan we don’t do protocol biopsy
Mujtaba Zuhair
3 years ago
The protocol biopsy is a biopsy that done at fixed time after transplantation with no clinical indication . it’s timing and frequency is center specific.
The advantages of protocol biopsy :
Detection of subclinical rejection ( histologic rejection with normal renal function tests and uranalysis ) and treatment of subclinical rejection leads to decrease in acute rejection and less chronic allograft nephropathy changes.
Detection of chronic allograft nephropathy early in the first post transplantation year and treatment intensification leads to better allograft outcome in some studies.
High risk patients ( patients with DGF and highly sensitized patients) had more benefit from protocol biopsy since it allow early detection of acute rejection and they had high rates subclinical rejection.
Detection of calcineurin nephrotoxicity and BK virus nephropathy.
Reducing the number of patients and time of clinical trial of new drugs in transplantation by utilizing CAN as marker of allograft outcome.
It’s a safe procedure with low level of seious complication.
The disadvantages of protocol biopsy :
The lack of widely agreed criteria for the diagnosis of subclinical rejection and chronic allograft nephropathy.
The optimal timing and frequency of protocol biopsy is not determined yet.
The studies that showed befit in protocol biopsy had many confounders like donor criteria and the level of immunosuppression and HLA matching which need to be addressed.
In our center , we do not use protocol biopsy to our patients.
Wessam Moustafa
3 years ago
Incidence of Acute rejections have been largely controlled in the past 20 years after the introduction of the more potent immunosuppressives, however the chronic allograft nephropathy remains a probleme as it s a major cause of graft loss .
Biopsies are only performed in the settings of established rejections , after an irreversible damage has been established , so less likely to benefit from therapies .
An ongoing immun damage may occur without significant decline in GFR and this adversely affect graft outcome
And bec the above listed items , came the idea of protocol biopsies
Pros of protocol biopsies including :
* detection of subclinical rejection.
* detection of CAN .
* detection of non immune causes of graft failure
* detection of acute rejection in high risk patients with DGF .
* protocol biopsies can be of great benefit in clinical trials
Cons include
* The wide range of reported incidence of SCR and CAN
* the reliability of the diagnosis of both conditions SCR and CAN
* lack of good evidence that supports benefit of protocol biopsies.
* although SCR almost always predict subsequent acute rejection episodes ,and so benefits from early intervention, yet, data on untreated cases of SCR is lacking, so effects of treating such patients on long term can’t be detected.
Ben Lomatayo
3 years ago
Pro of Protocol Biopsies ;
Detection of sub-clinical rejection : This was found in 30% of protocol biopsies(4-10). Protocol biopsies are very important for the diagnosis & treatment of acute rejection and plays major role in long-term graft survival.
Diagnosis of CAN by protocol biopsy: The incidence of CAN is up to 79% in the first 6 months ( 7,8,12,14,15). Graft survival was found to be superior in patients without CAN compared to those patients with CAN diagnosed in protocol biopsies(19).
Protocol Biopsies are valuable in High Risk Recipients : In this setting protocol biopsies allows early intervention which will determine the long term graft survival specially in patients with DGF
Detection of graft dysfunction as a result of non-immune factors :
1. Cyclosporine Nephrotoxicity : Seen in 42 % of protocol biopsies after one year of transplantation(23)
2. BKV Nephropathy : Protocol biopsies is also helpful to detect sub-clinical BKV BKV nephropathy which can lead to rapid reduction in renal function
Use of Protocol Biopsies in clinical trials designed to prevent CAN : There is some evidence that the natural course of CAN may be altered by therapeutic intervention. Currently we are still waiting RCT that evaluate therapies to prevent or treat CAN
Safety of protocol biopsies : The procedure is proved to be safe in many studies(26-29)
2.Con of protocol Biopsies ;
Variation in the reported incidence of SCR & CAN ; This may be due several reasons(6) ; 1. HLA match 2. some studies exclude pts with DGF 3. Immunosuppression used 4. some studies didn’t report their inclusion criteria 5. Variation in reporting of CAN ; mild, moderate 6. Donor related factors e.g. Age 7. Differences in methodologies of the studies
Reliability of the SCR and CAN diagnosis : Currently we are depending on BANFF criteria which is actually not meant for protocol biopsies. There is also the problem of inadequate sampling which again questioned the reliability of this procedure. Some centres discontinue the use of protocol biopsies due to reduction in the incidence of SCR after the introduction of the new immunosuppressive therapies e.g. MPA (10) (35)
How should utility of the protocol biopsy be tested ; At the moment no evidence to support the use of protocol biopsies on routine bases. The timing & frequency of protocol biopsies is not uniform. It is not clear whether the therapeutic decisions should be made on serial biopsies( standardization problem) or single biopsy (inaccuracy problem. So more studies are warranted.
Treatment of SCR & CAN : The benefit of treating SCR detected by protocol biopsies not yet confirmed. The effect of not treating SCR is largely unknown as most centres treat with immunosuppression once SCR is diagnosed. The window of time during which CAN will respond to therapy must be established before appropriate timing of protocol biopsies can be determined(31)
We don’t do protocol biopsies in our programme. All our transplant biopsies are indication biopsies.
Mohamed Fouad
3 years ago
kidney transplant protocol biopsy
The incidence of acute rejection episodes decreased relatively nowadays in comparison with the past due to emergence of the new potent immunosuppressive medications. However, chronic allograft nephropathy leading to loss of graft function remains the major problem after renal transplantation. Most of the kidney transplant practice are performing a diagnostic kidney biopsy when there is suspicion of graft dysfunction in terms of rising of serum creatinine, new onset proteinuria or hypertension and by the time of clinical diagnosis scaring of the graft tissue already happened.
Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy whichcan be treatable either by changing immunosuppression or adjusting the doses. Implementations of protocol biopsies may improve long-term graft function in high-risk patients, such as those with delayed graft function, long cold ischemia time and sensitized patients.
-Definition of protocol biopsy: Renal allograft protocol biopsy is defined as biopsy performed at predefined intervals after transplantation, which is unrelated to graft dysfunction.
-Advantages of protocol biopsy:
1- Subclinical rejection which is the histological signs of acute rejection with normal kidney function can be detected by protocol biopsies and can be managed early.
2-Early diagnosis and treatment of chronic allograft nephropathy (CAN) proved by serial protocol biopsies could have a dramatic effect on the outcome of the graft.
3-Detection and treatment of Subclinical rejection in high-risk group patients as DGF and sensitized high-risk renal transplant recipients with positive impact on long term graft survival.
4-Serial protocol biopsies can detect silent non immunological factors causing graft dysfunction as CNIs toxicity, subclinical BK virus (BKV) nephritis when diagnosed with protocol biopsy combined with urine sample and PCR.
5- It is mainly a safe procedure seems to be straightforward, done as one day surgery and patients can be discharged a few hours after the procedure.
-Disadvantages of protocol biopsy:
1- Variation in reported incidence of SCR and CAN results from protocol biopsies.
2- The lack of reliable methods to quantify histologic changes in protocol biopsies which is evaluated by use of Banff ’97 criteria. However, Banff criteria were designed to evaluate diagnostic biopsies with some form of clear histological diagnosis.
-Implementation of protocol biopsies:
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points. Thus, it could be several years before evidence supporting the benefit of protocol biopsies in renal transplant patients with stable kidney function.
Another point the optimal timing and frequency of protocol biopsies it should be serial biopsies or a single biopsy result which will be inaccurate.
The clinical significance of early detection of silent inflammatory infiltratesin stable allografts remains controversial.
In our practice we are only doing diagnostic kidney biopsies when the patient presented with suspicion of graft dysfunction e.g. Trending up of serum creatinine level above the baseline value by 25% and above, new onset proteinuria and high BP.
Professor Ahmed Halawa
Admin
3 years ago
Dear All Thank you very much for your fruitful contribution. Protocol biopsy was a common practice in the Cyclosporine era where the incidence of subclinical rejection with high. It reached 30% in some series. In the Tacrolimus era, subclinical rejection is hardly seen. Therefore protocol biopsy is usually not indicated except in highly sensitised.
Esmat MD
3 years ago
Although the incidence of acute rejection has fallen in recent years, chronic rejection and loss of graft function remain major problems after kidney transplantation. CAN is the most common cause of late graft rejection and is strongly correlated with the number of acute rejection episodes. Furthermore, CAN and acute rejection may be subclinical and low-grade inflammation may result in graft fibrosis and chronic rejection. Thus, it raised the possibility that protocol biopsy during the first year after transplantation may be useful for detection of early acute rejection and CAN. However, there are many pros or cons of surveillance biopsies.
Pros of protocol biopsies:
Detection of subclinical rejection
SCR (histologic signs of acute rejection in the presence of stable graft function) with reported incidences of up to 30% leads to long-term deterioration of graft function and early intervention with corticosteroids may improve outcomes.
Untreated SCR is correlated with an increase in IFTA in later biopsies. SCR is associated with a higher incidence of acute rejection. These data thus suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
Diagnosis of CAN by protocol biopsy
CAN can be identified with an incidence of up to 79% in early protocol biopsies. The presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival and rapidly increase during the first 6 months after kidney transplantation. In particular, patients with chronic graft damage score >6 had a higher rate of graft loss than those with scores <6. Thus, early detection and treatment of CAN can have a dramatic effect on the outcome of the graft.
Valuable in high-risk recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention. DGF is strongly associated with poor long term graft outcome and early detection of acute rejection in the presence of DGF is crucial to prevent adverse long-term outcome. Thus, there is a strong need to prompt diagnosis of acute rejection that may be met by protocol biopsies. In one study, half of acute rejection in patients with DGF was clinically undiagnosed.
It is suggested that much of the reduced graft survival associated with DGF may be explained by silent acute rejection, so surveillance biopsies and treatment of SCR during prolonged DGF is warranted.
In addition, Protocol biopsies may be an effective way of detecting subclinical ABMR in sensitized high-risk renal transplant recipients.
Detection of graft dysfunction as a result of non-immune factors
Appropriate therapy of immunologic and non-immunologic factors of graft dysfunction differs considerably and early detection of them is crucial. One of the most common causes of non-immunologic graft dysfunction is CNI toxicity that is reversible if immunosuppression is modified early enough. So utilizing protocol biopsy can be valuable in this setting.
Protocol biopsies may also be useful to detect BK virus nephritis, and commence of appropriate therapy with reducing immunosuppression.
In clinical trials designed to prevent CAN
Evidence suggests that the natural history of CAN may be changed by treatment and trials for evaluation of CAN need to use long term survival as an end point. Protocol biopsy can be a good surrogate marker. Histologic changes in graft biopsy provide the earliest evidence of graft damage and its predictive value on graft survival may be superior to AR or serum Cr. Thus, protocol biopsies may be useful for monitoring the progression of CAN and may be a valuable tool in the design of future trials aimed at modifying its natural history.
Safety of protocol biopsy
A number of studies suggest that the procedure is safe and the rate of reported major complications is less than 1%.
Cons of protocol biopsies
Variation in reported incidence of SCR and CAN
There is a big difference between the reported incidence of SCR and CAN varying from 1-29% for SCR and 0-79% for CAN
Some explanations for the difference in SCR is difference in HLA matching, incidence of DGF between studies, immunosuppressive protocols, and the lack of precise inclusion criteria.
Some explanations for the difference in CAN is the similarity of age-related changes to CAN, impact of donor variables on chronic histopathologic scores, and methodologic problems.
Reliability of SCR and CAN diagnosis
Because all transplants generate immune response to some extent, analysis of the histologic criteria for rejection is somehow problematic. In addition, utilizing of BANF criteria may lead to misclassification of borderline changes.
How Should Utility of Protocol Biopsies Be Tested?
It takes a long-time (at least 5 years) to evaluate fully the benefits of protocol biopsies on graft survival and function. On the other hand, the optimal timing and frequency of protocol biopsies is not clear. In addition, it is better that therapeutic decisions be based on serial biopsies, although standard analysis of them is problematic.
Treatment for SCR and CAN
Infiltration of kidney graft by mononuclear cells does not necessarily indicate rejection, and the benefit of treatment of SCR has not been confirmed, although most studies give immunosuppressive treatment for SCR. It is reported that increasing baseline immunosuppression reduces the incidence of clinical rejection not SCR and the benefit of treatment of SCR may be limited. The appropriate management of detected CAN in a protocol biopsy is not clear. Although it is likely that the management and underlying mechanisms of early and late CAN may completely differ.
Ibrahim Omar
3 years ago
Introduction:
Chronic allograft nephropathy (CAN) is the most common cause of late graft rejection and failure. also, CAN is strongly correlated with the number of acute rejection episodes in the 1st year post-transplantation. Subclinical rejection(SCR) means histologic signs of acute rejection in a stable graft function. It has been emphasized that early detection and treatment of both CAN and SCR can favorably affect the long-term graft survival.
Protocol biopsy has been thoroughly considered as a possible mean of identifying early SCR and CAN and so allowing an early and effective treatment, to get a final better graft survival. however, clear benefits of such approaches are still lacking and need more exhaustive evaluation.
Advantages of protocol biopsy:
Detection of SCR and CAN. in the 1st 6 months post-transplant, SCR was found in up to 30% and CAN was found in up to 80 % of grafts.
It was valuable in high risk recipients as it detected SCR in a percent of patients with delayed graft function.
Detection of graft dysfunction due to non-immune causes as Cyclosporin toxicity and BK virus. each of them needs a different treatment as decreasing immuno-suppressive drugs to get a better graft function.
It was useful in clinical trials designed for prevention of CAN.
It is an almost safe procedure in more than 90 % of patients and serious complications are extremly rare. in one study, serious hemorrhage occurred in 0.4%
Disadvantages of protocol biopsy:
Extreme variation in incidence of SCR(1-29%) and CAN(0-79) and consequently difficult explanation and interpretation.
Reliability of diagnosis of SCR and CAN, as all grafts generate an immune response to some degree. a great difficulty in interpretation will arise.
A minimum of 5 years is needed for evaluation of the usefulness of these approaches. also there are still some conflicts regarding the optimal timing and frequency of the procedure.
No hard evidence of benefits of treatment of SCR and CAN on long-term graft survival.
For my practice:
I will adhere to the local protocol and try to share benefits of protocol biopsy with senior colleagues. I will try to design a study of managing some cases with protocol biopsy to check for possible even short-term benefits.
Fatima AlTaher
3 years ago
Many transplantation centres consider protocol biopsy during first year post transplantation aiming at early diagnosis and proper treatment of any graft pathology to prolong graft survival . Protocol biopsy are beneficial for diagnosis of subclinical rejection early diagnosis of chronic graft rejection, for high risk patients as patients with DGD , for non immune causes of graft dysfunction as CNI toxicity and early BK nephropathy
Limitation for protocol biopsy are
1- Interventional related Complications as pain , bleeding , heamaturia and peritonitis
2- Difficluty in assessing cost –benefit of protocol biopsy due to marked variation in reported incidence of SCR and CAN between studies , that may be explained by different immunplogical risk of the studied population ( variable degrees of HLA mismatch , variable incidence of DGD ) or due to different immunesuppression protocols used in these studies as well as difficult diagnosis of early CAN as these histological changes resemble age related renal changes.
3- Dificult diagnosis of SCR and early CAN as
a- these histological changes resemble age related renal changes.
b- B- all transplanted allograft show some degree of histologic changes and mild infilteration with inflammatory cells
c- No agreed diagnosing and staging system for the histological changes in SCR , CAN.
4- No clear benefit from treating SCR as despite being associated with increase incidence of acute rejection rates , its treatment did not improve outcome of these rejections .
5- No strong evidence tested by large , multicentric studies to support protocol biopsy.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
WHAT IS PRTOCOL BIOBIES? they are surveillance biopsies performed during the first year after kidney transplantation, to identify early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment.
a-advantages
1-detection of subclinical rejection. 2- diagnosis of CAN 3- protocol biopsy are valuable in high-risk recipient(cadaveric, history of dsa befor transplantion) 4- detection of graft dysfunction as a result of none immune factors like cni toxcity and bk nephropathy. 5- use of protocol biopsy in clinical trials designed to prevent CAN.
b-disadavantages 1-no clear evidence on the ralation between SCR and subsequent development of CAN has not been proved.
2-incidences of SCR and CAN reported in biopsy specimens showed wide variations with the incidence of SCR in the first 6 mo posttransplantation varying from 1 to 29% and CAN from 0 to 79%.
3- SCR as mononuclear cell infiltration does not necessary mean rejection and benefit of treating SCR detected by protocol biopsy has yet to be confirmed. .
4- no clear studies support the benefit of protocol biopsies in renal transplant patients with stable kidney function yet and no standard timing for the protocol biopsies .
5-BANFF clasifiaction is not designed for protocol biobies .
IN OUR CENTER, WE DONT DO IT , BUT WE ARE PLNNING TO DO IT FOR HIGH RISK PT .
Professor Ahmed Halawa
Admin
3 years ago
Dear All Thank you for your input. Yes, Subclinical rejection is very uncommon in the tacrolimus era. We hardly do it unless there is a clinical suspicion based on graft dysfunction (it would not be called protocol biopsy).
Yes, it is justified in highly sensitised patients. I’m not sure if it has an impact on the graft survival and function due to the complexity of confounding factors (match, the cPRA, etc.). It may have prognostic value.
Asmaa Khudhur
3 years ago
acute rejection episodes and CAN may be subclinical without causing a measurable decrease in graft function. Moreover, persistent, unrecognized inflammatory injury, secondary to a low-grade rejection process, may result in long-term graft fibrosis and chronic dysfunc- tion in the absence of episodes of overt clinical rejection. This raises the possibility that surveillance or protocol biopsies, which are performed during the first posttransplantation year irrespective of graft function, may be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are amenable to treatment.
Pro: The Case for Use of Protocol Biopsies
Detection of Subclinical Rejection
the outcome of renal transplant patients who underwent protocol biopsies at 1, 2, 3, 6, and 12 mo (biopsy group) was compared with that of patients who received protocol biopsies at months 6 and 12 only (control group) .Corticosteroid treatment of SCR detected in the early postoperative period (1 to 3 mo) was found to be associated with an improved outcome.
use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
Diagnosis of CAN by Protocol Biopsy
Evidence suggests that the first few months after transplantation are critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of chronic allograft damage that have yet to become clinically apparent.
Protocol Biopsies Are Valuable in High-Risk Recipients
delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to prevent adverse long-term graft outcome. . However, it is extremely difficult to diagnose graft rejection in patients with DGF on purely clinical grounds. Accordingly, there is a strong need for a means of promptly diagnosing acute rejection in patients with DGF, a need that may be met by protocol biopsies.
Protocol biopsies thus may be an effective way of detecting subclinical antibody-mediated acute rejection in sensitized high-risk renal transplant recipients.
Detection of Graft Dysfunction as a Result of Nonimmune Factors
One of the most common causes of graft failure as a result of nonimmunologic factors is cyclosporine nephrotoxicity, yet the condition is reversible if immunosuppression is modified early enough, that is, reducing the dosage of cyclosporine while increasing the dose of other immunosuppressants. Use of protocol biopsies in this setting could be valuable by identifying cyclosporine nephrotoxicity in patients with sta- ble renal allografts.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis. Activation of BKV is increasingly common in renal transplant recip- ients and generally leads to a rapid decline of renal function. BKV nephropathy can be controlled only by reducing the in- tensity of immunosuppression; thus, early detection and treatment are vital.
Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
Evidence suggests that the natural history of CAN may be modified by pharmacologic intervention, yet results from large, randomized, prospective trials that evaluate therapies to pre- vent or treat CAN are lacking. This is due largely to the methodologic difficulties encountered in the design of such trials. such as the sample size and the follow-up time, Furthermore, no prospective methods to monitor the appearance/progression of CAN are available currently for the kidney; thus, clinical trials that are conducted in renal transplant patients, by necessity, need to use surrogate markers of long-term graft survival.
Safety of Protocol Biopsies
The procedure is safe.
Con: The Case Against Use of Protocol Biopsies
Variation in Reported Incidence of SCR and CAN
Reliability of SCR and CAN Diagnosis
How Should Utility of Protocol Biopsies Be Tested?
evaluation of the utility of protocol biopsies must consider the complex differences that exist between clinical trials, such as differences in patient se- lection, use of induction therapies, and baseline and mainte- nance immunosuppression.
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points
Treatment for SCR and CAN
Dalia Eltahir
3 years ago
Using of potent immunosuppressant drugs in last year’s leading to decrease incidence of graft loss . However, chronic allograft dysfunction remain the major cause of graft loss . Protocol biopsies in kidney transplant recipients make an early detection of subclinical rejection or chronic transplant glomerulopathy. Pros – Detection of early sub acute rejection and early intervention may improve outcome in long term graft function . Protocol biopsies need to be performed in the following clinical conditions in delayed graft function DGF because it affect graft survival so early diagnosis of SCR and early treatment improved graft outcome .Also using protocol biopsies in high risk pt and early detection of AMR may be effective .Early detection of nonimmunologic factors like Cyclosporine nephrotoxcity and BK virus and early reduce in the immunosuppressant drugs may be beneficial . There are variation in incidence of CAN and SCR detected ,this may be duto presence of HLA matching , DGF type of immunosuppressant drugs used and donor variables (e.g., deceased donor, increasing age, female gender, hypertension }. Also histologic criteria in protocol is problematic because every recipient generate immune response . The biopsy is safe there are small number of compilation . In our practice we didn’t do protocol biopsies . The biopsy done when there is impair renal function. SCR is 14% while 24% in CYA .Pt on tacrolimus had better graft survival. Treatment of SCR by anti-rejection because it will improve graft survival .
Mahmud Islam
3 years ago
Protocol biopsies are performed at previously determined intervals for the aim of detection of acute or chronic changes that mostly seem to be subclinical aiming for early determination and accordingly timely management.
The advantages of the protocol biopsies is can be summarized as :
the detection of subclinical rejection, this is valuable in high-risk recipients. Many studies detected early rejections in first 6 months post transplantation
detection of graft dysfunction because of non-immune factors the protocol biopsies can be used in clinical trials designed to prevent CAN
may show latent infections like BK earlier while subclinical, so it helps differentiate the immunologic from nonimmunologic reasons. this is very important as treatments may be opposite (increase vs decreasing immunosuppression)
one of the limitations for wide routine usage is safety
another limitation is variations in the reported incidence of CAN and SCRT
There is a problem regarding their reliability of diagnosis as the presence of mononuclear infiltrates in renal allografts may not necessarily indicate rejection. some of such patients showed good survival.
Abdulrahman Ishag
3 years ago
protocol biopsies performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment. Pro: The Case for Use of Protocol Biopsies; 1-detection of subclinical rejection; protocol biopsies is useful in detection acute and border line rejection and facilitate early treatment. 2- diagnosis of CAN; Detection of chronic allograft nephropathy in early protocol biopsy is predictive of subsequent graft function loss and early treatment is of great effect in graft out come . 3- protocol biopsy are valuable in high-risk recipient; Protocol biopsies is useful in detection of sub clinical rejection in sensitized patient. Also they have great value in patients with delayed graft function ,by allowing early interventions . . 4- detection of graft dysfunction as a result of none immune factors; Use of protocol biopsies in this setting could be valuable by identifying CNI nephrotoxicity in patients with stable allograft. Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis 5- use of protocol biopsy in clinical trials designed to prevent CAN use of protocol biopsies as a primary efficacy variable could well become a useful tool in the design of future trials aimed at preventing CAN; power calculations suggest that they may allow an important reduction in the number of patients involved in such trials, as well as reducing the follow-up time. 6- safety of protocol biopsy; Performing protocol biopsies seems to be relatively straightforward, with the procedure generally taking place in the outpatient clinic and patients being discharged a few hours after the procedure. Con: The Case Against Use of Protocol Biopsies 1-variation in reported incidence of SCR and CAN; although numerous reports suggest that the frequency of SCR and CAN in early protocol biopsies may be high, the lack of consistency between studies casts doubt on the use of these data to support adoption of protocol biopsies in the routine treatment of kidney transplant patients. 2-reliability of SCR and CAN diagnosis; the optimal timing of protocol biopsy and reliable methods to quantify the histologic changes observed in biopsy specimens have yet be determined . 3- how should utility of protocol? An additional problem for general implementation of protocol biopsies is that the optimal timing and frequency for such biopsies has not been evaluated. Furthermore, it is unclear whether decisions for intervention should be made on serial biopsies or based on a single biopsy result. If therapy decisions are to be made on serial biopsies, then it will be necessary to analyze the results of such biopsies in a standardized manner, which is problematic. Conversely, a single biopsy is likely to result in a high degree of inaccuracy. 4- treatment for SCR and CAN; the benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown, as most studies give anti-rejection treatment for SCR as soon as it is detected. The appropriate management steps to be taken after detection of CAN in a protocol biopsy may also not be clear cut, because it must be proved that the CAN will respond to therapy .
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Ala Ali
Admin
3 years ago
If you are practicing transplantation, please reflect on your experience in performing protocol biopsy?
With all these potential advantages of protocol biopsies, why some transplant units are not performing it? What are your thoughts?
I think part of the causes are patient related as some patients refuses to do these biopsies when they have normal graft function, other causes are related to the cost and the availability of the facilities to apply such protocol, so we need to educate the patients about the benefit of doing these biopsies at least till a less invasive markers of early rejection are available.
We don’t do protocol biopsy in our practice.
Many people don’t do it simply because they don’t know what to do with it. Some increases immunosuppression but this approach works better for clinical rejection rather than sub-clinical rejection.
The reason of not performing protocol biopsies in our program is because ours is a living related program with majority of the transplants between siblings and parent-child relations with most having a mismatch of <3/6.
The patients are hesitant in getting a biopsy done in presence of a normally functioning graft and the transplant team is also not very enthusiastic in view of a stable graft function.
Assafi Mohammed
3 years ago
Protocol Transplant Biopsies Protocol biopsies: are surveillance biopsies performed during the first year after kidney transplantation, to identify early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment.
Traditionally, renal allograft biopsies are performed mainly in the setting of acute graft dysfunction.
By the time the clinical diagnosis is confirmed histologically by biopsy, the renal scarring incurred is often too advanced to make delayed treatment a realistic option.
Persistent, unrecognized inflammatory injury, secondary to a low-grade rejection process, may result in long-term graft fibrosis and chronic dysfunction in the absence of episodes of overt clinical rejection.
Surveillance or protocol biopsies, which are performed during the first posttransplantation year irrespective of graft function:
May be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are amenable to treatment.
The benefit of protocol biopsies is largely unproved, and the strategy has yet to be widely implemented.
Pro: The Case for Use of Protocol Biopsies 1.Detection of Subclinical Rejection Although a clear link between Sub-Clinical Rejection (SCR) and subsequent development of CAN has not been proved, some studies suggest that SCR leads to long-term deterioration of graft function and that early intervention may well improve outcomes.
In one study, the outcome of renal transplant patients who underwent protocol biopsies at 1, 2, 3, 6, and 12 mo (biopsy group) was compared with that of patients who received protocol biopsies at months 6 and 12 only (control group). Corticosteroid treatment of SCR detected in the early postoperative period (1 to 3 mo) was found to be associated with an improved outcome. In particular, compared with control subjects, patients in the biopsy group had a significant decrease in early (months 2 and 3; 69 versus 41%, respectively; P= 0.02) and late (months 7 and 12; 33 versus 11%; P = 0.03) acute rejection episodes, showed less chronic damage at month 6 (chronic tubulointerstitial score 1.02 versus 0.5; P=0.12), and had a lower serum creatinine at 2 yr (183 versus 133 micromol/L; P = 0.05).
Further evidence for a benefit of treating SCR has been provided by two reports in which early protocol biopsies were obtained at 3 mo post-transplantation; untreated SCR was found to be correlated with an increase in interstitial fibrosis and tubular atrophy in later biopsies in both studies.
A recent study has reported a continuous correlation for both acute rejection and borderline rejection, between the degree of functional graft impairment at the time of biopsy (protocol biopsies performed at 6 wk and 3 and 6 mo) and outcome at 1 yr (acute rejection, r= 0.40, borderline rejection, r =0.34; P = 0.01).
A 10-yr study of 304 patients with stable graft function, those with borderline changes or SCR in protocol biopsy specimens at 14 d post-transplantation were found to have a higher incidence of acute rejection than those with normal biopsies (0.48 and 0.60 versus 0.23, respectively; P= 0.05). Moreover, the graft survival rates in patients with SCR in day 14 biopsies in this study were lower than those with normal or borderline changes at 1 yr (88.4 versus 97.9 and 99.1%; P =0.05), 5 yr (77.8 versus 96.2 and 95.9%; P= 0.05), and 10 yr (62.3 versus 96.2 and 93.7%; P= 0.05). These data thus suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
2.Diagnosis of CAN by Protocol Biopsy
The frequency of CAN in early protocol biopsies up to 6 mo post-transplantation has been reported in a number of studies, with incidences of up to 79%,early protocol biopsies have shown that the presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival.
In one study of 98 kidney transplant recipients, protocol biopsies were performed at 3 mo post-transplantation . Com- pared with patients without CAN, those with CAN detected by protocol biopsy had an increased incidence of acute rejection before the biopsy (3.9 versus 24.3%, respectively; P= 0.003), a higher mean cyclosporine level prebiopsy (214 versus 242 ng/ml; P= 0.049), and lower actuarial graft survival (94.4 versus 80.5%; P = 0.024). Conversely, late allograft outcome in patients with borderline changes in this study was comparable to that of patients with normal histology.
An additional study—in which a chronic graft damage score was used to categorize the degree of chronic changes—has reported that early chronic pathology, detected by protocol biopsy at 6 mo, predicted graft function and loss at 2 and 3 yr post-transplantation
3.Protocol Biopsies Are Valuable in High-Risk Recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention. For example, delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to prevent adverse long-term graft outcome.
It is extremely difficult to diagnose graft rejection in patients with DGF on purely clinical grounds. Accordingly, there is a strong need for a means of promptly diagnosing acute rejection in patients with DGF, a need that may be met by protocol biopsies.
The usefulness of protocol biopsies in detecting SCR in pa- tients with DGF was examined in a study of 83 renal transplant patients, 33 of whom had DGF. SCR was detected in 7-d protocol biopsy specimens in 18% of patients with DGF versus 4% of patients with early graft function.
In another study of 410 kidney transplants, protocol biopsies were performed at 7 and 10 d post-transplantation; the risk for graft failure from acute rejection in patients with DGF was found to be 2.91 and was similar to the risk from early acute rejection in patients without DGF (2.95)
Further evidence for the benefit of protocol biopsies in high- risk patients has been provided by a study conducted in 230 renal transplant patients grouped according to pre-transplant antibody status. Humoral/vascular acute rejection was detected in 17% of biopsies performed 10 to 30 d post-transplantation, 53% of which were in recipients with antibodies to class I HLA antigens, 25% in recipients with class II antigens, and 75% with both class I and II. Protocol biopsies thus may be an effective way of detecting subclinical antibody-mediated acute rejection in sensitized high-risk renal transplant recipients.
4.Detection of Graft Dysfunction as a Result of Nonimmune Factors
Use of protocol biopsies in the setting of non-immune conditions causing rejection( eg; CsA toxicity) could be valuable by identifying eg; cyclosporine nephrotoxicity in patients with stable renal allografts and then accurate plan of management will be clear.
One study, in which protocol biopsies were performed on renal transplant recipients 12 mo after transplantation; evidence of cyclosporine nephrotoxicity was found in up to 42% of specimens.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis. a recent study of 547 renal transplants in which biopsies were performed at 4, 12, and 24 mo post-transplantation; SCR was observed in 3.5, 2.2, and 2.0% of biopsies, respectively, and subclinical BKV nephritis was detected in 2.6, 5.0, and 2.0% of samples that were taken the same time points.
Moreover, one transplant center has detected no new cases of polyomavirus nephropathy since implementation of a monitoring program for BKV infection involving protocol biopsy coupled with urine, serum, and plasma sampling.
5.Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
Evidence suggests that the natural history of CAN may be modified by pharmacologic intervention, yet results from large, randomized, prospective trials that evaluate therapies to prevent or treat CAN are lacking.
No prospective methods to monitor the appearance/progression of CAN are available currently for the kidney; thus, clinical trials that are conducted in renal transplant patients, by necessity, need to use surrogate markers of long-term graft survival.
Protocol biopsies from patients with stable grafts may be useful to monitor the progression of CAN and may be a valuable tool in the design of future trials aimed at modifying its natural history.
Protocol biopsies could well become a useful primary efficacy variable in trials aimed at preventing CAN.
6.Safety of Protocol Biopsies
Use of protocol biopsies has been limited in some centers by concerns over their safety; nevertheless, a number of studies suggest that the procedure is safe . For example, a retrospective audit of sequential protocol biopsies performed in four transplant centers has revealed a low incidence of clinically significant complications after protocol biopsy. Of the 2127 biopsy events assessed for major complications and 1486 for minor ones, there were three episodes of hemorrhage and three episodes of peritonitis, and three patients required transfusion. No deaths were observed, and only one graft was lost; all complications presented within 4hrs of biopsy.
Of 277 renal biopsies that were performed in a single-center study, there was only one (0.4%) serious hemorrhagic complication .
A study of 1171, protocol biopsies has reported rates of major complications of just 0.7% when a 16-gauge needle was used to perform the procedure and 1% when an 18-gauge needle was used.
Performing protocol biopsies seems to be relatively straightforward, with the procedure generally taking place in the outpatient clinic and patients being discharged a few hours after the procedure. Indeed, transplant recipients’ compliance with the procedure is high, with the consent rate in one center reported to be=90%.
Con: The Case Against Use of Protocol Biopsies 1.Variation in Reported Incidence of SCR and CAN
The incidences of SCR and CAN reported in biopsy specimens thus far have differed widely, with the incidence of SCR in the first 6 mo post-transplantation varying from 1 to 29% and CAN from 0 to 79%. Furthermore, it is difficult to draw any firm conclusions on the frequency of SCR and CAN from these studies as methodologic differences between studies make comparisons problematic.
A number of explanations exist for the differences in SCR incidence reported between studies:
One possible reason may be differences in human leukocyte antigen (HLA) matching.
The variation may be due to differences in the incidences of DGF between studies.
The impact of the immunosuppressive protocol used. Indeed, Nickerson et al. showed that increasing baseline immunosuppression reduces the frequency of clinical but not subclinical rejection. This indicates that studies that use a higher initial level of immunosuppression may well produce a higher proportion of patients with SCR.
Some studies include few patients and that precise inclusion criteria in many studies are not reported.
The reported frequency of CAN in early protocol biopsies also varies considerably, with the changes observed being relatively mild, chronic lesions, usually classified as Banff grade 1.
It should be noted, however, that age-related, chronic renal changes can resemble those of CAN, yet four of the five studies mentioned did not control for donor changes by undertaking a donor biopsy. The remaining study reported an incidence of donor chronic changes of 54% and an incidence of new CAN of only 26% . This suggests that donor-related changes may explain a large proportion of the variability in the reported incidence of CAN. This is supported by a recent study that reported that donor variables had little effect on acute histopathology scores in protocol biopsy specimens taken at 6 to 12 mo posttransplantation, although donor variables (e.g., deceased donor, increasing age, female gender, hypertension) explained approximately one third of the variability observed in chronic histopathology scores.
The methodologic problems associated with the reporting of the incidence of SCR may also apply to the interpretation of CAN incidence data.Thus, although numerous reports suggest that the frequency of SCR and CAN in early protocol biopsies may be high, the lack of consistency between studies casts doubt on the use of these data to support adoption of protocol biopsies in the routine treatment of kidney transplant patients.
2.Reliability of SCR and CAN Diagnosis
Assessment of the histologic changes detected by protocol biopsy is fraught with difficulties as all transplants generate an immune response to some degree, rendering analysis of histologic criteria for rejection in protocol biopsies problematic.
The lack of reliable methods to quantify histologic changes in protocol biopsies has led to such specimens’ being evaluated by use of Banff ’97 criteria. However, Banff criteria were devised to evaluate diagnostic biopsies for which the findings are likely to be more easily interpretable, not protocol biopsies for which the degree of interstitial fibrosis is mild, particularly in early biopsies (0 to 20%). This leads to a high probability of misclassification of biopsies with borderline changes or grade 1 CAN.
a recent study reported a decreased incidence of SCR when mycophenolate mofetil was used as the primary immunosuppressant compared with patients without such treatment (odds ratio 0.23; P =0.05).
an additional study, 310 protocol biopsies were obtained from 155 patients at 4 and 14 mo posttransplantation, and lesions were graded according to Banff criteria. Graft survival was found to be significantly better in patients without CAN versus those with CAN at both time points (P = 0.05 for both comparisons), with the incidence of CAN progressing from 40% at month 4 to 53% at month 14. However, approximately 25% of the biopsy specimens could not be classified properly, and the increase observed in the incidence of CAN between months 4 and 14 was lower than the proportion of misclassified biopsies. This suggests that evaluation of two sequential protocol biopsies (taken at months 4 and 14) by Banff criteria is not an accurate way of monitoring the progression of CAN in renal transplant patients and that care must be taken in interpreting the results of protocol biopsy specimens.
3.How Should Utility of Protocol Biopsies Be Tested?
To date, good evidence supporting the general implementation of protocol biopsies into clinical practice is lacking.
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points.
An additional problem for general implementation of protocol biopsies is that the optimal timing and frequency for such biopsies has not been evaluated.
It is unclear whether decisions for intervention should be made on serial biopsies or based on a single biopsy result.
If therapy decisions are to be made on serial biopsies, then it will be necessary to analyze the results of such biopsies in a standardized manner, which is problematic.
Conversely, a single biopsy is likely to result in a high degree of inaccuracy.
4.Treatment for SCR and CAN
The presence of mononuclear infiltrates in renal allografts does not necessarily indicate rejection, and some recipients maintain good long-term graft function despite signs of SCR.
The benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown, as most studies give anti-rejection treatment for SCR as soon as it is detected.
The appropriate management steps to be taken after detection of CAN in a protocol biopsy may also not be clearcut, because it must be proved that the CAN will respond to therapy. CAN detected at 5 yr is rarely therapy responsive; thus, it is likely that the appropriate management for CAN detected at 6 mo or 5 yr posttransplantation are different.
In our practice we don’t attempt protocol biopsy. Graft biopsy is only considered when there’s clinical suspicion of rejection that may benefit from graft biopsy and further plan of management based mostly on the biopsy findings.
Weam Elnazer
3 years ago
Protocol biopsies to detect CAN and SCR in stable renal allografts are a huge step forward in the attempt to enhance long-term transplant outcomes.
Due to a lack of evidence, it is difficult to determine if protocol biopsies increase long-term graft function and survival, and whether treating SCR discovered by protocol biopsy is beneficial.
In the absence of a clinical diagnosis, early identification and treatment of CAN may promote long-term graft function. Protocol biopsies are also safe and may help treat renal transplant patients, according to research. Also, using protocol biopsies as a key effectiveness measure may help future studies focused on avoiding CAN.
There are three possible strategies, which units may consider:1- no protocol biopsies; 2-biopsies only in high-risk individuals or 3- a universal screening protocol biopsy program:
1 –No biopsy. This is the default position of the vast majority of transplant units worldwide and assumes that either SCR is unimportant and can be ignored, or that is relevant but can be controlled by high-dose anti-rejection therapy. Penalties from heavy immunosuppression include increased rates of BK nephropathy, nosocomial infections and post-transplant lymphoproliferative disease.
2- Individualized biopsy. This involves the selection of higher-risk individuals for protocol biopsy at one or more predetermined time intervals to establish (or exclude) the diagnosis of SCR. It is cheaper than universal biopsy programs but practical disadvantages include patient selection (defining who is ‘high risk’).
3 –Universal biopsy policy. Protocol biopsy is used to detect and treat SCR in all recipients as the standard of care. Advantages include simplicity of implementation; detection of unsuspected SCR in low-risk individuals; aiding clinical decision making (e.g. renal dysfunction soon after normal protocol histology usually means CNI nephrotoxicity) and early detection of other diagnoses such as polyomavirus nephropathy. Disadvantages include costs, consumption of clinical and pathology resources, workforce capability.
I prefer individualized biopsy in my practice.
Heba Wagdy
3 years ago
Renal allograft biopsies are usually performed to confirm the clinical diagnosis histologically.
Recent studies showed that chronic allograft nephropathy (CAN) and acute rejection may be subclinical without decline in kidney functions leading to delayed diagnosis and delayed start of treatment which may affect graft outcome.
Protocol biopsies during first year post transplant could help in detection and early treatment of SCR and CAN but this benefit is still unproven Pro: Detection of subclinical rejection:
Studies showed that
Incidence of subclinical rejection detected in early protocol biopsies was up to 30%
early detection and treatment of SCR is associated with reduced rate of early and late rejection
untreated SCR is associated with increased interstitial fibrosis and tubular atrophy.
Diagnosis of CAN by protocol biopsy:
Studies showed that
CAN is detected frequently in protocol biopsies especially in first 6 months and was associated with lower rate of graft survival and increased incidence of acute rejection
Early detection of interstitial and vascular chronic damage had better outcome as this damage progress rapidly in the first 6 months
Delayed graft function (DGF) was associated with decreased graft survival due to silent acute rejection so protocol biopsy could help in prolonged DGF
Subclinical AMR was detected in 17% of protocol biopsies performed in sensitized high risk recipients in day 10 to day 30
Detection of graft dysfunction due to non immune factors:
Protocol biopsies can detect cyclosporine nephrotoxicity (before deterioration of kidney function) and Subclinical BK virus nephritis
Use of protocol biopsy in clinical trials to prevent CAN Studies showed that CAN could predict long term graft survival and incipient chronic tubulointerstitial lesions with shorter follow up time than other predictors.
Safety of protocol biopsies
Studies showed that graft biopsy is safe with low incidence of complications
Con: Variation of reported incidence of SCR and CAN
The incidence of early SCR varied from 1-29% in different studies due to difference in HLA matching, incidence of DGF and immunosuppressive protocols used.
The incidence of early CAN also varied from 0-79% in different studies, this may be due to donor related factors, the changes detected are relatively mild lesions and similar to age related renal changes.
Reliability of SCR and CAN diagnosis
Histological changes are difficult to be detected as degree of interstitial fibrosis is mild.
Protocol biopsies are evaluated by Banff criteria which are designed to evaluate diagnostic biopsies with different degree of fibrosis
Recent studies showed that new immunosuppressive agents (mycophenolate mofetil, azathioprine) decreased the incidence of SCR so decreased the need for protocol biopsies
How should utility of protocol biopsies be tested:
The evaluation of utility of protocol biopsies should consider differences between clinical trials in patient selection, induction therapy used and immunosuppression protocol.
5-year graft survival should be the endpoint to evaluate long term outcome.
The optimal timing and frequency of biopsy is not determined.
It is not clear whether therapy decision should be based on single or serial biopsies
Treatment of SCR and CAN:
Studies showed that
treatment of SCR was not associated with better graft survival
untreated SCR was not an adverse prognostic factor
increasing immunosuppression was associated with reduction of frequency of clinical rejection not SCR so the advantage of treatment of SCR is doubtful
The time during which CAN would respond to treatment is not well determined as the underlying mechanism of CAN may differ with window of time.
In my practice, protocol biopsy is not performed, only diagnostic biopsies.
Ahmed Saleh
3 years ago
summarise pros and cons of protocol biopsy Pros Detection of subclinical rejection:
Defined as histological evidence of rejection despite stable graft function, one study showed better outcomes in patients who underwent protocol biopsy at 1, 2, 3, 6, and 12 months compared to patients who underwent graft biopsy at 6 and 12 months only post-renal transplantation. Therefore, early detection of SCR may prevent further deterioration and improve graft outcomes in long term (1).
Early diagnosis of chronic allograft nephropathy
Number of studies reported that CAN may develop post-renal transplantation as early as 6 months and the incidence of CAN may reach up to 79%, Therefore, the importance of protocol biopsy may be valuable in detecting early signs of chronic allograft nephropathy which is not clinically apparent yet (2,3).
Detection of non-immune factors of graft dysfunction
As :
1- Cyclosporin cytotoxicity
2- BKV nephropathy
Both of the above causes should be reversible or treatable by immunosuppression modification/reduction therefore, protocol biopsy again showed an advantage here.
Cons
Wide variation in reporting SCR and CAN
We can tell from reported studies that there is a wide range reported for the incidence of SCR (1-29%) AND CAN (0- 79%)
Why?
Regarding SCR
i. The differences in human leukocyte antigen (HLA) matching, which will reflect on the risk of rejection and SCR
ii. If a study already excluded DGF patients and another study included them in the study, therefore, there will be a difference in the pool of patients involved and consequently this will affect final results as DGF is known to be a risk factor for rejection.
iii. Different immunosuppression protocols used in different studies will affect the incidence of SCR (4)
Regarding CAN
Age-related changes can be histologically similar to CAN, therefore the diagnosis of CAN might be overestimated and one study confirmed that possibility when it showed that The incidence of donor chronic changes of 54% and an incidence of new CAN of only 26% (5).
Conclusion and own reflection
Therefore despite numerous studies suggesting that early protocol biopsies can detect SCR and CAN early and consequently can improve long term outcome, however, the lack of consistency between studies made it hard to adopt routine protocol kidney biopsy in renal transplant, actually, this is one of the reasons we dont adopt routine renal graft biopsies in my transplant unit. Another factor that supports not doing routine transplant biopsy at our unit is that the presence of mononuclear infiltrates doesn’t confirm rejection or SCR, even with histological signs of SCR, some patients can have a long-term good graft function. Moreover, when it comes to managing SCR it is very difficult to have a consensus on whether to treat or not as Robert et al, reported in their study that day 7 post-transplant graft biopsy is strongly predictive for subsequent clinical rejection, however, day 28 post-transplant graft biopsy showing SCR and borderline changes which werent treated, didn`t have an adverse impact on the long term which was measured by graft survival and mean serum creatinine at 1 and 6 years post-transplantation (6). This raises the question about The clinical relevance and the benefits of treating SCR detected by protocol biopsy.
Additionally CAN detection in protocol graft biopsy is controversial when it comes to management as we need first to know whether CAN is likely to be reversible and when is the ideal time for intervention to be able to reverse it, if we manage to answer this question then protocol biopsy to detect CAN can be timed accordingly.
References:
1- Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, Cheung E, Allen RD, O’Connell PJ, Chapman JR: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71: 515–523, 2001
2- Seron D, Moreso F, Ramon JM, Hueso M, Condom E, Fulladosa X: Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy. Transplantation 69: 1849–1855, 2000
3- Nicholson ML, McCulloch TA, Harper SJ, Wheatley TJ, Edwards CM, Feehally J, Furness PN: Early measurement of interstitial fibrosis predicts long-term renal function and graft survival in renal transplantation. Br J Surg 83: 1082–1085, 1996.
4- Nickerson P, Jeffery J, Gough J, Grimm P, McKenna R, BirkP, Rush D: Effect of increasing baseline immunosuppression on the prevalence of clinical and subclinical rejection:A pilot study. J Am Soc Nephrol 10: 1801–1805, 1999.
5- Kuypers DRJ, Chapman JR, O’Connell PJ, Allen RDM, Nankivell BJ: Predictors of renal transplant histology at three months. Transplantation 67: 1222–1230, 1999
6- Roberts ISD, Reddy S, Russell C, Davies DR, Friend PJ, Handa AI, Morris PJ: Subclinical rejection and borderline changes in early protocol biopsy specimens after renal transplantation. Transplantation 77: 1194–1198, 2004
Last edited 3 years ago by Ahmed Saleh
Doaa Elwasly
3 years ago
Acute rejection episodes and Chronic allograft nephropathy (CAN) can be subclinical without causing a noticeable affection of graft function due to low grade rejection process occurring resulting in long term fibrosis leading to chronic graft dysfunction which justifies performing graft biopsies within the first year of transplantation on screening bases without overt graft dysfunction.
On the other hand protocol biopsies are not put as a routine procedure in following renal transplant patients . PROS of doing the biopsy
–Detection of Subclinical Rejection(SCR)
SCR leads to long-term worsening of graft function and early intervention can improve the outcome as studies showed that early treatment with corticosterois can improve long term graft survival,while untreated SCR had an increase in interstitial fibrosis and tubular atrophy in later biopsies as publisehed in 2 studies.
Acute rejection and borderline rejection, collorated with the degree of functional graft impairment at the time of biopsy and outcome at 1year .
Studies concluded that protocol biopsies can detect early and enhances treatment of acute and borderline rejection which in turn preserves long-term graft function. –Diagnosis of CAN by Protocol Biopsy
The first few months after transplantation are crucial for the occurrence of CAN and protocol biopsies can be important in detecting early chronic allograft damage that will appear later as early protocol biopsies revealed tubulointerstitial damage and vascular chronic damage which are indicative of allograft survival
Also it revealed that interstitial and vascular chronic damage exaggerates during the first 6 months after transplantation, then slowly after wards . -Protocol Biopsies Are Valuable in High-Risk Recipients
Delayed graft function (DGF) is accompanied by poor long-term graft survival, and early treatment is mandatory which cannot be diagnosed on clinical bases ,only discovered by biopsy.
Studies concluded that reduced graft survival with DGF can be due to silent acute rejection, therefore protocol biopsies and treatment of SCR during prolonged DGF is essential .
Also protocol biopsies can detect subclinical antibody-mediated acute rejection in sensitized high-risk renal transplant patients . –Detection of Graft Dysfunction as a Result of Nonimmune Factors
Non immunological factors are the most common to cause graft dysfunction as cyclosporine nephrotoxicity, but it is reversible if detected early enough, therefore protocol biopsies is important in discovering cyclosporine nephrotoxicity in those with stable renal allografts.
Another example is detection of subclinical BK virus (BKV) nephritis managed by reduction of immunosuppression doses which can improve the outcome . Con: The Case Against Use of Protocol Biopsies Variation in Reported Incidence of SCR and CAN
The incidence of SCR in the first 6 months after transplantation varying from 1 to 29% and CAN from 0 to 79% , also a precise conclusion on the frequency of SCR and CAN from such studies was difficult could be due to differences in human leukocyte antigen (HLA) matching, or due to differences in the incidences of DGF between studies,or the level of different immunosuppression used in each study as well as the inclusion criteria and interpreting CAN incidence data. Reliability of SCR and CAN Diagnosis Assessment of the histologic changes
is in fact difficult so new molecular techniques was developed, as identification of pro inflammatory transcripts in tissue or urine by PCR,urine spectroscopy ,and measuring of cell activation markers, which is not applied till now
So Banff criteria was used to evaluate diagnostic biopsies not protocol biopsies .
To evaluate the benefit of protocol biopsies in terms of long-term survival and function, outcome should include a minimum of 5-yr graft survival and function end points.
It is a grey zone whether to treat SCR or not as some studies showed that increasing immunosuppression reduced the frequency of clinical rejection but not SCR.
Another aspect is the gap of time during which CAN will respond to therapy need to be estimated before the appropriate timing for protocol biopsies can be known .
Professor Ahmed Halawa
Admin
3 years ago
Dear All Many of you mentioned protocol biopsy if there is graft disfunction. It would not be called protocol biopsy. It will be a diagnostic biopsy.
Protocol biopsy is the biopsy at set interval without association of graft dysfunction.
Ban Mezher
3 years ago
One of the most difficult & important complication of renal transplantation is cute graft rejection with subsequent graft loss. Although the incidence of it decreased after using of more potent immunosuppression, but it is still problem due to chronic graft dysfunction.
Renal biopsy usually only done when there is a suspected clinical graft dysfunction, that confirmed by histological findings which may include advance fibrosis. Several studies suggest that graft dysfunction may be clinically inapparent but histological finding confirm low grade rejection that can be progressed to graft fibrosis & dysfunction. So protocol biopsied may have a role in improve graft survival especially in first year post transplantation.
Sub clinical rejection (SCR) defined as presence of histological features of acute rejection in absence of clinical signs of rejection, which can occur in 30% of protocol biopsies done in first 6 months post transplantation .
Several studies proved that protocol biopsies at 1, 2,3,6,12 months show a benefit from early diagnosis & treatment of SCR & borderline rejection on long term graft survival.
Another studies in adult & pediatrics show that protocol biopsies can detect interstitial fibrosis & vascular changed before occurrence of clinical graft failure.
It was found that protocol biopsies in high risk patients is important in patients with DGF which may be caused by SCR so early treatment can improve outcome. Also using of protocol biopsies in some centers can detect asymptomatic CNI toxicity & subclinical BKV infection.
The safety of protocol biopsies was a major concern so just few centers used it, but some studies proved that it is a straight forward procedure with low risk of major & minor complication. There were difference in the incidence of CAN & SCR between studies , this may be due to
difference in HLA matching
difference in DGF incidence
the changes may be due to age-related which resemble CAN changes
Protocol biopsy has a limitation that it using Banff criteria which evaluate changes in diagnostic biopsy while protocol biopsy may show mild interstitial fibrosis & this lead to misclassification of biopsy with borderline changes or CAN
Chronic allograft nephropathy is the commonest cause of late graft rejection and is strongly correlated with the incidence of acute rejection episodes during the first year after renal transplantation.
In most transplant centers, renal allograft biopsies are not routinely performed, instead, only done to evaluate the causes of kidney dysfunction. In some cases, clinical deterioration in kidney function only occurs when, already chronic histological changed are apparent.
Some reports suggested that episode of acute rejection or chronic allograft nephropathy could be subclinical, which means that recipient has normal kidney function detected by routine laboratory testing. In this context, unrecognized subclinical persistent rejection could lead to long-term graft interstitial fibrosis/tubular atrophy and chronic dysfunction.
Implementation of protocol biopsies regardless of allograft function could be of great benefit in individuals with risk of allograft rejection.
Pro: Detection of Subclinical Rejection: Some studies reported UO TO 30% incidence of acute subclinical rejection detected in protocol biopsies performed in the first 6 months post-transplantation. Protocol biopsies for early detection and treatment of acute rejection may be a major factor in preserving long-term graft function. Diagnosis of CAN by Protocol Biopsy: There is evidence that the development of CAN primarily occurs in the first few months after transplantation. In this setting, protocol biopsies may be a diagnostic in detecting early signs of subclinical chronic allograft damage. The presence of tubule-interstitial fibrosis and vascular –damage, which usually occur in the first 6 months following transplantation, are powerful predictors of allograft survival. Protocol Biopsies Are Valuable in High-Risk Recipients: Delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital. In pretransplant sensitized patients, protocol kidney biopsy is warranted to detect subclinical rejection. Detection of Graft Dysfunction as a Result of Nonimmune Factors: Nonimmune mediated kidney damage could also be cause of kidney injury. For example CNI renal toxicity even in the therapeutic ranges should be suspected. Because CNI nephrotoxicity is reversible protocol biopsies may be a useful. Protocol biopsies could also detect renal diseases such as subclinical BK virus (BKV) nephritis. Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN: Studies have shown that CAN diagnosed in protocol biopsy is an independent predictor of long-term outcome. Safety of Protocol Biopsies: Studies suggest that the procedure is safe and minor complication are rare.
Cons Variation in Reported Incidence of SCR and CAN: There are differences in the methodology between studies which make comparisons problematic. Studies also lack consistency these to support the adoption of protocol biopsies in the routine clinical practice. Reliability of SCR and CAN Diagnosis: Reliable methods to quantify histologic changes in protocol biopsies were lacking. The histologic criteria used in the studies differs and some used the old Banff criteria. How Should Utility of Protocol Biopsies Be Tested? The general implementation of protocol biopsies into clinical practice is lacking even in large multicenter hospital. Treatment for SCR and CAN: The presence of mononuclear infiltrates in renal allografts does not always indicate rejection, and some recipients maintain good long-term graft function despite signs of SCR.
The benefit of treating SCR detected by protocol biopsy need to be confirmed, because the effect of not treating SCR is unknown, because most studies give anti-rejection treatment for SCR when detected in protocol biopsies
In my clinical practice, allograft biopsy is not routinely done in protocol based form, but reserved for patients with kidney dysfunction.
With improvement of immunosuppression protocols acute graft rejection rates have markedly improved.
Chronic allo-graft nephropathy (CAN) which is the most common cause of late graft rejection and is strongly correlated with the number of acute rejection episodes during the first year after renal transplantation .
protocol biopsies performed during the first posttransplantation year irrespective of graft function, may be help in early identification acute rejection or CAN when treatment is still an option and no permanent scarring has occurred.
pros of protocol biopsies
1 early detection of histological subclinical rejection episodes which detected in up to one third of the patients in first 6 month ;even without clinical decline in graft function.
2 steroid treatment of SCR detected in the early postoperative period (1 to 3 mo) improved outcome with decrease in early and late acute rejection episodes, and patients showed less chronic damage at month 6 and had a lower s creatinine at 2 years posttransplantation.
3 untreated SCR was found to be correlated with an increase in interstitial fibrosis and tubular atrophy in later biopsies in 2 studies.
4 10- years study of 304 patients suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
5 the presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival number of studies showed that early detection and treatment of CAN have greatly improved long-term graft survival,frequency of CAN in early protocol biopsies up to 6 mo posttransplantation was high up to 79% and early protocol biopsies is very helpful in early detection of CAN befor decline in graft function.
6 Protocol biopsies have also been reported to be useful in the detection of CAN in pediatric transplant recipients.
7 protocol biopsies is very helpful in high risk patients as those with DGF allowing early detection and treatment to prevent long term adverse effects.
7 Protocol biopsy is effective for detecting subclinical AMR in sensitized recipients.
8 protocol biopsies also help to dignose other causes of graft failure such as cyclosporine nephrotoxicity which is correctable early and subclinical Bk virus nephritis.
9 the predictive value on graft survival of incipient chronic tubulointerstitial lesions in protocol biopsies was found to be superior to other predictors of outcome, such as acute rejection or serum creatinine.
10 protocol biopsies are generally safe
procedure with reported rates of major complications of just 0.7% when a 16-gauge needle was used to perform the procedure and 1% when an 18-gauge needle was used.
cons of protocol biopsies
1 No clear evidence on the ralation between SCR and subsequent development of CAN has not been proved.
2 a study on 98 patients showed late allograft outcome in patients with borderline changes was comparable to that of patients with normal histology.
3 incidences of SCR and CAN reported in biopsy specimens showed wide variations with the incidence of SCR in the first 6 mo posttransplantation varying from 1 to 29% and CAN from 0 to 79%.
4 chronic renal changes that occure with CAN may resemble those occurred due do doner factor as deceased donor, increasing age, female gender, hypertension.
5 SCR as mononuclear cell infiltration does not necessary mean rejection and benefit of treating SCR detected by protocol biopsy has yet to be confirmed. .
6 High percentage of protocol biopsies are found to be inadequate when using Banff criteria and that evaluation of two sequential protocol biopsies (taken at months 4 and 14) by Banff criteria is not an accurate way of monitoring the progression of CAN.
7 no clear studies support the benefit of protocol biopsies in renal transplant patients with stable kidney function yet and no standard timing for the protocol biopsies .
8 management steps after detection of CAN in a protocol biopsy is also not clear .
In my practice are not doing protocol biopsies and only perform biopsy for clinically evident allograft dysfunction
detection of subclinical rejection ( 30% in the first 6 months post transplant).
diagnosis of chronic allograft nephropathy(79% in the first 6 months post transplant).
for high risk patients as those with DGF and acute rejection
detection of graft dysfunction as a result of nonimmune factors such as CNI toxicity, BK nephropathy
the procedure is safe
CONS:
Variation in the reported incidence of subclinical rejection and chronic allograft nephropathy due to many factors such as the degree of HLA matching, incidence of DGF, immunosuppressive regimen, donor factors.
reliability of subclinical rejection and chronic allograft nephropathy diagnosis as all transplants generate an immune response to some degree making the analysis of histological criteria for rejection in protocol biopsies problematic.
optimal timing and frequency for such biopsies has not been evaluated.
lacking of good evidence to support the implementation of protocol biopsies.
benefit of treating subclinical rejection has yet to be confirmed
the appropriate management steps for chronic allograft nephropathy are not clear cut.
In our practice we do protocol biopsy only when the patient accepts the idea, otherwise the majority of the biopsies done at our center are for cause biopsies.
The presented article highlights one of the debatable subjects in the field of kidney transplantation which is the cost-effectiveness of implementing a protocol of routine kidney allograft biopsy.
The advantages of protocol biopsy can be summarized in the following points:
Ø It can detect histological evidence of rejection before it is apparent clinically.
Ø Early detection of immunological injury and subsequent early initiation of appropriate management is associated with a better long term allograft outcome.
Ø Allograft biopsy can also detect non-immunological causes of allograft dysfunction like BK nephropathy and CNI toxicity before they can cause irreversible clinical sequel.
Ø Allograft biopsy is easier than native kidney biopsy (due to its anatomical position to be easily accessed), which makes it relatively safe with a low incidence of serious complications.
On the other hand, some critical points need to be considered before adopting such a protocol as a universal recommendation, which includes:
· There is significant variability in the incidence of subclinical rejection (which is diagnosed by protocol biopsy) between different transplant centres and even between different transplant recipients subgroups.
· The histological findings in the protocol biopsy need standardization to define the clinically relevant histological criteria that require treatment.
· There is a lack of evidence regarding the benefit of early treatment of minor histological injury diagnosed by protocol biopsy.
In our practice, we do not have a protocol biopsy regimen in our hospital, and we perform allograft biopsy only upon clinical indications. Furthermore, our local population is usually afraid of invasive allograft biopsy. They are reluctant to agree to allograft biopsy unless they realize progressive deterioration of kidney functions.
Protocol biopsy
Chronic allograft nephropathy CAN is the major cause of graft failure, and is related to the numbers of acute rejection which happened throughout the whole life of the graft especially first year, and also subclinical rejection can happened without any reflection on renal function, so multiple attacks of subclinical rejection can end by scarring and CAN , at that time the treatment will be impossible, hence the role of protocol graft biopsy which should be done especially in the first year even with normal renal function.
Pros of protocol biopsy:
1- Detection of SCR (subclinical rejection) it is histological rejection without affection of renal function. Treatment of subclinical rejection with steroid of course will improve graft outcome and survival.
2- Diagnosis of CAN Occurrence of CAN may be related to multiple attacks of untreated subclinical rejection, and indicated by interstitial fibrosis and vascular damage which become faster early after transplantation and slower in late period post-transplant, they are strong predictor of graft survival. Early treatment and management of CAN will affect positively on graft survival.
3- Protocol biopsy is of high benefit in patients with DGF (delayed graft function), as in DGF patients, subclinical rejection may happened, and DGF and these patients vulnerable to SCR because of under immunosuppression status due to DGF mask it, so detection of SCR in those patients is very useful with serial biopsies in early period post-transplant.
4- Also should be done in the patients with DSA pretransplant, as they are at high risk of subclinical antibody mediated rejection, for early detection and management especially early post-transplant.
5- Detect early cyclosporine nephrotoxicity without marked graft function affection, so for early management.
6- Detection of subclinical infection as BK virus BK nephritis, because when happened will enforce us to decrease immunosuppression and expose the graft to be lost, so early detection by protocol biopsy can save the graft. In addition, detection of SCR with BK nephritis will not happened except by protocol biopsy.
7- Histopathological diagnosis of CAN in early period post-transplant indicated by vascular damage and interstitial fibrosis is the only tool to diagnose CAN, which is the strong predictor for graft survival.
8- Low incidence of its major complications in relation to its benefits regarding early diagnosis and management.
Cons of protocol biopsy 1- Variations in the reporting incidence of SCR in the studies may be related to low numbers of studies, low sample size, also presence of other factors like extent of HLA mismatch, immunosuppression protocol used, DGF. 2- Variations in the reporting incidence of CAN in the studies , may be also related to low sample size, low number of studies , and donor related changes (donor may refuse biopsy before transplant), also CAN can be mistaken for age. 3- No clear reliable method to measure or quantify the degree of CAN , as it depends on Banff 97 criteria which can be used in diagnostic biopsy not for protocol biopsy. 4- Introduction of MMF lower the incidence of SCR, so early biopsy not needed if not indicated clinically. 5- Implementation of protocol biopsy to improve graft survival and outcome should be tested for at least 5 years before general implementation , also timing when to do , and plan of therapy will be based on single biopsy or to wait for serial…so many problems. 6- Some studies showed that there is no difference between treatment of SCR and not to treat SCR on outcome and graft survival, also the evidence suggest that high immunosuppression status will not prevent SCR but prevent acute rejection will add no benefit in early detection of SCR for aim of its treatment.
Pros:
1-Detection of Subclinical Rejection
2-Diagnosis of CAN
3-High risk recipients e.g DGF
4-Detection of Graft Dysfunction as a Result of Nonimmune Factors e.g
cyclosporine toxicity and sub clinical BK Nephro patchy
No prospective methods to monitor the appearance/progression of CAN are available currently for the kidney; thus, clinical trials that are conducted in renal transplant patients, by necessity, need to use surrogate markers of long-term graft survival
Histologic changes in transplant biopsies provide the earliest available evidence of graft damage.
Safety should be considered as biopsy may lead to severe hemorrahge and loss of graft .
Cons:
1-Variation in Reported Incidence of SCR and CAN
2-Reliability of SCR and CAN Diagnosis: sometimes inadequate biopsy sample ,sometimes needs 2 serial biopsies to confirm diagnosis ,so we need new markers e.g urine spectroscopy and PCR to detect pro inflammatory transcripts
Another issue, that recent trials found that SCR incidence decreased with MMF and azathioprine introduction
So if protocol biopsies are indicated to diagnose CAN and SCR and in both biopsies may be inconclusive in diagnosis also ,if diagnosed there is no specific therapy for both of them.
Clinical experience : protocol biopsy not done
Sherif Yusuf
3 years ago
Currently renal biopsy is indicated when there is evidence of renal graft dysfunction such as renal impairment or occurrence of proteinuria
Protocol biopsy is doing renal biopsy for renal transplant patients in the first year of transplantation without the evidence of renal allograft dysfunction
Pros of protocol biopsy
1. Subclinical rejection (histologic evidence of acute rejection without clinically detected graft dysfunction) and CAN (histological evidence of tubulointerstitial damage and vascular chronic damage ) occur commonly in the first year (in up to 30%, and 79% of protocol biopsies, respectively) and these are associated with poor graft survival.
2. Early treatment of subclinical rejection (with corticosteroids) can improve renal allograft survival
3. Protocol biopsy has a prognostic significance since it can predict graft survival. the occurrence of CAN is associated with lower graft survival when compared to patients without CAN in protocol biopsy.
4. Aid in diagnosis of CNI toxicity which is common in first year post transplantation and is reversible cause of renal allograft dysfunction
5. Can detect subclinical BK virus nephritis which is common in first year post transplant with subsequent reduction of immunosuppression before occurrence of irreversible damage
6. Doing renal allograft biopsy in the setting of renal graft dysfunction means that there is sufficient injury to the kidney with possible fibrosis and irreversibility moreover the occurrence of frequent rejection episodes are associated with CAN and graft loss.
7. Renal allograft biopsy is relatively safe procedure with the incidence of major complication was reported by one study to be 0.7% when using 16-gauge needle and 1% when using 18-gauge needle.
Cons of protocol biopsy
1- No clear correlation between occurrence of subclinical rejection and long term graft survival, Moreover the impact of treatment of subclinical rejection on long term graft survival has not been proven in all studies.
2- No clear protocol is set but it was found that there is no difference when protocol biopsies are done at 1, 2, 3, 6, and 12 months and if it was done at months 6 and 12 only.
3- Problems in diagnosis :
⦁ In SCR as mononuclear cell infiltration does not necessary mean rejection
⦁ In CAN can be confused with chronic allograft changes due to donor characteristics such as age, female gender, HTN or deceased donor kidney.
⦁ High percentage of protocol biopsies are found to be inadequate when using Banff criteria
4- Problems in treatment :
⦁ In SCR intensification of immunosuppression was found to decrease the incidence of clinical but not subclinical rejection suggesting a doubt in the effect of treatment of SCR
⦁ In CAN no definite plan in the treatment of early detected CAN
Patients that may benefit from of protocol biopsy
1- Sensitized high risk patients since the incidence of subclinical ABMR is extremely high in this group.
2- Patients with DGF a 7-day protocol biopsy was found to be of great significance since the occurrence of subclinical rejection in this group is more common, and co treatment of SCR may improve outcome.
Clinical experience
We are not doing protocol biopsies and only perform allograft biopsy in the setting of allograft dysfunction
Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%.With Tacrolimus it is 2.6%.
it is better to treat SCR as it progresses to chronic allograft nephropathy.
Subclinical rejection in tacrolimus-treated renal transplant recipients James M Gloor
52% pts experienced subclinical rejection in sentisized patients at 3rd month protocol biopsy.
Time course of histologic injury in total of 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch HLA-incompatible kidney between 2000 and 2010 (follow up: 1-9 years). (Bagnasco et al Transplantation 2014).
1)with the introduction of tacrolimus the incidence of SCR is 2.6% and surveillance biopsies may not be necessary with this regimen. 2) cost factor as most patients here pay from their pocket. 3) in our unit after an indication biopsy patient developed hematuria which just didnt resolve, so explaining to a patient if such an event happens after a protocol biopsy would be difficult in our setup.
Pros for protocol biopsies
1)SCR leads to long-term deterioration of graft function and its detection and early intervention may well improve
outcomes .
2)early detection and treatment of CAN could have a dramatic effect on the outcome of the graft.
3) there is a strong need for a means of promptly diagnosing acute rejection in patients with DGF.
4)Will be of help to identify non immunologic cause of graft dysfunction.
5)Procedure is safe with low incidence of clinically significant complications after protocol biopsy.
Cons for protocol biopsies
1)variable results from previous studies about incidence of CAN and SCR casts doubt about the adoption of protocol biopsies in routine treatment.
2)no histological criteria to uniformly label protocol biopsies into various categories.
3)optimal timing and frequency of protocol biopsies is subjective, plus should decisions be taken on serial biopsies or a single biopsy is not clear.
4)clear proof that treating SCR and CAN on protocol biopsies improves long term outcome is lacking .
Many of you rightly mentioned subclinical rejection
Cyclosporine was associated with SCR & borderline rejection more when compared with tacrolimus. And it was found that among patient with high immunological risk the using of protocol biopsy has a great value in diagnosis of SCR, & treatment of SCR improve graft outcome.
Dear Dr Ahmed,
The incidence of subclinical rejection is variable due to variable inclusion criteria in different studies.
The use of Tacrolimus was associated with a subacute rejection prevalence of 4.6% only in comparison to about 30% with the previous immune suppression a decade earlier (1).
2. How common in highly sensitized patient?
The incidence of subacute rejection may reach up to 36% in sensitized patients (2).
3. Would it be better to treat it? why?
The detection of subacute rejection is associated with a worse allograft outcome (1). Therefore, I will proceed with anti-rejection measures once subclinical rejection is detected.
References:
1) Daniel C Brennan, Tarek Alhamad, and Andrew Malone. Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection. © 2021 UpToDate. (Accessed on 30 November 2021).
2) Yamanaga S, Watarai Y, Yamamoto T, et al. Frequent development of subclinical chronic antibody-mediated rejection within 1 year after renal transplantation with pre-transplant positive donor-specific antibodies and negative CDC crossmatches. Hum Immunol. 2013 Sep; 74(9):1111-8.
Excellent answer Ahmed
subclinical ABMR at 1 year has 3.5 fold increase in graft loss independent on immunological status high risk or not, DSA de novo or not, presence or absent of comorbidities.
subclinical T cell mediated rejection also associated with poor graft survival at one year but less than subclinical ABMR.
incidence of SCR in tacrolimus based regimen is lower.
treatment of SCR early with steroid has better prognosis
references:
1- James M Gloor , Ari J Cohen, Donna J Lager, Joseph P Grande, Mary E Fidler, Jorge A Velosa, Timothy S Larson, Thomas R Schwab, Matthew D Griffin, Mikel Prieto, Scott L Nyberg, Sylvester Sterioff, Walter K Kremers, Mark D Stegall. Subclinical rejection in tacrolimus-treated renal transplant recipients. Transplantation. 2002 Jun 27;73(12):1965-8.
2- D Rush , P Nickerson, J Gough, R McKenna, P Grimm, M Cheang, K Trpkov, K Solez, J Jeffery. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol. 1998 Nov;9(11):2129-34.
3- Terence Kee, Philip J O’Connell, Caroline L-S Fung. Treatment of Subclinical Rejection Diagnosed by Protocol Biopsy of Kidney Transplants. July 2006Transplantation 82(1):36-42.
4- Dewi Vernerey, Claire Tinel, Olivier Aubert,Jean-Paul Duong van Huyen, Marion Rabant, Jérôme Verine, Dominique Nochy, Jean-Philippe Empana, Frank Martinez, Denis Glotz, Xavier Jouven, Christophe Legendre, and Carmen Lefaucheur. Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts.J Am Soc Nephrol. 2015 Jul; 26(7): 1721–1731.
Excellent answer Riham
Subclinical acute rejection and chronic allograft nephropathy, in pre-transplant sensitized patients are common at 6 months post-transplant in kidney recipients with stable allograft function.
One study reported subclinical CMR in 39.7% of the biopsies at 1 month and >20% at all other time points. The presence of diffuse C4d on biopsies obtained at each time interval ranged from 20 to 30%, indicative of AMR.
In another study published in 2021, evaluating patients receiving tacrolimus as part of their maintenance therapy, using revised Banff criteria, detected subclinical inflammation in 31%, with the majority (75%) having a subclinical borderline phenotype (at least minimal inflammation with mild tubulitis.
Would it be better to treat it?
There is no RCT comparing SAR receiving immunosuppressive treatment to control groups. however it is known that patient with histologic signs of acute rejection, even with normal allograft function, are at high risk for graft loss. They are also at risk to develop interstitial fibrosis and tubular atrophy, which is independent risk factor for kidney loss.
References
DOI:10.1111/j.1600-6143.2009.02701.x
doi: 10.1097/TXD.0000000000001119
1/ Subclinical rejection: defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection.
{Transplantation.2002 Jun 27;73(12):1965-8. doi: 10.1097/00007890-20020627000023.
Subclinical rejection in tacrolimus-treated renal transplant recipients}
2/ DD transplant, presence of DSA and DGF were associated with a higher incidence of SCR
{Mehta R, Sood P, Cherukuri A, Chen S, Mour G, Wu C, Shah N, Puttarajappa C, Randhawa P, Tevar A, Hariharan S. Impact of Subclinical Rejection (SCR) and Acute Clinical (ACR) in Renal Transplant Recipients [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/impact-of-subclinical-rejection-scr-and-acute-clinical-acr-in-renal-transplant-recipients/. Accessed November 29, 2021.}
3/better to treat with MethylPred pulses.
**As the tacrolimus is more potent than cyclosporin one could predict that there may be no need for surveillance of routine biopsies (as may be supported by this study in 2002: Subclinical rejection in tacrolimus-treated renal transplant recipients, https://journals.lww.com/transplantjournal/Fulltext/2002/06270/Subclinical_Rejection_in_**Tacrolimus_Treated_Renal.23.aspx. one important point is this was an evaluation for two years. so this was reappraised as long-term follow-up still carries the risk of subclinical rejection. https://journals.lww.com/transplantjournal/Fulltext/2016/08000/Subclinical_Rejection_in_Renal_Transplantation_.13.aspx
**Early treatment of subclinical rejection well ameliorates changes and help increase graft survival
Transplantation: July 15, 2006 – Volume 82 – Issue 1 – p 36-42
doi: 10.1097/01.tp.0000225783.86950.c2
Yes, Mahmud
This why protocol biopsy is not a standard practice in the UK since the introduction of Tacrolimus.
Cya era is more common in causing subclinical rejection
SCR is highly prevalent in sensitized patients
If SCR not treated early will lead to poor graft outcome
How common in Tacrolimus era compared to Cya era?
Subclinical rejection is less prevalent in immunosuppressive protocols that use tacrolimus compared to CSA.
How common in highly sensitised patient?
It is common in highly sensitized patients( A study found it in 40-50% of patients with positive crossmatching in the first 2 months post transplantation).
Would it be better to treat it? why?
Patients with treated subclinical rejection had better graft outcome.
References:
1.Subclinical rejection is less seen in tacrolimus era compared to cyclosporine era .Some studies showed up to 30% subclinical rejection with cyclosporine.
2.In sensitised patient, subclinical rejection increases and this reason for protocol biopsy in this group of transplant population.
3.SCR is associated with long-term deterioration of graft function and early intervention may result in better outcome.
.
Subclinical rejection incidence is quiet variable it dependes on the degree of HLA matching , DSAs level , immunsuppressive protocal and the occurance of DGF
the rate is lower in the first six months post KTX due to the improvement of both the sensitivity of the HLA typing , DSA screening assay , in addition to the development in the immunsuppresive therapy.
– the incidence of SCR in tacrolimus based IS in much lower 4.6 % only compared to
> 30% in cyclosporine group(1).
-SCR with ABMR with diffuse and focal C4D staining was found in 2-2.4% in protocal biopies(2). even higher in senesitized patients with SCR-ABMR was up to 36% (1) and its assocaited with worse graft outcome .one study shows one year graft survival of 56% only compared with 885 in patinets with SCR – ACMR.
would you treat SCR :
—————————————————————
as per available evidnece there is no clear aggreament in regards SCR treatment
some centres preferred just to augment the current IS for example if patinet on cyclosprine based IS will modify to tacroimus based and target higher level 6-8 ng , with full dose MMF or some centres give short course steriods espically in ACMR and FU closely by DSA and protocal biopsy.
SCR preferred to be treated espcially in sensitazed patient with ABMR and DSA postive assay or denovo DSAs and the response to therapy depends on some histological fininding like those with less vascular intimal sclerosis, less arteriolar hyalinosis and IFTA likely will have better response to the treatment,
-SCR-TCMR ususlly steriod responsive and had better graft survival up to 90% in the first year which is comparable to non SCR group(1)
-patients with SCR with more chronic histological changes most likely will progress to chronic allograft nephropathy and the treatment will be hampered by the incresed risk of side effects like infection , malignancy .
References:
1-UPTo Date,kideny transplant in adult:Clinical features and diagnosis of acute kidney allograft rejection.2021 .
2-Subclinical rejection in tacrolimus-treated renal transplant recipients
James M Gloor 1, Ari J Cohen, Donna J Lager, Joseph P Grande, Mary E Fidler, Jorge A Velosa, Timothy S Larson, Thomas R Schwab, Matthew D Griffin, Mikel Prieto, Scott L Nyberg, Sylvester Sterioff, Walter K Kremers, Mark D StegallTransplantation2002 Jun 27;73(12):1965-8.
SCR was more common in cyclosporine era comparing tacrolimus era.
It is more common in highly sensitized patients.
It’s better to treat SCR because if left untreated is associated with worse graft outcome.
Subclinical rejection (SCR):
1. How common in Tacrolimus era compared to CyA era?
The subclinical rejection rates in cyclosporine era was upto 30%. (1) Subclinical rejection rates are lower in tacrolimus era, 4.6%. (2)
2. How common in highly sensitised patient?
In Sensitized patients, the incidence of SCR maybe as high as 36%. (3)
3. Would it be better to treat it? why?
Once a diagnosis of SCR has been made, it is better to treat as it has been shown to decrease early and late acute rejection as well as chronic graft damage. (1)
References:
1) Rush D, Nickerson P, Gough J, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998;9:2129.
2) Rush D, Arlen D, Boucher A, et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study. Am J Transplant 2007;7:2538-2545.
3) Yamanaga S, Watarai Y, Yamamoto T, et al. Frequent development of subclinical chronic antibody-mediated rejection within 1 year after renal transplantation with pre-transplant positive donor-specific antibodies and negative CDC crossmatches. Hum Immunol 2013;74:1111-1118.
1.Sub clinical rejection is less with tacrolimus based immunosuppression.
2.It is more common among highly sensitized patients.
3. Yes .it is better to treat sub clinical infection .
1-Subclinical rejection is much improved in Tac era compared to Cys era(4.6% vs 30% )
2-In sensitized patients, subacute rejection can reach up to 36%
3- Yes, it is better to treat as it is important to improve the graft outcome.
Uptodate,2021
Protocol biopsy it is the biopsy set with intervals without the association of graft dysfunction.
Chronic allograft nephropathy (CAN) and acute rejection may be subclinical without a decline in kidney functions leading to delayed diagnosis and delayed start of treatment which may affect graft outcome.
Protocol biopsies post-transplant could help in the detection and early treatment of SCR and CAN but this benefit is still unproven.
PROS of doing the biopsy
–Detection of Subclinical Rejection(SCR)
SCR leads to long-term worsening of graft function and early intervention can improve the outcome.
Con: The Case Against Use of Protocol Biopsies
Variation in Reported Incidence of SCR and CAN
The incidence of SCR in the first 6 months after transplantation varies from 1 to 29% and CAN from 0 to 79% .
The recent introduction of protocol biopsies in some centers to determine the presence of CAN and SCR in stable renal allograft should be seen as a major step forward in the quest to improve long-term transplant outcomes. Paucity of data has meant that clear proof that protocol biopsies improve long-term graft function and survival is lacking and that the benefits of treating SCR detected by protocol biopsy in particular are not
clearcut. However, available evidence suggests that early detection and treatment of CAN that cannot be diagnosed clinically will benefit long-term graft function. Furthermore, reports indicate that protocol biopsies are safe and that their use is likely to improve the treatment of renal transplant patients. In addition, use of protocol biopsies as a primary efficacy variable could well become a useful tool in the design of future trials
aimed at preventing CAN; power calculations suggest that they may allow an important reduction in the number of patients involved in such trials, as well as reducing the follow-up time.
An additional potential benefit of protocol biopsies may in differentiating chronic loss of renal function caused by immunologic causes from nonimmunologic causes. Nevertheless, future studies must focus on reliable methods to quantify histologic changes in protocol biopsies. Furthermore, large-scale, multicenter, prospective trials of protocol biopsies are required to determine the criteria and optimal timing for such biopsies and assess fully their place in the routine treatment of renal transplant patients.
There’s studies point that surveillance biopsy is useful in :
SCR.
chronic allograft nephropathy
delayed graft function, by allowing for early intervention for acute rejection.
Nevertheless, paucity of data has meant that clear proof of a benefit of early treatment
of subclinical rejection and chronic allograft nephropathy detected by protocol biopsy is
lacking.
Moreover, the optimal timing of protocol biopsies and reliable methods to quantify the
histologic changes observed in biopsy specimens have yet to be determined.
Detection of Graft Dysfunction as a Result of Nonimmune Factors .(BK nephropathy
,CNi nephropathy).
Safety of Protocol Biopsy:
Safe ,straightforward. Procedure.
Cons:
Protocol Biopsies Variation in Reported Incidence of SCR and CAN .
Reliability of SCR and CAN Diagnosis by Protocol biopsy.
How Should Utility of Protocol Biopsies Be Tested.
Timing of protocol biopsy ,no agreement.
Treatment for SCR and Can, still no agreement. That treatment of biopsy detected will
improve. CAN and reduce graft loss.
Reflection on our practice:
We are not using protocol. Biopsies in out center ,more LRD and triple immunotherapy
base on TAC and MMF.
1. In your own words, summarise pros and cons of protocol biopsy.
Protocol Biopsy during the first year postTx was of great value in early detection of subclinical graft lesions and unrecognized inflammatory injury, secondary to a low-grade rejection process that may with time end in long-term graft fibrosis and chronic dysfunction eventually graft loss. Early detection and intervention would offer great benefits to the graft survival.
Shall we consider this procedure in the routine follow up of post Tx patients?
Pro
Detection of Subclinical Rejection
Some studies suggest that SCR eventually ends in long term deterioration of graft function hence early detection and intervention would help improve outcomes (1). data thus suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
CAN
Evidence suggest that the development of CAN is preceded by the development of early histological chnges within the graft during the first few months early postTx (2). It thus follows that early detection and treatment of CAN could have a dramatic effect on the outcome of the graft.
in High-Risk Recipients
for early intervention and management of acute rejection episodes
DGF: delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to prevent adverse long-term graft outcome. However it is hard to diagnose AR in patient with DGF on clinical basis, hence a protocol biopsy in crucial.
Positive DSA Recipients: early intervention and detection of subclinical AMR episodes in highly sensitized patients
Detecion of graft dysfunction due to nonimmune factors:
CNI nephrotoxicity: One of the most common causes of graft failure, and is reversible if reduction of doses is done early enough.
BK nephropathy: leads to rapid decline in renal function and early detection of subclinical BK virus (BKV) nephritis is vital for early reduction of IS dose and ttt to save the graft.
Con:
Incidence of SCR and CAN : inconsistant
incidences of SCR and CAN reported in biopsy specimens are inconsistent and widely vary.
Reliability of SCR and CAN Diagnosis
There is no available standerd criteria to interpret histologic lesions found in proetocol renal biopsies , using Banff criteria otherwise would be associated with high possibility of misclassification (3).
the optimal timing and frequency for biopsies has not been evaluated.
Should intervention be made based on serial biopsies ? then it will be necessary to analyze the results in a standardized manner, which is problematic. Conversely, a single biopsy is likely to result in a high degree of inaccuracy.
Treatment for SCR and CAN
the benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown
as regard evaluation of pros and cons further studies on a large scale should be conducted .
Please reflect on your practice if possible.
Would prefer performing Biopsy whenever indicated , aotherise protocol Biopsy would be of great value for high risk patients positive DSA Recipients ,with previous failed transplants, high donor mismatching PLNF patients and who exhibited DGF.
References:
(1) Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, Cheung E, Allen RD, O’Connell PJ, Chapman JR: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71: 515–523, 2001
(2) Seron D, Moreso F, Ramon JM, Hueso M, Condom E, Fulladosa X: Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy. Transplantation 69: 1849–1855, 2000
(3) Seron D, Moreso F, Fulladosa X, Hueso M, Carrera M, Grinyo JM: Reliability of chronic allograft nephropathy diagnosis in sequential protocol biopsies. Kidney Int 61: 727–733, 2002
Pros:
1- detection of subclinical rejection
which has an incidence about 30% in the 1st 6 months of transplantation
2- Detection of chronic allograft nephropathy, which has an occurrence of about 79% 6 months post transplantation.
3- early screen tool in high risk transplantation, allowing early intervention..
Delayed graft function was detected in protocol biopsy even with clinically undiagnosed graft dysfunction.
Cons:
1- the when and frequency of protocol biopsy still not universally agreed upon.
2- the discrepancy between pathology and clinical status may refer to no need for biopsy as therapy will be provided for those who develop DGF with good outcome.
3- The need of good expertise to avoid post biopsy complications e.g. bleeding
*
Pro
Detection of Subclinical Rejection
with reported incidences in protocol biopsies performed in the first 6 mo posttransplantation of up to 30%
subsequent development of CAN has not been proved, some studies suggest that SCR leads to long-term deterioration of graft function and that early intervention may well improve outcomes
protocol biopsies at 1, 2, 3, 6, and 12 mo (biopsy group) was compared with that of patients who received protocol biopsies at months 6 and 12 only
continuous correlation for both acute rejection and borderline rejection, between the degree of functional graft impairment at the time of biopsy (protocol biopsies performed at 6 wk and 3 and 6 mo) and outcome at 1 yr
*Diagnosis of CAN by Protocol Biopsy
The frequency of CAN in early protocol biopsies up to 6 mo posttransplantation has been reported in a number of studies, with incidences of up to 79%
suggests that the first few months after transplantation are critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of chronic allograft damage that have yet to become clinically apparent
CAN diagnosed in protocol biopsies at 3 and 6 mo has been shown to predict renal allograft function at 2 yr posttransplantation . In addition, graft survival was found to be significantly better in patients without CAN versus those with CAN detected in protocol biopsies performed at 4
or14 months
Protocol biopsies have also been reported to be useful in the detection of CAN in pediatric transplant recipients. CAN was observed in 30.4% of protocol biopsies that were taken from stable allografts of pediatric patients approximately 100 d after renal transplantation; creatinine clearance decreased in the following year in patients in whom CANwasdetected,evenwhen renal function had been normal at the time of biopsy
*Protocol Biopsies Are Valuable in High-Risk Recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention. For example, delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to
prevent adverse long-term graft outcome. However, it is extremely difficult to diagnose graft rejection in patients with DGF on purely clinical grounds
*Detection of Graft Dysfunction as a Result of Nonimmune Factors
The appropriate therapy for graft dysfunction as a result of immunologic or nonimmunologic factors differs considerably; consequently, it is crucial to identify early the cause of the dysfunction. One of the most common causes of graft failure as a result of nonimmunologic factors is cyclosporine nephrotoxicity, yet the condition is reversible if immunosuppression is modified early enough, that is, reducing the dosage of cyclosporine while increasing the dose of other immunosuppressants. Use of protocol biopsies in this setting could be valuable by identifying cyclosporine nephrotoxicity in patients with stable renal allografts.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis. Activation of BKV is increasingly common in renal transplant recipients and generally leads to a rapid decline of renal function. BKV nephropathy can be controlled only by reducing the intensity of immunosuppression; thus, early detection and treatment are vital
*Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
Evidence suggests that the natural history of CAN may be modified by pharmacologic intervention, yet results from large, randomized, prospective trials that evaluate therapies to prevent or treat CAN are lacking.
*Safety of Protocol Biopsies
Performing protocol biopsies seems to be relatively straightforward, with the procedure generally taking place in the outpatient clinic and patients being discharged a few hours after the procedure. Indeed, transplant recipients’ compliance with the procedure is high, with the consent jjrate in one center reported to be 90%
*Con:
The Case Against Use of Protocol Biopsies
incidence of SCR in the first 6 moposttransplantation varying from 1 to 29% and CAN from 0 to 79%. Furthermore, it is difficult to draw any firm conclusions on the frequency of SCR and CAN from these studies as methodologic differences between studies make comparisons problematic.
*Reliability of SCR and CAN Diagnosis
The lack of reliable methods to quantify histologic changes in protocol biopsies has led to such specimens’ being evaluated by use of Banff ’97 criteria (34). However, Banff criteria were devised to evaluate diagnostic biopsies for which the findings are likely to be more easily interpretable, not protocol biopsies for which the degree of interstitial fibrosis is mild, particularly in early biopsies (0 to 20%) (19). This leads to a high probability of misclassification of biopsies with borderline changes or grade 1 CAN.
*How Should Utility of Protocol Biopsies Be Tested?
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points. Thus, it could be several years before evidence supporting the benefit of protocol biopsies in renal transplant patients with stable kidney function becomes available (36). An additional problem for general implementation of protocol biopsies is that the optimal timing and frequency for such biopsies has not been evaluated.
*Treatment for SCR and CAN
The presence of mononuclear infiltrates in renal allografts does not necessarily indicate rejection, and some recipients maintain good long-term graft function despite signs of SCR (37). Furthermore, the benefit of treating SCR detected by protocol biopsy has yet to be confirmed.
The appropriate management steps to be taken after detection of CAN in a protocol biopsy may also not be clearcut, because it must be proved that the CAN will respond to therapy . CAN detected at 5 yr is rarely therapy responsive;
Since patients might have sub clinical rejection without obvious clinical findings, protocol biopsies has emerged as a surveillance measure to assess AMR early on. Subclinical rejection was found to be associated with poor graft survival and late AMR. Early treatment of subclinical rejection might help rescuing the graft. Furthermore, CAN was detected in 79% of protocol biopsies . In the early 6 months, detection of tubulointerstitial damage and vascular chronic can be early signs of CAN even in the absence of changes in creatinine clearance. It can also be used to monitor the progression of CAN in the future. In high risk patients like those with DGF and in those with high pre transplant anti HLA antibodies, protocol biopsies can detect early signs of rejection. CNI nephrotoxicity in patients with stable renal allografts and subclinical BK virus nephritis can be detected early protocol biopsies. The procedure of protocol biopsy was considered safe with low percentage of complications .There are different incidences of subclinical rejection and CAN between centers which could be due to differences in HLA matching, DGF, immunosuppressive protocol etc. The varying incidence may raise questions regarding the routine use of protocol biopsies in centers with low incidences. Analysis of histological findings need reproducible and easily interpretable methods ( identification of pro-inflammatory transcripts in tissue or urine by PCR , urine spectroscopy , and measurement of cell activation markers) but these are all experimental and cannot be used to predict long term graft function or used as a basis for initiating acute rejection therapy in patients with stable kidney function. So we still depend on Banff ’97 criteria. In protocol biopsies the findings can be easily misdiagnosed as borderline or inadequate .
So we need to evaluate fully the benefit of protocol biopsies regarding long-term survival and function, outcome parameters .optimal timing , frequency ,number of biopsies whether single or serial and using a standardized manner for serial, need to be determined the decision of treatment of subclinical rejection detected on protocol biopsy is controversial since not treated cases had no difference in outcome .
Protocol biopsy:
pros
1- Easy and safe procedure serving for detection of subclinical rejection ;in 30 % and diagnosis of CAN ;in 79% in first 6 months following transplantation.
2-needed in high risk patents like those of delayed graft function ‘
3- helps in diagnosis of cause of graft dysfunction like CNI toxicity and BK nephropathy.
CONS
-lack of good evidence
-optimal timing not established
-benefit of treating subclinical rejection not confirmed
-Lines of CAN management not clear enough
Patient compliance is an essential factor for protocol implementation.
CAN is the most common cause of late graft rejection and failure. Subclinical rejection means histologic signs of acute rejection in a stable graft function. Early detection and treatment of both CAN and SCR can favorably affect the long-term graft survival. Protocol biopsy may be a possible mean of identifying early SCR and CAN and so allowing an early and effective treatment however, clear benefits of such approaches are still lacking .
Pros:
Detection of SCR and CAN in the 1st 6 months post-transplant, SCR was found in up to 30% and CAN was found in up to 80 % of grafts. It was valuable in high risk recipients as it detected SCR in a percent of patients with delayed graft function.Detection of graft dysfunction due to non-immune causes as Cyclosporin toxicity and BK virus. It is an almost safe procedure in more than 90 % of patients and serious complications are rare. in one study, serious hemorrhage occurred in 0.4%
Cons:
Reliability of diagnosis of SCR and CAN, as all grafts generate an immune response to some degree. Extreme variation in incidence of SCR(1-29%) and CAN(0-79) and consequently difficult explanation and interpretation. A minimum of 5 years is needed for evaluation of the usefulness of these approaches. also there are still some conflicts regarding the optimal timing and frequency of the procedure. No hard evidence of benefits of treatment of SCR and CAN on long-term graft survival.
Regarding my practice:
In my center , protocol biopsy may be used in the setting of high risk , sensitized recipients ; more than 1 transplant , 1ry glomerular disease , known immunological disease .
●Pro:
1:Detection of Subclinical Rejection:
acute subclinical rejection detected in protocol biopsies performed in the first 6 months post-transplantation. Protocol biopsies for early detection and treatment of acute rejection may be a major factor in preserving long-term graft function.
2:Diagnosis of CAN by Protocol Biopsy:
The presence of tubule-interstitial fibrosis and vascular –damage, which usually occur in the first 6 months following transplantation, are powerful predictors of allograft survival.
3:Protocol Biopsies Are Valuable in Highly sensitizedpatients :
Delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital. In pretransplant sensitized patients, protocol kidney biopsy is warranted to detect subclinical rejection.
4:Detection of Graft Dysfunction as a Result ofNonimmunFactors: Nonimmune mediated kidney damage could also be cause of kidney injury. For example CNI renal toxicity even in the therapeutic ranges should be suspected. Because CNI nephrotoxicity is reversible protocol biopsies may be a useful. Protocol biopsies could also detect renal diseases such as subclinical BK virus (BKV) nephritis.
●Cons 🙁
1- Variations in the reporting incidence of SCR in the studies and CAN variation may be related to low numbers of studies, low sample size, also presence of other factors like extent of HLA mismatch, immunosuppression protocol used, DGF.
2- No clear reliable method to measure or quantify the degree of CAN , as it depends on Banff 97 criteria which can be used in diagnostic biopsy not for protocol biopsy.
3- Introduction of MMF lower the incidence of SCR, so early biopsy not needed if not indicated clinically.
4- Implementation of protocol biopsy to improve graft survival and outcome should be tested for at least 5 years before general implementation , also timing when to do , and plan of therapy will be based on single biopsy or to wait for serial…so many problems.
5- Some studies showed that there is no difference between treatment of SCR and not to treat SCR on outcome and graft survival.
1. In your own words, summarise pros and cons of protocol biopsy.
A protocol biopsy is defined as a graft biopsy performed at a pre-specified interval regardless of the graft function. It has its own pros and cons.
Pros of performing a protocol biopsy: In this era of ultrasound guided real-time biopsies and availability of better biopsy guns, the procedure has become very safe with very low complication rates.
1) Most important reason of performing a protocol biopsy is to diagnose subclinical rejection (SCR) as it has been shown to be associated with increased incidence of acute rejection, interstitial fibrosis and tubular atrophy as well as reduced graft survival.
2) Diagnosis of chronic allograft damage leading to early diagnosis of chronic allograft nephropathy (CAN) which will help in taking countermeasures for the well being of graft and prognosticating about the graft life as CAN on protocol biopsies has been shown to be associated with poor graft survival.
3) In high risk patients, protocol biopsies can detect acute rejection and SCR in patients with delayed graft function (DGF) because timely action can prevent long-term damage. Similarly, diagnosing subclinical antibody mediated rejection in presence of DSAs can lead to early treatment and prevention of graft loss.
4) Sometimes non-immunological causes of graft dysfunction can be diagnosed before clinical signs, like Calcineurin inhibitor nephrotoxicity, BK virus nephropathy. It can help in timely intervention and prolonging the graft life.
5) Protocol biopsy has a role in clinical trials for prevention of CAN.
A the same time, protocol biopsies have some cons also, which include:
1) Although SCR can be diagnosed, there is still inconsistent data regarding the incidence of SCR (especially in tacrolimus era) and CAN. There is lot of variation due to difference in HLA mismatch, DGF incidence and immunosuppression protocols used.
2) Another issue is regarding diagnosis SCR and CAN. No standardized histological parameters have been defined for SCR and CAN, hence there are issues with the reliability of histological diagnosis.
3) There is still no consensus on when to perform a protocol biopsy, how frequently to perform it, and what action needs to be taken on the basis of the biopsy (whether a repeat biopsy to confirm the diagnosis to be performed or take action on basis of a single biopsy). Evidence base to recommend protocol biopsy is very low, as no large multicentre trial has studied this aspect.
4) Further, it is also not clear whether treatment of SCR changes the future course of the graft life as there is no case-control study to validate the assumption that SCR treatment helps in improving graft life.
5) Similarly, the action required after diagnosing CAN is not clear (when to treat and how to treat CAN is not clear). It has been shown that CAN, if diagnosed in first year post-transplant is amenable to treatment, but if diagnosed later, does not respond to treatment.
Hence performing a protocol biopsy in all transplant recipients might not be a good idea. It is better to perform protocol biopsies in sensitized patients, or patients with DGF to prevent missing acute rejection as the cause of graft dysfunction superadded on the underlying DGF.
2. Please reflect on your practice if possible.
Ours is a living related transplant program. We do not perform protocol biopsy in our unit. The reasons are:
Most of our donor-recipient pairs are related with <3/6 mismatch. We use Tacrolimus, MMF and steroid as standard immunosuppression protocol. Most of the patients do not have any history of sensitization, hence the risk of subclinical rejection is low.
Also, the patients do not want to undergo an invasive procedure if the graft function is normal and the transplant team is also hesitant in insisting for a protocol biopsy in view of low rates of subclinical rejection in tacrolimus era.
Protocol biopsies means performance of allograft biopsy without a clinical indication and just based on defined intervals especially during first year after transplantation. These biopsy can detect subclinical rejecting (SCR). People who agree on protocol biopsy believe that up to 30% of these biopsy showed SCR and early corticosteroid treatment was associated with improved outcome and long-term function.
The other advantage of protocol biopsy on belief of these group is early detection of chronic allograft nephropathy (CAN) and prediction of graft survival and trials to prevent CAN. Protocols biopsy has great value in high risk patients such as patients with DGF or pre-sensitized recipients to detect subclinical AMR. In addition CNI nephrotoxicity or BK virus nephritis could be detect easily.
On contrary opposition group believe that different incidence of SCR and CAN depends on immunosuppression potency and there is few advantage for protocol biopsy in all cases. In addition there are many new markers to diagnose SCR or CAN. Interpretation of protocol biopsy using Banff criteria leads to improper classification. Optimal time and proper frequency of protocol biopsies are not investigated and there is not a unique agreement on it.
In our practice we do protocol biopsy only in sensitized patients.
-Acute rejection (AR) is responsible for up to 12 % of graft loss commonly within the first 6 months after transplantation.AR can be classified into humoral and cellular rejection.
-Cellular rejection develop when donor alloantigen, presented by an antigen-presenting cell (APCs) through class I or class II HLA molecules, activate an immune response against the allograft, resulting in activation of naïve T cell which differentiates into cytotoxic CD8+ and helper CD4+cells (TH1) and TH2 or cytoprotective immunoregulatory T cell (Tregs), also Tregs cell originate from the thymus gland.
-Tregs in CD4+T cell expressing CD25 and T lymphocyte antigen 4 (CTLA-4).
-Treg cells are about 5% of T lymphocytes.
-Tregs maintain T cell homeostasis
-prevent activation of autoreactive immune response
-contribute to maintaining self-tolerance and homeostasis of the microbial gut flora
-promote the immunogenic escape of cancer cells.
-Tregs produce IL- 10 which inhibit, either directly or indirectly effector T cells during infection, autoimmunity, and cancer.
-CTLA-4 –expressing Tregs can down-regulate the expression of costimulatory molecules CD80 and CD86 on dendritic cells of lymphoid tissues resulting in impaired co stimulation via CD 28 and defective T cell stimulation.
-Treg cells can inhibit dendritic cells(DC) by stable Treg-DC contact lead to Tregs- mediated inhibition and also Tregs can induce perforin-dependent cytolysis of DC.
-Foxp3 in the urine analysis was high in patients with acute rejection and associated with better response to steroids and lower risk for graft failure.
-Multivariate analysis revealed that Foxp3/IL-17 ratio was a significant predictor for allograft outcome.
-Patients who maintain high Treg levels at both 6 and 12months display better long-term graft survival at 4qnd 5 years follow up.
-According to Banff classification, higher Foxp3 expression was associated with higher levels of interstitial inflammation and tubulitis.
–
I am sorry, I upload it here by mistake.
Summary:
many studies suggest that using protocol biopsies post kidney transplant would help in early detection and promptly timing treatment of both subclinical rejection(SCR) and chronic allograft nephropathy(CAN) and this would impact the graft survival and outcome especially in high risk recipients like sensitized candidate or those at risk of DGF , the procedure is safe however the available data about the true benefit of early treatment of SCR , CAN detected by protocol biopsy is limited to few observational studies . Moreover, the optimal timing of the protocol biopsies and the methods used to quantify the histological lesions is not yet determined. So, this article addresses the advantages and disadvantages of protocol biopsies based on the review of the available studies
Pro: The Case for Use of Protocol Biopsies
1-Detection of Subclinical Rejection
SCR indicate histological evidence OF acute rejection in patient with stable graft function, the incidence of SCR was higher in the first 6 months post transplantation, based on protocol biopsy surveillance report the incidence of SCR up to 30%, a clear link between SCR and subsequent development of CAN has not been proved, some studies suggest Corticosteroid treatment of SCR detected in the early postoperative period (1 to 3 mo) was found to be associated with an improved outcome. Another two reports suggest early protocol biopsies 1-3 months with SCR diagnosis and left untreated SCR was found to be progressed to CAN with increased interstitial fibrosis andtubular atrophy in FU biopsies in both studies (9,12).
2-Diagnosis of CAN by Protocol Biopsy
The available evidence supports the use of protocol biopsy for detection of CAN as it can impact the graft survival with early pharmacological intervention, but need more studies with better design and longer Fu. CAN detected by protocol biopsy had significant increased incidence of acute rejection before the biopsy .
CAN diagnosed in early protocol biopsy samples is an independent predictor of long-term outcome.
protocol biopsies could well become a useful primary efficacy variable in trials aimed at preventing CAN (7,15). but need further studies with good sample size and longer FU period.
3-Protocol Biopsies for High-Risk Recipient
is preferred tool for the diagnosis of acute rejection like in one study showed SCR was detected in 7-d protocol biopsy specimens in 18% of patients with DGF versus 4% of patients with normal early graft function. Also, humoral/vascular acute rejection was detected in 17% of biopsies performed 10 to 30 d post transplantation, 53% of which were in recipients with antibodies to class I HLA antigens, 25% in recipients with class II antigens, so protocol graft biopsies effective tool for detection of SCR in both high risks sensitized patients and those with DGF post-transplant.
4-Detection of Graft Dysfunction as a Result of Nonimmune Factors
Post-transplant protocol biopsies useful for the early diagnosis of CNI toxicity, one report reached 42% at 12-month post-transplant in protocol biopsies surveillance also found useful in early detection of BKV nephropathy which found in the range of 2-5% based on available studies.
Safety of the protocol biopsies;
Based on available evidence the protocol biopsies found to be safe with minimal complications in the range of 0.2, o.7, 1% for major bleed (27,28,29) can be done as OP procedure with good patient’s compliance reported up to 90%.
Con: The Case Against Use of Protocol Biopsies
Due to the heterogenicity of the reviewed studies by methodology and also the different timing of the protocol biopsies we can see the results are very variables as showed in table 1 the frequency of the SCR from different studies based on protocol biopsies vary from1% in mon3 to 43% in first months, the same for the frequency of mild CAN it vary from 0% in mon1 to 79% in mon3in two studies. This can be explained by the heterogenicity of the inclusion and exclusion criteria in regard s to HLA Matching, the frequency of DGF, the type of immunosuppressive medications and the early timing and frequency of protocol biopsies all these variables can affect the frequency of SCR , also age related chronic changes can interpreted as CAN , was missing in 4 studies This suggests that donor-related changes may explain a large proportion of the variability in the reported incidence of CAN.
Reliability of SCR and CAN Diagnosis
The large number of inadequate by adopting the Banff criteria This leads to a high probability
of misclassification of biopsies with borderline changes orgrade 1 CAN. Especially in early protocol biopsies
introduction of MMF in the IS Protocol help in reduction of the frequency of SCR in early biopsy protocol and according to this observation some centers stop doing the protocol biopsies.
One of the problems that affect the adopting the protocol biopsies is the difference in the timing and frequency, a single biopsy is likely to result in a high degree of inaccuracy.
Treatment for SCR and CAN:
still therre is no consensus regarding the benefit from the treatment of SCR from the available evidence ,also no difference in outcome (measured by graft survival and mean serum creatinine) at 1 and 6 yr post-transplantation were found between patients with SCR or borderline changes and those with no rejection or borderline changes.
Conclusion:
The protocol biopsies that adopted by many centers for screening of SCR and CAN still important despites the limited data from the current available studies, still needed especially for high risk group of kidney transplant patients ,protocol biopsies are safe and that their use likley improve the treatment especially early diagnosis and treatment of CAN ,in order to address their real advantage and effect on transplant outcome we need for large randomised control trails with longer follow up with the use of protocol biopsies as a primary efficacy variable with standardization of the histopathological criteria, timing and frequency of the biopsies ,and standardized immunosuppressive therapy .
In our center we do the graft biopsy based on indication and in regards to protocal biopies we individualized their use case by case with many limitation including the patient acceptance and compliance.
-Chronic allograft nephropathy (CAN)is the most common cause of late graft rejection and is strongly correlated with several acute rejection episodes during the first year after renal transplantation.
-Acute rejection and CAN can be subclinical without causing a measurable decrease in graft function.
-Persistent, unrecognized inflammatory injury due to a low–grade rejection process raises the possibility that surveillance or protocol biopsies, which are performed during the first post-transplantation year irrespective of graft function, may be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are treatable.
-used of protocol biopsies has been limited in some centers by concern over their safety but several studies suggest that the procedure is safe.
Pros of protocol biopsies :
1-Detection of subclinical rejection (SCR): SCR leads to long-term deterioration of graft function and early detection and intervention may be improved outcome. Corticosteroid treatment was found to be associated with an improved outcome.
2. Diagnosis of CAN: The first few months after transplantation is critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of CAN that have yet to become clinically apparent.CAN increase during the first 6 months after transplantation, then slowly thereafter.
3. High-risk recipient: Protocol biopsies have great value in detection DGF and acute rejection that lead to reduced graft survival in high- risk recipient
4. Detection of graft dysfunction as a result of nonimmune factors: non-immunological factors like cyclosporine nephrotoxicity and subclinical BKV nephritis can affect graft survival.
5. Used in clinical trial designed to prevent CAN.
Cons of protocol biopsies :
1. Variation in the reported incidence of CAN and SCR.
2. Reliability of SCR and CAN diagnosis is difficult to be assessed.
– To date, there is no good evidence supporting the general implementation of protocol biopsies into clinical practice.
-In our practice in Sudan, we donot do protocol biopsies. if the recipient after transplantation develops complications we do diagnostic allograft biopsy.
Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment. Although the benefit of this approach has yet to be evaluated in large, multicentre, prospective trials, numerous studies suggest that implementation of protocol biopsies may improve long-term graft function.
Chronic allograft nephropathy (CAN) is the most common cause of late graft rejection and is strongly correlated with the number of acute rejection episodes during the first year after renal transplantation.
Recent reports have suggested that acute rejection episodes and CAN may be subclinical without causing a measurable decrease in graft function. Moreover, persistent, unrecognized inflammatory injury, secondary to a low-grade rejection process, may result in long-term graft fibrosis and chronic dysfunction in the absence of episodes of overt clinical rejection. This
raises the possibility that surveillance or protocol biopsies, which are performed during the first post-transplantation year irrespective of graft function, may be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are amenable to treatment.
Pro: The Case for Use of Protocol Biopsies
1- Detection of Subclinical Rejection
Although a clear link between SCR and subsequent development of CAN has not been proved, some studies suggest that SCR leads to long-term deterioration of graft function and that early intervention may well improve outcomes. The use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
2-Diagnosis of CAN by Protocol Biopsy
Protocol biopsies have also been reported to be useful in the detection of CAN
3- Protocol Biopsies Are Valuable in High-Risk Recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention as in delayed graft function (DGF).
4- Detection of Graft Dysfunction as a Result of Nonimmune Factors
The appropriate therapy for graft dysfunction as a result of immunologic or nonimmunologic factors differs considerably; consequently, it is crucial to identify early the cause of the
dysfunction. One of the most common causes of graft failure as a result of nonimmunologic factors is cyclosporine nephrotoxicity, yet the condition is reversible if immunosuppression is
modified early enough, that is, reducing the dosage of cyclosporine while increasing the dose of other immunosuppressants. Use of protocol biopsies in this setting could be valuable by identifying cyclosporine nephrotoxicity.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis.
5- Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
protocol biopsies from patients with stable grafts may be useful to monitor the progression of CAN and may be a valuable tool in the design of future trials aimed at modifying its natural history.
Con: The Case Against Use of Protocol Biopsies
1- Variation in Reported Incidence of SCR and CAN
The incidences of SCR and CAN reported in biopsy specimens thus far have differed widely, with the incidence of SCR in the first 6 ms post-transplantation varying from 1 to 29% and CAN from 0 to 79%. Furthermore, it is difficult to draw any firm conclusions on the frequency of SCR and CAN as methodologic differences between studies make comparisons problematic
2- Reliability of SCR and CAN Diagnosis
The lack of reliable methods to quantify histologic changes in protocol biopsies has led to such specimens’ being evaluated by use of Banff ’97 criteria (34). However, Banff criteria were
devised to evaluate diagnostic biopsies for which the findings are likely to be more easily interpretable, not protocol biopsies for which the degree of interstitial fibrosis is mild, particularly in early biopsies (0 to 20%) (19). This leads to a high probability
of misclassification of biopsies with borderline changes or grade 1 CAN
3-How Should Utility of Protocol Biopsies Be Tested?
the optimal timing and frequency for such biopsies has not been evaluated. Furthermore, it is unclear whether decisions for intervention should be made on serial biopsies or based on a single biopsy result.
4-Treatment for SCR and CAN
the benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown, as most studies give anti-rejection treatment for SCR as soon as it is detected.
protocol biopsy:
The more rejection episodes occur in the first year, the more CAN incidence.
Even if these episodes may not be clinically overt but they are still injurious to the graft leading to fibrosis and malfunction. So it looks wise to perform protocol biopsy in the early post-transplant year hoping for early detection and better management
pros
1- Detection of subclinical rejection which found to occur in 30% of the first 6 months post-transplant
Early detection and management were found to be associated with a better outcome, less fibrosis and atrophy, and better 2-year survival especially with protocol biopsies performed in the first 3 month
Untreated borderline rejection and borderline rejection were associated with more acute rejection episodes after 10 years
2- Early diagnosis of CAN
The presence of CAN early in the protocol biopsy was associated with the risk of acute rejection episodes.
3- For high-risk patients
a. Patients with delayed graft function distinguishing subacute rejection and early management so a better prognosis.
b. Patients with anti HLA antibodies.
4- Early diagnosis and management of other non-immunological causes of graft dysfunction
a. BK virus early signs of infection combined with urine investigations led to marked reduction in the incidence of BK virus nephropathy
b. Identification of histological alarms of CNI induced toxicity so the dose can be modulated with better graft survival
Cons
1. Diagnosis of CAN:
no definite criteria differentiate CAN vs early or borderline changes
2. Absence of definite criteria histopathological classification of protocol biopsies
Reflection on the practice:
In our practice, we don’t use protocol biopsies as a routine (only indication biopsy).
I think protocol biopsy should be adopted in our center especially for sensitized patients and those with slowly declining serum creatinine (not meeting the criteria of DGF)
But yet I could not preclude which time may be better (first week, first month, or 3-month)
Protocol graft biopsy is known as doing frequent graft biopsy within different intervals regardless the level of graft function ,it has advantages and disadvantages.
Advantages
Early detection of subclinical rejection SCR which means normal renal function but there is a change in histological features, early detection, early management and better outcome.
Diagnosis of CAN
By determining the high risk groups and doing protocol biopsy this help to detect any rejection and improve graft survival. High risk groups like patients with DGF and highly sensitived patients .
Detect silent other non immunological factors like BK virus and CNI toxicity.
Help to decrease rate of hospitalization post operative.
Disadvantages
Difficulties in interpretation of the histological changes as most of the transplanted kidneys show some degree of changes.
Variation reported incidence of SCR and CAN.
In summary this article tried to compare between the pros and cons of protocol biopsy; so it is useful in detecting early histological changes in the graft ,it has role in diagnose subclinical rejection (SCR) and chronic allograft nephropathy (CAN) ; also it has great benefit in improving graft survival after delay graft function (DGF) ,it positively affect graft and patient survival. It can also detect non immune graft dysfunction like viral infections (BK nephropathy) and it is a safe procedure. In contrast there’s some cons like over diagnosis of SCR and CAN,difficulty in interpretation of the histological Changes because it almost borderline , the most challenged part which is to treating this subclinical changes or not.
In our transplant centers in Sudan we don’t do protocol biopsy
The protocol biopsy is a biopsy that done at fixed time after transplantation with no clinical indication . it’s timing and frequency is center specific.
The advantages of protocol biopsy :
The disadvantages of protocol biopsy :
In our center , we do not use protocol biopsy to our patients.
Incidence of Acute rejections have been largely controlled in the past 20 years after the introduction of the more potent immunosuppressives, however the chronic allograft nephropathy remains a probleme as it s a major cause of graft loss .
Biopsies are only performed in the settings of established rejections , after an irreversible damage has been established , so less likely to benefit from therapies .
An ongoing immun damage may occur without significant decline in GFR and this adversely affect graft outcome
And bec the above listed items , came the idea of protocol biopsies
Pros of protocol biopsies including :
* detection of subclinical rejection.
* detection of CAN .
* detection of non immune causes of graft failure
* detection of acute rejection in high risk patients with DGF .
* protocol biopsies can be of great benefit in clinical trials
Cons include
* The wide range of reported incidence of SCR and CAN
* the reliability of the diagnosis of both conditions SCR and CAN
* lack of good evidence that supports benefit of protocol biopsies.
* although SCR almost always predict subsequent acute rejection episodes ,and so benefits from early intervention, yet, data on untreated cases of SCR is lacking, so effects of treating such patients on long term can’t be detected.
2.Con of protocol Biopsies ;
We don’t do protocol biopsies in our programme. All our transplant biopsies are indication biopsies.
kidney transplant protocol biopsy
The incidence of acute rejection episodes decreased relatively nowadays in comparison with the past due to emergence of the new potent immunosuppressive medications. However, chronic allograft nephropathy leading to loss of graft function remains the major problem after renal transplantation. Most of the kidney transplant practice are performing a diagnostic kidney biopsy when there is suspicion of graft dysfunction in terms of rising of serum creatinine, new onset proteinuria or hypertension and by the time of clinical diagnosis scaring of the graft tissue already happened.
Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy which can be treatable either by changing immunosuppression or adjusting the doses. Implementations of protocol biopsies may improve long-term graft function in high-risk patients, such as those with delayed graft function, long cold ischemia time and sensitized patients.
-Definition of protocol biopsy:
Renal allograft protocol biopsy is defined as biopsy performed at predefined intervals after transplantation, which is unrelated to graft dysfunction.
-Advantages of protocol biopsy:
1- Subclinical rejection which is the histological signs of acute rejection with normal kidney function can be detected by protocol biopsies and can be managed early.
2-Early diagnosis and treatment of chronic allograft nephropathy (CAN) proved by serial protocol biopsies could have a dramatic effect on the outcome of the graft.
3-Detection and treatment of Subclinical rejection in high-risk group patients as DGF and sensitized high-risk renal transplant recipients with positive impact on long term graft survival.
4-Serial protocol biopsies can detect silent non immunological factors causing graft dysfunction as CNIs toxicity, subclinical BK virus (BKV) nephritis when diagnosed with protocol biopsy combined with urine sample and PCR.
5- It is mainly a safe procedure seems to be straightforward, done as one day surgery and patients can be discharged a few hours after the procedure.
-Disadvantages of protocol biopsy:
1- Variation in reported incidence of SCR and CAN results from protocol biopsies.
2- The lack of reliable methods to quantify histologic changes in protocol biopsies which is evaluated by use of Banff ’97 criteria. However, Banff criteria were designed to evaluate diagnostic biopsies with some form of clear histological diagnosis.
-Implementation of protocol biopsies:
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points. Thus, it could be several years before evidence supporting the benefit of protocol biopsies in renal transplant patients with stable kidney function.
Another point the optimal timing and frequency of protocol biopsies it should be serial biopsies or a single biopsy result which will be inaccurate.
The clinical significance of early detection of silent inflammatory infiltrates in stable allografts remains controversial.
In our practice we are only doing diagnostic kidney biopsies when the patient presented with suspicion of graft dysfunction e.g. Trending up of serum creatinine level above the baseline value by 25% and above, new onset proteinuria and high BP.
Dear All
Thank you very much for your fruitful contribution. Protocol biopsy was a common practice in the Cyclosporine era where the incidence of subclinical rejection with high. It reached 30% in some series. In the Tacrolimus era, subclinical rejection is hardly seen. Therefore protocol biopsy is usually not indicated except in highly sensitised.
Although the incidence of acute rejection has fallen in recent years, chronic rejection and loss of graft function remain major problems after kidney transplantation. CAN is the most common cause of late graft rejection and is strongly correlated with the number of acute rejection episodes. Furthermore, CAN and acute rejection may be subclinical and low-grade inflammation may result in graft fibrosis and chronic rejection. Thus, it raised the possibility that protocol biopsy during the first year after transplantation may be useful for detection of early acute rejection and CAN. However, there are many pros or cons of surveillance biopsies.
Pros of protocol biopsies:
Detection of subclinical rejection
SCR (histologic signs of acute rejection in the presence of stable graft function) with reported incidences of up to 30% leads to long-term deterioration of graft function and early intervention with corticosteroids may improve outcomes.
Untreated SCR is correlated with an increase in IFTA in later biopsies. SCR is associated with a higher incidence of acute rejection. These data thus suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
Diagnosis of CAN by protocol biopsy
CAN can be identified with an incidence of up to 79% in early protocol biopsies. The presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival and rapidly increase during the first 6 months after kidney transplantation. In particular, patients with chronic graft damage score >6 had a higher rate of graft loss than those with scores <6. Thus, early detection and treatment of CAN can have a dramatic effect on the outcome of the graft.
Valuable in high-risk recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention. DGF is strongly associated with poor long term graft outcome and early detection of acute rejection in the presence of DGF is crucial to prevent adverse long-term outcome. Thus, there is a strong need to prompt diagnosis of acute rejection that may be met by protocol biopsies. In one study, half of acute rejection in patients with DGF was clinically undiagnosed.
It is suggested that much of the reduced graft survival associated with DGF may be explained by silent acute rejection, so surveillance biopsies and treatment of SCR during prolonged DGF is warranted.
In addition, Protocol biopsies may be an effective way of detecting subclinical ABMR in sensitized high-risk renal transplant recipients.
Detection of graft dysfunction as a result of non-immune factors
Appropriate therapy of immunologic and non-immunologic factors of graft dysfunction differs considerably and early detection of them is crucial. One of the most common causes of non-immunologic graft dysfunction is CNI toxicity that is reversible if immunosuppression is modified early enough. So utilizing protocol biopsy can be valuable in this setting.
Protocol biopsies may also be useful to detect BK virus nephritis, and commence of appropriate therapy with reducing immunosuppression.
In clinical trials designed to prevent CAN
Evidence suggests that the natural history of CAN may be changed by treatment and trials for evaluation of CAN need to use long term survival as an end point. Protocol biopsy can be a good surrogate marker. Histologic changes in graft biopsy provide the earliest evidence of graft damage and its predictive value on graft survival may be superior to AR or serum Cr. Thus, protocol biopsies may be useful for monitoring the progression of CAN and may be a valuable tool in the design of future trials aimed at modifying its natural history.
Safety of protocol biopsy
A number of studies suggest that the procedure is safe and the rate of reported major complications is less than 1%.
Cons of protocol biopsies
Variation in reported incidence of SCR and CAN
There is a big difference between the reported incidence of SCR and CAN varying from 1-29% for SCR and 0-79% for CAN
Some explanations for the difference in SCR is difference in HLA matching, incidence of DGF between studies, immunosuppressive protocols, and the lack of precise inclusion criteria.
Some explanations for the difference in CAN is the similarity of age-related changes to CAN, impact of donor variables on chronic histopathologic scores, and methodologic problems.
Reliability of SCR and CAN diagnosis
Because all transplants generate immune response to some extent, analysis of the histologic criteria for rejection is somehow problematic. In addition, utilizing of BANF criteria may lead to misclassification of borderline changes.
How Should Utility of Protocol Biopsies Be Tested?
It takes a long-time (at least 5 years) to evaluate fully the benefits of protocol biopsies on graft survival and function. On the other hand, the optimal timing and frequency of protocol biopsies is not clear. In addition, it is better that therapeutic decisions be based on serial biopsies, although standard analysis of them is problematic.
Treatment for SCR and CAN
Infiltration of kidney graft by mononuclear cells does not necessarily indicate rejection, and the benefit of treatment of SCR has not been confirmed, although most studies give immunosuppressive treatment for SCR. It is reported that increasing baseline immunosuppression reduces the incidence of clinical rejection not SCR and the benefit of treatment of SCR may be limited. The appropriate management of detected CAN in a protocol biopsy is not clear. Although it is likely that the management and underlying mechanisms of early and late CAN may completely differ.
Introduction:
Advantages of protocol biopsy:
Disadvantages of protocol biopsy:
For my practice:
I will adhere to the local protocol and try to share benefits of protocol biopsy with senior colleagues. I will try to design a study of managing some cases with protocol biopsy to check for possible even short-term benefits.
Many transplantation centres consider protocol biopsy during first year post transplantation aiming at early diagnosis and proper treatment of any graft pathology to prolong graft survival . Protocol biopsy are beneficial for diagnosis of subclinical rejection early diagnosis of chronic graft rejection, for high risk patients as patients with DGD , for non immune causes of graft dysfunction as CNI toxicity and early BK nephropathy
Limitation for protocol biopsy are
1- Interventional related Complications as pain , bleeding , heamaturia and peritonitis
2- Difficluty in assessing cost –benefit of protocol biopsy due to marked variation in reported incidence of SCR and CAN between studies , that may be explained by different immunplogical risk of the studied population ( variable degrees of HLA mismatch , variable incidence of DGD ) or due to different immunesuppression protocols used in these studies as well as difficult diagnosis of early CAN as these histological changes resemble age related renal changes.
3- Dificult diagnosis of SCR and early CAN as
a- these histological changes resemble age related renal changes.
b- B- all transplanted allograft show some degree of histologic changes and mild infilteration with inflammatory cells
c- No agreed diagnosing and staging system for the histological changes in SCR , CAN.
4- No clear benefit from treating SCR as despite being associated with increase incidence of acute rejection rates , its treatment did not improve outcome of these rejections .
5- No strong evidence tested by large , multicentric studies to support protocol biopsy.
WHAT IS PRTOCOL BIOBIES?
they are surveillance biopsies performed during the first year after kidney transplantation, to identify early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment.
a-advantages
1-detection of subclinical rejection.
2- diagnosis of CAN
3- protocol biopsy are valuable in high-risk recipient(cadaveric, history of dsa befor transplantion)
4- detection of graft dysfunction as a result of none immune factors like cni toxcity and bk nephropathy.
5- use of protocol biopsy in clinical trials designed to prevent CAN.
b-disadavantages
1-no clear evidence on the ralation between SCR and subsequent development of CAN has not been proved.
2-incidences of SCR and CAN reported in biopsy specimens showed wide variations with the incidence of SCR in the first 6 mo posttransplantation varying from 1 to 29% and CAN from 0 to 79%.
3- SCR as mononuclear cell infiltration does not necessary mean rejection and benefit of treating SCR detected by protocol biopsy has yet to be confirmed. .
4- no clear studies support the benefit of protocol biopsies in renal transplant patients with stable kidney function yet and no standard timing for the protocol biopsies .
5-BANFF clasifiaction is not designed for protocol biobies .
IN OUR CENTER, WE DONT DO IT , BUT WE ARE PLNNING TO DO IT FOR HIGH RISK PT .
Dear All
Thank you for your input. Yes, Subclinical rejection is very uncommon in the tacrolimus era. We hardly do it unless there is a clinical suspicion based on graft dysfunction (it would not be called protocol biopsy).
Yes, it is justified in highly sensitised patients. I’m not sure if it has an impact on the graft survival and function due to the complexity of confounding factors (match, the cPRA, etc.). It may have prognostic value.
acute rejection episodes and CAN may be subclinical without causing a measurable decrease in graft function. Moreover, persistent, unrecognized inflammatory injury, secondary to a low-grade rejection process, may result in long-term graft fibrosis and chronic dysfunc- tion in the absence of episodes of overt clinical rejection. This raises the possibility that surveillance or protocol biopsies, which are performed during the first posttransplantation year irrespective of graft function, may be clinically useful by allowing the identification of early acute rejection or CAN at a point when they are amenable to treatment.
Pro: The Case for Use of Protocol Biopsies
Detection of Subclinical Rejection
the outcome of renal transplant patients who underwent protocol biopsies at 1, 2, 3, 6, and 12 mo (biopsy group) was compared with that of patients who received protocol biopsies at months 6 and 12 only (control group) .Corticosteroid treatment of SCR detected in the early postoperative period (1 to 3 mo) was found to be associated with an improved outcome.
use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
Diagnosis of CAN by Protocol Biopsy
Evidence suggests that the first few months after transplantation are critical in the development of CAN and that protocol biopsies may be a valuable means of detecting early signs of chronic allograft damage that have yet to become clinically apparent.
Protocol Biopsies Are Valuable in High-Risk Recipients
delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to prevent adverse long-term graft outcome. . However, it is extremely difficult to diagnose graft rejection in patients with DGF on purely clinical grounds. Accordingly, there is a strong need for a means of promptly diagnosing acute rejection in patients with DGF, a need that may be met by protocol biopsies.
Protocol biopsies thus may be an effective way of detecting subclinical antibody-mediated acute rejection in sensitized high-risk renal transplant recipients.
Detection of Graft Dysfunction as a Result of Nonimmune Factors
One of the most common causes of graft failure as a result of nonimmunologic factors is cyclosporine nephrotoxicity, yet the condition is reversible if immunosuppression is modified early enough, that is, reducing the dosage of cyclosporine while increasing the dose of other immunosuppressants. Use of protocol biopsies in this setting could be valuable by identifying cyclosporine nephrotoxicity in patients with sta- ble renal allografts.
Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis. Activation of BKV is increasingly common in renal transplant recip- ients and generally leads to a rapid decline of renal function. BKV nephropathy can be controlled only by reducing the in- tensity of immunosuppression; thus, early detection and treatment are vital.
Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
Evidence suggests that the natural history of CAN may be modified by pharmacologic intervention, yet results from large, randomized, prospective trials that evaluate therapies to pre- vent or treat CAN are lacking. This is due largely to the methodologic difficulties encountered in the design of such trials. such as the sample size and the follow-up time, Furthermore, no prospective methods to monitor the appearance/progression of CAN are available currently for the kidney; thus, clinical trials that are conducted in renal transplant patients, by necessity, need to use surrogate markers of long-term graft survival.
Safety of Protocol Biopsies
The procedure is safe.
Con: The Case Against Use of Protocol Biopsies
Variation in Reported Incidence of SCR and CAN
Reliability of SCR and CAN Diagnosis
How Should Utility of Protocol Biopsies Be Tested?
evaluation of the utility of protocol biopsies must consider the complex differences that exist between clinical trials, such as differences in patient se- lection, use of induction therapies, and baseline and mainte- nance immunosuppression.
To evaluate fully the benefit of protocol biopsies in terms of long-term survival and function, outcome parameters should include a minimum of 5-yr graft survival and function end points
Treatment for SCR and CAN
Using of potent immunosuppressant drugs in last year’s leading to decrease incidence of graft loss . However, chronic allograft dysfunction remain the major cause of graft loss .
Protocol biopsies in kidney transplant recipients make an early detection of subclinical rejection or chronic transplant glomerulopathy.
Pros – Detection of early sub acute rejection and early intervention may improve outcome in long term graft function . Protocol biopsies need to be performed in the following clinical conditions in delayed graft function DGF because it affect graft survival so early diagnosis of SCR and early treatment improved graft outcome .Also using protocol biopsies in high risk pt and early detection of AMR may be effective .Early detection of nonimmunologic factors like Cyclosporine nephrotoxcity and BK virus and early reduce in the immunosuppressant drugs may be beneficial .
There are variation in incidence of CAN and SCR detected ,this may be duto presence of HLA matching , DGF type of immunosuppressant drugs used and donor variables (e.g.,
deceased donor, increasing age, female gender, hypertension }.
Also histologic criteria in protocol is problematic because every recipient generate immune response . The biopsy is safe there are small number of compilation .
In our practice we didn’t do protocol biopsies . The biopsy done when there is impair renal function.
SCR is 14% while 24% in CYA .Pt on tacrolimus had better graft survival.
Treatment of SCR by anti-rejection because it will improve graft survival .
Protocol biopsies are performed at previously determined intervals for the aim of detection of acute or chronic changes that mostly seem to be subclinical aiming for early determination and accordingly timely management.
The advantages of the protocol biopsies is can be summarized as :
the detection of subclinical rejection, this is valuable in high-risk recipients. Many studies detected early rejections in first 6 months post transplantation
detection of graft dysfunction because of non-immune factors the protocol biopsies can be used in clinical trials designed to prevent CAN
may show latent infections like BK earlier while subclinical, so it helps differentiate the immunologic from nonimmunologic reasons. this is very important as treatments may be opposite (increase vs decreasing immunosuppression)
one of the limitations for wide routine usage is safety
another limitation is variations in the reported incidence of CAN and SCRT
There is a problem regarding their reliability of diagnosis as the presence of mononuclear infiltrates in renal allografts may not necessarily indicate rejection. some of such patients showed good survival.
protocol biopsies performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment.
Pro: The Case for Use of Protocol Biopsies;
1-detection of subclinical rejection; protocol biopsies is useful in detection acute and border line rejection and facilitate early treatment.
2- diagnosis of CAN; Detection of chronic allograft nephropathy in early protocol biopsy is predictive of subsequent graft function loss and early treatment is of great effect in graft out come .
3- protocol biopsy are valuable in high-risk recipient; Protocol biopsies is useful in detection of sub clinical rejection in sensitized patient. Also they have great value in patients with delayed graft function ,by allowing early interventions . .
4- detection of graft dysfunction as a result of none immune factors; Use of protocol biopsies in this setting could be valuable by identifying CNI nephrotoxicity in patients with stable allograft. Protocol biopsies may also be a useful tool to detect renal diseases such as subclinical BK virus (BKV) nephritis
5- use of protocol biopsy in clinical trials designed to prevent CAN use of protocol biopsies as a primary efficacy variable could well become a useful tool in the design of future trials aimed at preventing CAN; power calculations suggest that they may allow an important reduction in the number of patients involved in such trials, as well as reducing the follow-up time.
6- safety of protocol biopsy; Performing protocol biopsies seems to be relatively straightforward, with the procedure generally taking place in the outpatient clinic and patients being discharged a few hours after the procedure.
Con: The Case Against Use of Protocol
Biopsies
1-variation in reported incidence of SCR and CAN; although numerous reports suggest that the frequency of SCR and CAN in early protocol biopsies may be high, the lack of consistency between studies casts doubt on the use of these data to support adoption of protocol biopsies in the routine treatment of kidney transplant patients.
2-reliability of SCR and CAN diagnosis; the optimal timing of protocol biopsy and reliable methods to quantify the histologic changes observed in biopsy specimens have yet be determined .
3- how should utility of protocol? An additional problem for general implementation of protocol biopsies is that the optimal timing and frequency for such biopsies has not been evaluated. Furthermore, it is unclear whether decisions for intervention should be made on serial biopsies or based on a single biopsy result. If therapy decisions are to be made on serial biopsies, then it will be necessary to analyze the results of such biopsies in a standardized manner, which is problematic. Conversely, a single biopsy is likely to result in a high degree of inaccuracy.
4- treatment for SCR and CAN; the benefit of treating SCR detected by protocol biopsy has yet to be confirmed. This is in part because the effect of not treating SCR is largely unknown, as most studies give anti-rejection treatment for SCR as soon as it is detected. The appropriate management steps to be taken after detection of CAN in a protocol biopsy may also not be clear cut, because it must be proved that the CAN will respond to therapy .
.
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If you are practicing transplantation, please reflect on your experience in performing protocol biopsy?
With all these potential advantages of protocol biopsies, why some transplant units are not performing it? What are your thoughts?
no protocol biopsy done in my practice, only diagnostic biopsy whenever indicated
some centers not performing it because of complication, operator dependent, decision may need serial biopsy
I think part of the causes are patient related as some patients refuses to do these biopsies when they have normal graft function, other causes are related to the cost and the availability of the facilities to apply such protocol, so we need to educate the patients about the benefit of doing these biopsies at least till a less invasive markers of early rejection are available.
We don’t do protocol biopsy in our practice.
Many people don’t do it simply because they don’t know what to do with it. Some increases immunosuppression but this approach works better for clinical rejection rather than sub-clinical rejection.
We do not perform protocol biopsies.
The reason of not performing protocol biopsies in our program is because ours is a living related program with majority of the transplants between siblings and parent-child relations with most having a mismatch of <3/6.
The patients are hesitant in getting a biopsy done in presence of a normally functioning graft and the transplant team is also not very enthusiastic in view of a stable graft function.
Protocol Transplant Biopsies
Protocol biopsies: are surveillance biopsies performed during the first year after kidney transplantation, to identify early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment.
Surveillance or protocol biopsies, which are performed during the first posttransplantation year irrespective of graft function:
Pro: The Case for Use of Protocol Biopsies
1.Detection of Subclinical Rejection
Although a clear link between Sub-Clinical Rejection (SCR) and subsequent development of CAN has not been proved, some studies suggest that SCR leads to long-term deterioration of graft function and that early intervention may well improve outcomes.
2.Diagnosis of CAN by Protocol Biopsy
The frequency of CAN in early protocol biopsies up to 6 mo post-transplantation has been reported in a number of studies, with incidences of up to 79%,early protocol biopsies have shown that the presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival.
3.Protocol Biopsies Are Valuable in High-Risk Recipients
Protocol biopsies have the potential to be of great value in high-risk renal transplant recipients by allowing for early intervention. For example, delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital to prevent adverse long-term graft outcome.
4.Detection of Graft Dysfunction as a Result of Nonimmune Factors
Use of protocol biopsies in the setting of non-immune conditions causing rejection( eg; CsA toxicity) could be valuable by identifying eg; cyclosporine nephrotoxicity in patients with stable renal allografts and then accurate plan of management will be clear.
5.Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN
6.Safety of Protocol Biopsies
Con: The Case Against Use of Protocol Biopsies
1.Variation in Reported Incidence of SCR and CAN
The incidences of SCR and CAN reported in biopsy specimens thus far have differed widely, with the incidence of SCR in the first 6 mo post-transplantation varying from 1 to 29% and CAN from 0 to 79%. Furthermore, it is difficult to draw any firm conclusions on the frequency of SCR and CAN from these studies as methodologic differences between studies make comparisons problematic.
A number of explanations exist for the differences in SCR incidence reported between studies:
The reported frequency of CAN in early protocol biopsies also varies considerably, with the changes observed being relatively mild, chronic lesions, usually classified as Banff grade 1.
It should be noted, however, that age-related, chronic renal changes can resemble those of CAN, yet four of the five studies mentioned did not control for donor changes by undertaking a donor biopsy. The remaining study reported an incidence of donor chronic changes of 54% and an incidence of new CAN of only 26% . This suggests that donor-related changes may explain a large proportion of the variability in the reported incidence of CAN. This is supported by a recent study that reported that donor variables had little effect on acute histopathology scores in protocol biopsy specimens taken at 6 to 12 mo posttransplantation, although donor variables (e.g., deceased donor, increasing age, female gender, hypertension) explained approximately one third of the variability observed in chronic histopathology scores.
The methodologic problems associated with the reporting of the incidence of SCR may also apply to the interpretation of CAN incidence data.Thus, although numerous reports suggest that the frequency of SCR and CAN in early protocol biopsies may be high, the lack of consistency between studies casts doubt on the use of these data to support adoption of protocol biopsies in the routine treatment of kidney transplant patients.
2.Reliability of SCR and CAN Diagnosis
Assessment of the histologic changes detected by protocol biopsy is fraught with difficulties as all transplants generate an immune response to some degree, rendering analysis of histologic criteria for rejection in protocol biopsies problematic.
The lack of reliable methods to quantify histologic changes in protocol biopsies has led to such specimens’ being evaluated by use of Banff ’97 criteria. However, Banff criteria were devised to evaluate diagnostic biopsies for which the findings are likely to be more easily interpretable, not protocol biopsies for which the degree of interstitial fibrosis is mild, particularly in early biopsies (0 to 20%). This leads to a high probability of misclassification of biopsies with borderline changes or grade 1 CAN.
3.How Should Utility of Protocol Biopsies Be Tested?
4.Treatment for SCR and CAN
In our practice we don’t attempt protocol biopsy. Graft biopsy is only considered when there’s clinical suspicion of rejection that may benefit from graft biopsy and further plan of management based mostly on the biopsy findings.
Protocol biopsies to detect CAN and SCR in stable renal allografts are a huge step forward in the attempt to enhance long-term transplant outcomes.
Due to a lack of evidence, it is difficult to determine if protocol biopsies increase long-term graft function and survival, and whether treating SCR discovered by protocol biopsy is beneficial.
In the absence of a clinical diagnosis, early identification and treatment of CAN may promote long-term graft function. Protocol biopsies are also safe and may help treat renal transplant patients, according to research. Also, using protocol biopsies as a key effectiveness measure may help future studies focused on avoiding CAN.
There are three possible strategies, which units may consider:1- no protocol biopsies; 2-biopsies only in high-risk individuals or 3- a universal screening protocol biopsy program:
3 –Universal biopsy policy. Protocol biopsy is used to detect and treat SCR in all recipients as the standard of care. Advantages include simplicity of implementation; detection of unsuspected SCR in low-risk individuals; aiding clinical decision making (e.g. renal dysfunction soon after normal protocol histology usually means CNI nephrotoxicity) and early detection of other diagnoses such as polyomavirus nephropathy. Disadvantages include costs, consumption of clinical and pathology resources, workforce capability.
I prefer individualized biopsy in my practice.
Renal allograft biopsies are usually performed to confirm the clinical diagnosis histologically.
Recent studies showed that chronic allograft nephropathy (CAN) and acute rejection may be subclinical without decline in kidney functions leading to delayed diagnosis and delayed start of treatment which may affect graft outcome.
Protocol biopsies during first year post transplant could help in detection and early treatment of SCR and CAN but this benefit is still unproven
Pro:
Detection of subclinical rejection:
Studies showed that
Diagnosis of CAN by protocol biopsy:
Studies showed that
Detection of graft dysfunction due to non immune factors:
Protocol biopsies can detect cyclosporine nephrotoxicity (before deterioration of kidney function) and Subclinical BK virus nephritis
Use of protocol biopsy in clinical trials to prevent CAN
Studies showed that CAN could predict long term graft survival and incipient chronic tubulointerstitial lesions with shorter follow up time than other predictors.
Safety of protocol biopsies
Studies showed that graft biopsy is safe with low incidence of complications
Con:
Variation of reported incidence of SCR and CAN
Reliability of SCR and CAN diagnosis
How should utility of protocol biopsies be tested:
Treatment of SCR and CAN:
Studies showed that
In my practice, protocol biopsy is not performed, only diagnostic biopsies.
summarise pros and cons of protocol biopsy
Pros
Detection of subclinical rejection:
Defined as histological evidence of rejection despite stable graft function, one study showed better outcomes in patients who underwent protocol biopsy at 1, 2, 3, 6, and 12 months compared to patients who underwent graft biopsy at 6 and 12 months only post-renal transplantation. Therefore, early detection of SCR may prevent further deterioration and improve graft outcomes in long term (1).
Early diagnosis of chronic allograft nephropathy
Number of studies reported that CAN may develop post-renal transplantation as early as 6 months and the incidence of CAN may reach up to 79%, Therefore, the importance of protocol biopsy may be valuable in detecting early signs of chronic allograft nephropathy which is not clinically apparent yet (2,3).
Detection of non-immune factors of graft dysfunction
As :
1- Cyclosporin cytotoxicity
2- BKV nephropathy
Both of the above causes should be reversible or treatable by immunosuppression modification/reduction therefore, protocol biopsy again showed an advantage here.
Cons
Wide variation in reporting SCR and CAN
We can tell from reported studies that there is a wide range reported for the incidence of SCR (1-29%) AND CAN (0- 79%)
Why?
Regarding SCR
i. The differences in human leukocyte antigen (HLA) matching, which will reflect on the risk of rejection and SCR
ii. If a study already excluded DGF patients and another study included them in the study, therefore, there will be a difference in the pool of patients involved and consequently this will affect final results as DGF is known to be a risk factor for rejection.
iii. Different immunosuppression protocols used in different studies will affect the incidence of SCR (4)
Regarding CAN
Age-related changes can be histologically similar to CAN, therefore the diagnosis of CAN might be overestimated and one study confirmed that possibility when it showed that The incidence of donor chronic changes of 54% and an incidence of new CAN of only 26% (5).
Conclusion and own reflection
Therefore despite numerous studies suggesting that early protocol biopsies can detect SCR and CAN early and consequently can improve long term outcome, however, the lack of consistency between studies made it hard to adopt routine protocol kidney biopsy in renal transplant, actually, this is one of the reasons we don
t adopt routine renal graft biopsies in my transplant unit. Another factor that supports not doing routine transplant biopsy at our unit is that the presence of mononuclear infiltrates doesn’t confirm rejection or SCR, even with histological signs of SCR, some patients can have a long-term good graft function. Moreover, when it comes to managing SCR it is very difficult to have a consensus on whether to treat or not as Robert et al, reported in their study that day 7 post-transplant graft biopsy is strongly predictive for subsequent clinical rejection, however, day 28 post-transplant graft biopsy showing SCR and borderline changes which werent treated, didn`t have an adverse impact on the long term which was measured by graft survival and mean serum creatinine at 1 and 6 years post-transplantation (6). This raises the question about The clinical relevance and the benefits of treating SCR detected by protocol biopsy.Additionally CAN detection in protocol graft biopsy is controversial when it comes to management as we need first to know whether CAN is likely to be reversible and when is the ideal time for intervention to be able to reverse it, if we manage to answer this question then protocol biopsy to detect CAN can be timed accordingly.
References:
1- Nankivell BJ, Fenton-Lee CA, Kuypers DRJ, Cheung E, Allen RD, O’Connell PJ, Chapman JR: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71: 515–523, 2001
2- Seron D, Moreso F, Ramon JM, Hueso M, Condom E, Fulladosa X: Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy. Transplantation 69: 1849–1855, 2000
3- Nicholson ML, McCulloch TA, Harper SJ, Wheatley TJ, Edwards CM, Feehally J, Furness PN: Early measurement of interstitial fibrosis predicts long-term renal function and graft survival in renal transplantation. Br J Surg 83: 1082–1085, 1996.
4- Nickerson P, Jeffery J, Gough J, Grimm P, McKenna R, BirkP, Rush D: Effect of increasing baseline immunosuppression on the prevalence of clinical and subclinical rejection:A pilot study. J Am Soc Nephrol 10: 1801–1805, 1999.
5- Kuypers DRJ, Chapman JR, O’Connell PJ, Allen RDM, Nankivell BJ: Predictors of renal transplant histology at three months. Transplantation 67: 1222–1230, 1999
6- Roberts ISD, Reddy S, Russell C, Davies DR, Friend PJ, Handa AI, Morris PJ: Subclinical rejection and borderline changes in early protocol biopsy specimens after renal transplantation. Transplantation 77: 1194–1198, 2004
Acute rejection episodes and Chronic allograft nephropathy (CAN) can be subclinical without causing a noticeable affection of graft function due to low grade rejection process occurring resulting in long term fibrosis leading to chronic graft dysfunction which justifies performing graft biopsies within the first year of transplantation on screening bases without overt graft dysfunction.
On the other hand protocol biopsies are not put as a routine procedure in following renal transplant patients .
PROS of doing the biopsy
–Detection of Subclinical Rejection(SCR)
SCR leads to long-term worsening of graft function and early intervention can improve the outcome as studies showed that early treatment with corticosterois can improve long term graft survival,while untreated SCR had an increase in interstitial fibrosis and tubular atrophy in later biopsies as publisehed in 2 studies.
Acute rejection and borderline rejection, collorated with the degree of functional graft impairment at the time of biopsy and outcome at 1year .
Studies concluded that protocol biopsies can detect early and enhances treatment of acute and borderline rejection which in turn preserves long-term graft function.
–Diagnosis of CAN by Protocol Biopsy
The first few months after transplantation are crucial for the occurrence of CAN and protocol biopsies can be important in detecting early chronic allograft damage that will appear later as early protocol biopsies revealed tubulointerstitial damage and vascular chronic damage which are indicative of allograft survival
Also it revealed that interstitial and vascular chronic damage exaggerates during the first 6 months after transplantation, then slowly after wards .
-Protocol Biopsies Are Valuable in High-Risk Recipients
Delayed graft function (DGF) is accompanied by poor long-term graft survival, and early treatment is mandatory which cannot be diagnosed on clinical bases ,only discovered by biopsy.
Studies concluded that reduced graft survival with DGF can be due to silent acute rejection, therefore protocol biopsies and treatment of SCR during prolonged DGF is essential .
Also protocol biopsies can detect subclinical antibody-mediated acute rejection in sensitized high-risk renal transplant patients .
–Detection of Graft Dysfunction as a Result of Nonimmune Factors
Non immunological factors are the most common to cause graft dysfunction as cyclosporine nephrotoxicity, but it is reversible if detected early enough, therefore protocol biopsies is important in discovering cyclosporine nephrotoxicity in those with stable renal allografts.
Another example is detection of subclinical BK virus (BKV) nephritis managed by reduction of immunosuppression doses which can improve the outcome .
Con: The Case Against Use of Protocol Biopsies
Variation in Reported Incidence of SCR and CAN
The incidence of SCR in the first 6 months after transplantation varying from 1 to 29% and CAN from 0 to 79% , also a precise conclusion on the frequency of SCR and CAN from such studies was difficult could be due to differences in human leukocyte antigen (HLA) matching, or due to differences in the incidences of DGF between studies,or the level of different immunosuppression used in each study as well as the inclusion criteria and interpreting CAN incidence data.
Reliability of SCR and CAN Diagnosis Assessment of the histologic changes
is in fact difficult so new molecular techniques was developed, as identification of pro inflammatory transcripts in tissue or urine by PCR,urine spectroscopy ,and measuring of cell activation markers, which is not applied till now
So Banff criteria was used to evaluate diagnostic biopsies not protocol biopsies .
To evaluate the benefit of protocol biopsies in terms of long-term survival and function, outcome should include a minimum of 5-yr graft survival and function end points.
It is a grey zone whether to treat SCR or not as some studies showed that increasing immunosuppression reduced the frequency of clinical rejection but not SCR.
Another aspect is the gap of time during which CAN will respond to therapy need to be estimated before the appropriate timing for protocol biopsies can be known .
Dear All
Many of you mentioned protocol biopsy if there is graft disfunction. It would not be called protocol biopsy. It will be a diagnostic biopsy.
Protocol biopsy is the biopsy at set interval without association of graft dysfunction.
One of the most difficult & important complication of renal transplantation is cute graft rejection with subsequent graft loss. Although the incidence of it decreased after using of more potent immunosuppression, but it is still problem due to chronic graft dysfunction.
Renal biopsy usually only done when there is a suspected clinical graft dysfunction, that confirmed by histological findings which may include advance fibrosis. Several studies suggest that graft dysfunction may be clinically inapparent but histological finding confirm low grade rejection that can be progressed to graft fibrosis & dysfunction. So protocol biopsied may have a role in improve graft survival especially in first year post transplantation.
Sub clinical rejection (SCR) defined as presence of histological features of acute rejection in absence of clinical signs of rejection, which can occur in 30% of protocol biopsies done in first 6 months post transplantation .
Several studies proved that protocol biopsies at 1, 2,3,6,12 months show a benefit from early diagnosis & treatment of SCR & borderline rejection on long term graft survival.
Another studies in adult & pediatrics show that protocol biopsies can detect interstitial fibrosis & vascular changed before occurrence of clinical graft failure.
It was found that protocol biopsies in high risk patients is important in patients with DGF which may be caused by SCR so early treatment can improve outcome. Also using of protocol biopsies in some centers can detect asymptomatic CNI toxicity & subclinical BKV infection.
The safety of protocol biopsies was a major concern so just few centers used it, but some studies proved that it is a straight forward procedure with low risk of major & minor complication. There were difference in the incidence of CAN & SCR between studies , this may be due to
Protocol biopsy has a limitation that it using Banff criteria which evaluate changes in diagnostic biopsy while protocol biopsy may show mild interstitial fibrosis & this lead to misclassification of biopsy with borderline changes or CAN
Well done
Chronic allograft nephropathy is the commonest cause of late graft rejection and is strongly correlated with the incidence of acute rejection episodes during the first year after renal transplantation.
In most transplant centers, renal allograft biopsies are not routinely performed, instead, only done to evaluate the causes of kidney dysfunction. In some cases, clinical deterioration in kidney function only occurs when, already chronic histological changed are apparent.
Some reports suggested that episode of acute rejection or chronic allograft nephropathy could be subclinical, which means that recipient has normal kidney function detected by routine laboratory testing. In this context, unrecognized subclinical persistent rejection could lead to long-term graft interstitial fibrosis/tubular atrophy and chronic dysfunction.
Implementation of protocol biopsies regardless of allograft function could be of great benefit in individuals with risk of allograft rejection.
Pro:
Detection of Subclinical Rejection: Some studies reported UO TO 30% incidence of acute subclinical rejection detected in protocol biopsies performed in the first 6 months post-transplantation. Protocol biopsies for early detection and treatment of acute rejection may be a major factor in preserving long-term graft function.
Diagnosis of CAN by Protocol Biopsy: There is evidence that the development of CAN primarily occurs in the first few months after transplantation. In this setting, protocol biopsies may be a diagnostic in detecting early signs of subclinical chronic allograft damage. The presence of tubule-interstitial fibrosis and vascular –damage, which usually occur in the first 6 months following transplantation, are powerful predictors of allograft survival.
Protocol Biopsies Are Valuable in High-Risk Recipients: Delayed graft function (DGF) is strongly associated with poor long-term graft survival, and early treatment of acute rejection in such patients is vital. In pretransplant sensitized patients, protocol kidney biopsy is warranted to detect subclinical rejection.
Detection of Graft Dysfunction as a Result of Nonimmune Factors: Nonimmune mediated kidney damage could also be cause of kidney injury. For example CNI renal toxicity even in the therapeutic ranges should be suspected. Because CNI nephrotoxicity is reversible protocol biopsies may be a useful. Protocol biopsies could also detect renal diseases such as subclinical BK virus (BKV) nephritis.
Use of Protocol Biopsies in Clinical Trials Designed to Prevent CAN: Studies have shown that CAN diagnosed in protocol biopsy is an independent predictor of long-term outcome.
Safety of Protocol Biopsies: Studies suggest that the procedure is safe and minor complication are rare.
Cons
Variation in Reported Incidence of SCR and CAN: There are differences in the methodology between studies which make comparisons problematic. Studies also lack consistency these to support the adoption of protocol biopsies in the routine clinical practice.
Reliability of SCR and CAN Diagnosis: Reliable methods to quantify histologic changes in protocol biopsies were lacking. The histologic criteria used in the studies differs and some used the old Banff criteria.
How Should Utility of Protocol Biopsies Be Tested? The general implementation of protocol biopsies into clinical practice is lacking even in large multicenter hospital.
Treatment for SCR and CAN: The presence of mononuclear infiltrates in renal allografts does not always indicate rejection, and some recipients maintain good long-term graft function despite signs of SCR.
The benefit of treating SCR detected by protocol biopsy need to be confirmed, because the effect of not treating SCR is unknown, because most studies give anti-rejection treatment for SCR when detected in protocol biopsies
In my clinical practice, allograft biopsy is not routinely done in protocol based form, but reserved for patients with kidney dysfunction.
Excellent
With improvement of immunosuppression protocols acute graft rejection rates have markedly improved.
Chronic allo-graft nephropathy (CAN) which is the most common cause of late graft rejection and is strongly correlated with the number of acute rejection episodes during the first year after renal transplantation .
protocol biopsies performed during the first posttransplantation year irrespective of graft function, may be help in early identification acute rejection or CAN when treatment is still an option and no permanent scarring has occurred.
pros of protocol biopsies
1 early detection of histological subclinical rejection episodes which detected in up to one third of the patients in first 6 month ;even without clinical decline in graft function.
2 steroid treatment of SCR detected in the early postoperative period (1 to 3 mo) improved outcome with decrease in early and late acute rejection episodes, and patients showed less chronic damage at month 6 and had a lower s creatinine at 2 years posttransplantation.
3 untreated SCR was found to be correlated with an increase in interstitial fibrosis and tubular atrophy in later biopsies in 2 studies.
4 10- years study of 304 patients suggest that use of protocol biopsies for the early detection and treatment of acute and borderline rejection may be a major factor in preserving long-term graft function.
5 the presence of tubulointerstitial damage and vascular chronic damage are powerful predictors of allograft survival number of studies showed that early detection and treatment of CAN have greatly improved long-term graft survival,frequency of CAN in early protocol biopsies up to 6 mo posttransplantation was high up to 79% and early protocol biopsies is very helpful in early detection of CAN befor decline in graft function.
6 Protocol biopsies have also been reported to be useful in the detection of CAN in pediatric transplant recipients.
7 protocol biopsies is very helpful in high risk patients as those with DGF allowing early detection and treatment to prevent long term adverse effects.
7 Protocol biopsy is effective for detecting subclinical AMR in sensitized recipients.
8 protocol biopsies also help to dignose other causes of graft failure such as cyclosporine nephrotoxicity which is correctable early and subclinical Bk virus nephritis.
9 the predictive value on graft survival of incipient chronic tubulointerstitial lesions in protocol biopsies was found to be superior to other predictors of outcome, such as acute rejection or serum creatinine.
10 protocol biopsies are generally safe
procedure with reported rates of major complications of just 0.7% when a 16-gauge needle was used to perform the procedure and 1% when an 18-gauge needle was used.
cons of protocol biopsies
1 No clear evidence on the ralation between SCR and subsequent development of CAN has not been proved.
2 a study on 98 patients showed late allograft outcome in patients with borderline changes was comparable to that of patients with normal histology.
3 incidences of SCR and CAN reported in biopsy specimens showed wide variations with the incidence of SCR in the first 6 mo posttransplantation varying from 1 to 29% and CAN from 0 to 79%.
4 chronic renal changes that occure with CAN may resemble those occurred due do doner factor as deceased donor, increasing age, female gender, hypertension.
5 SCR as mononuclear cell infiltration does not necessary mean rejection and benefit of treating SCR detected by protocol biopsy has yet to be confirmed. .
6 High percentage of protocol biopsies are found to be inadequate when using Banff criteria and that evaluation of two sequential protocol biopsies (taken at months 4 and 14) by Banff criteria is not an accurate way of monitoring the progression of CAN.
7 no clear studies support the benefit of protocol biopsies in renal transplant patients with stable kidney function yet and no standard timing for the protocol biopsies .
8 management steps after detection of CAN in a protocol biopsy is also not clear .
In my practice are not doing protocol biopsies and only perform biopsy for clinically evident allograft dysfunction
Excellent
Protocol biopsies
PROS:
CONS:
In our practice we do protocol biopsy only when the patient accepts the idea, otherwise the majority of the biopsies done at our center are for cause biopsies.
Excellent
The presented article highlights one of the debatable subjects in the field of kidney transplantation which is the cost-effectiveness of implementing a protocol of routine kidney allograft biopsy.
The advantages of protocol biopsy can be summarized in the following points:
Ø It can detect histological evidence of rejection before it is apparent clinically.
Ø Early detection of immunological injury and subsequent early initiation of appropriate management is associated with a better long term allograft outcome.
Ø Allograft biopsy can also detect non-immunological causes of allograft dysfunction like BK nephropathy and CNI toxicity before they can cause irreversible clinical sequel.
Ø Allograft biopsy is easier than native kidney biopsy (due to its anatomical position to be easily accessed), which makes it relatively safe with a low incidence of serious complications.
On the other hand, some critical points need to be considered before adopting such a protocol as a universal recommendation, which includes:
· There is significant variability in the incidence of subclinical rejection (which is diagnosed by protocol biopsy) between different transplant centres and even between different transplant recipients subgroups.
· The histological findings in the protocol biopsy need standardization to define the clinically relevant histological criteria that require treatment.
· There is a lack of evidence regarding the benefit of early treatment of minor histological injury diagnosed by protocol biopsy.
In our practice, we do not have a protocol biopsy regimen in our hospital, and we perform allograft biopsy only upon clinical indications. Furthermore, our local population is usually afraid of invasive allograft biopsy. They are reluctant to agree to allograft biopsy unless they realize progressive deterioration of kidney functions.
Excellent
Protocol biopsy
Chronic allograft nephropathy CAN is the major cause of graft failure, and is related to the numbers of acute rejection which happened throughout the whole life of the graft especially first year, and also subclinical rejection can happened without any reflection on renal function, so multiple attacks of subclinical rejection can end by scarring and CAN , at that time the treatment will be impossible, hence the role of protocol graft biopsy which should be done especially in the first year even with normal renal function.
Pros of protocol biopsy:
1- Detection of SCR (subclinical rejection) it is histological rejection without affection of renal function. Treatment of subclinical rejection with steroid of course will improve graft outcome and survival.
2- Diagnosis of CAN Occurrence of CAN may be related to multiple attacks of untreated subclinical rejection, and indicated by interstitial fibrosis and vascular damage which become faster early after transplantation and slower in late period post-transplant, they are strong predictor of graft survival. Early treatment and management of CAN will affect positively on graft survival.
3- Protocol biopsy is of high benefit in patients with DGF (delayed graft function), as in DGF patients, subclinical rejection may happened, and DGF and these patients vulnerable to SCR because of under immunosuppression status due to DGF mask it, so detection of SCR in those patients is very useful with serial biopsies in early period post-transplant.
4- Also should be done in the patients with DSA pretransplant, as they are at high risk of subclinical antibody mediated rejection, for early detection and management especially early post-transplant.
5- Detect early cyclosporine nephrotoxicity without marked graft function affection, so for early management.
6- Detection of subclinical infection as BK virus BK nephritis, because when happened will enforce us to decrease immunosuppression and expose the graft to be lost, so early detection by protocol biopsy can save the graft. In addition, detection of SCR with BK nephritis will not happened except by protocol biopsy.
7- Histopathological diagnosis of CAN in early period post-transplant indicated by vascular damage and interstitial fibrosis is the only tool to diagnose CAN, which is the strong predictor for graft survival.
8- Low incidence of its major complications in relation to its benefits regarding early diagnosis and management.
Cons of protocol biopsy
1- Variations in the reporting incidence of SCR in the studies may be related to low numbers of studies, low sample size, also presence of other factors like extent of HLA mismatch, immunosuppression protocol used, DGF.
2- Variations in the reporting incidence of CAN in the studies , may be also related to low sample size, low number of studies , and donor related changes (donor may refuse biopsy before transplant), also CAN can be mistaken for age.
3- No clear reliable method to measure or quantify the degree of CAN , as it depends on Banff 97 criteria which can be used in diagnostic biopsy not for protocol biopsy.
4- Introduction of MMF lower the incidence of SCR, so early biopsy not needed if not indicated clinically.
5- Implementation of protocol biopsy to improve graft survival and outcome should be tested for at least 5 years before general implementation , also timing when to do , and plan of therapy will be based on single biopsy or to wait for serial…so many problems.
6- Some studies showed that there is no difference between treatment of SCR and not to treat SCR on outcome and graft survival, also the evidence suggest that high immunosuppression status will not prevent SCR but prevent acute rejection will add no benefit in early detection of SCR for aim of its treatment.
in my practice, protocol biopsy is not used. and we do graft biopsy whenever indicated.
Excellent
Protocol biopsy
Pros:
1-Detection of Subclinical Rejection
2-Diagnosis of CAN
3-High risk recipients e.g DGF
4-Detection of Graft Dysfunction as a Result of Nonimmune Factors e.g
cyclosporine toxicity and sub clinical BK Nephro patchy
No prospective methods to monitor the appearance/progression of CAN are available currently for the kidney; thus, clinical trials that are conducted in renal transplant patients, by necessity, need to use surrogate markers of long-term graft survival
Histologic changes in transplant biopsies provide the earliest available evidence of graft damage.
Safety should be considered as biopsy may lead to severe hemorrahge and loss of graft .
Cons:
1-Variation in Reported Incidence of SCR and CAN
2-Reliability of SCR and CAN Diagnosis: sometimes inadequate biopsy sample ,sometimes needs 2 serial biopsies to confirm diagnosis ,so we need new markers e.g urine spectroscopy and PCR to detect pro inflammatory transcripts
Another issue, that recent trials found that SCR incidence decreased with MMF and azathioprine introduction
So if protocol biopsies are indicated to diagnose CAN and SCR and in both biopsies may be inconclusive in diagnosis also ,if diagnosed there is no specific therapy for both of them.
Clinical experience : protocol biopsy not done
Currently renal biopsy is indicated when there is evidence of renal graft dysfunction such as renal impairment or occurrence of proteinuria
Protocol biopsy is doing renal biopsy for renal transplant patients in the first year of transplantation without the evidence of renal allograft dysfunction
Pros of protocol biopsy
1. Subclinical rejection (histologic evidence of acute rejection without clinically detected graft dysfunction) and CAN (histological evidence of tubulointerstitial damage and vascular chronic damage ) occur commonly in the first year (in up to 30%, and 79% of protocol biopsies, respectively) and these are associated with poor graft survival.
2. Early treatment of subclinical rejection (with corticosteroids) can improve renal allograft survival
3. Protocol biopsy has a prognostic significance since it can predict graft survival. the occurrence of CAN is associated with lower graft survival when compared to patients without CAN in protocol biopsy.
4. Aid in diagnosis of CNI toxicity which is common in first year post transplantation and is reversible cause of renal allograft dysfunction
5. Can detect subclinical BK virus nephritis which is common in first year post transplant with subsequent reduction of immunosuppression before occurrence of irreversible damage
6. Doing renal allograft biopsy in the setting of renal graft dysfunction means that there is sufficient injury to the kidney with possible fibrosis and irreversibility moreover the occurrence of frequent rejection episodes are associated with CAN and graft loss.
7. Renal allograft biopsy is relatively safe procedure with the incidence of major complication was reported by one study to be 0.7% when using 16-gauge needle and 1% when using 18-gauge needle.
Cons of protocol biopsy
1- No clear correlation between occurrence of subclinical rejection and long term graft survival, Moreover the impact of treatment of subclinical rejection on long term graft survival has not been proven in all studies.
2- No clear protocol is set but it was found that there is no difference when protocol biopsies are done at 1, 2, 3, 6, and 12 months and if it was done at months 6 and 12 only.
3- Problems in diagnosis :
⦁ In SCR as mononuclear cell infiltration does not necessary mean rejection
⦁ In CAN can be confused with chronic allograft changes due to donor characteristics such as age, female gender, HTN or deceased donor kidney.
⦁ High percentage of protocol biopsies are found to be inadequate when using Banff criteria
4- Problems in treatment :
⦁ In SCR intensification of immunosuppression was found to decrease the incidence of clinical but not subclinical rejection suggesting a doubt in the effect of treatment of SCR
⦁ In CAN no definite plan in the treatment of early detected CAN
Patients that may benefit from of protocol biopsy
1- Sensitized high risk patients since the incidence of subclinical ABMR is extremely high in this group.
2- Patients with DGF a 7-day protocol biopsy was found to be of great significance since the occurrence of subclinical rejection in this group is more common, and co treatment of SCR may improve outcome.
Clinical experience
We are not doing protocol biopsies and only perform allograft biopsy in the setting of allograft dysfunction
Well done
In the setting of graft dysfunction, biopsy would not be a protocol biopsy. Excellent
protocol biopsy were not done in our unit
Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%.With Tacrolimus it is 2.6%.
it is better to treat SCR as it progresses to chronic allograft nephropathy.
Subclinical rejection in tacrolimus-treated renal transplant recipients
James M Gloor
52% pts experienced subclinical rejection in sentisized patients at 3rd month protocol biopsy.
Time course of histologic injury in total of 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch HLA-incompatible kidney between 2000 and 2010 (follow up: 1-9 years). (Bagnasco et al Transplantation 2014).
1)with the introduction of tacrolimus the incidence of SCR is 2.6% and surveillance biopsies may not be necessary with this regimen.
2) cost factor as most patients here pay from their pocket.
3) in our unit after an indication biopsy patient developed hematuria which just didnt resolve, so explaining to a patient if such an event happens after a protocol biopsy would be difficult in our setup.
Pros for protocol biopsies
1)SCR leads to long-term deterioration of graft function and its detection and early intervention may well improve
outcomes .
2)early detection and treatment of CAN could have a dramatic effect on the outcome of the graft.
3) there is a strong need for a means of promptly diagnosing acute rejection in patients with DGF.
4)Will be of help to identify non immunologic cause of graft dysfunction.
5)Procedure is safe with low incidence of clinically significant complications after protocol biopsy.
Cons for protocol biopsies
1)variable results from previous studies about incidence of CAN and SCR casts doubt about the adoption of protocol biopsies in routine treatment.
2)no histological criteria to uniformly label protocol biopsies into various categories.
3)optimal timing and frequency of protocol biopsies is subjective, plus should decisions be taken on serial biopsies or a single biopsy is not clear.
4)clear proof that treating SCR and CAN on protocol biopsies improves long term outcome is lacking .