Title: Importance of Formal Classification of Rejection for Collaborative Studies in Transplantation
1Importance of Formal Classification of Rejection
for Collaborative Studies in Transplantation
- L. G. Hunsicker, M.D.
- U. of Iowa College of Medicine
- Stephen M. Rose, Ph.D.
- NIAID
2Outline
- Major NIH initiatives in transplantation.
- The importance of histology for understanding
mechanism, and relating this to practice. - The future endpoints for efficacy in clinical
trials structure and function. - Early changes and the importance of structure.
- What the transplant pathology community needs to
address.
3NIH Program in Transplantation
- NIH provides gt 260M to support basic,
preclinical and clinical studies and trials in
transplantation designed to - reduce graft rejection, and
- increase long-term graft survival,
- eventually leading to immunosuppression free
indefinite graft survival (i.e. transplantation
tolerance).
4NIH/NIAID Support Relevant to Transplantation
- Adult and Pediatric Kidney Transplantation trials
- Immune Tolerance Network
- Islet transplantation
- Kidney transplantation
- Liver transplantation (too be implemented)
- Autoimmunity
- Asthma and allergic diseases
5NIH/NIAID Support Relevant to Transplantation
- Autoimmunity Centers of Excellence
- Stem Cell Transplantation for Autoimmune Diseases
- Asthma and Allergic Diseases Cooperative Centers
- Innovative Research in Tolerance for
Immune-mediated diseases (PPGs)
6Other NIH Support Relevant to Transplantation
- Genetics of Renal Diseases
- Type I diabetes
- DPT-1 and TrialNet
- Lung transplantation trials
- Heart transplantation trials
- Occular transplantation trials
- Bone Marrow/Stem Cell transplantation
7Standardization is essential!
- All NIH efforts require standardized, validated,
and community accepted histopathology as the
platform for development of new, less invasive
techniques that can detect clinically relevant
changes BEFORE irreversible damage is done!
8Outline
- Major NIAID initiatives in transplantation.
- The importance of histology for understanding
mechanism, and relating this to practice. - The future endpoints for efficacy in clinical
trials structure and function. - Early changes and the importance of structure.
- What the transplant pathology community needs to
address.
9Current Status of Renal Transplantation
- One year graft survival has improved over the
past 30 years from about 40 to almost 90. - Recent analyses (Hariharan S, N Engl J Med 2000
342605) have documented improved long-term renal
graft survival over the past decade, possibly due
to - Better immunosuppressives
- Better/earlier diagnosis of rejection
- Better treatments for rejection
- BUT
10Current Status of Renal Transplantation
- Data still shows that even just one serious
rejection episode significantly compromises
long-term survival. Therefore - NIH is focusing its resources on studies to
develop validated surrogates and biomarkers of
rejection AND induction, maintenance and loss of
tolerance.
11Surrogate- and biomarkers of rejection and graft
survival
- All NIAID supported transplant trials have
integrated mechanistic studies (ex. gene
expression analyses, ELISPOT, tetramer analyses
for TcR expression) - BUT
- The utility of these new assays need to be
validated against established clinical data. - Todays gold standard is still classic
histopathology!
12Immune Tolerance NetworkTissue Analysis Core
Facility
- Scope of Work Includes
- Interpreting biopsies from transplanted kidneys,
livers, islet transplants, and other tissues, - Performing assays for tolerance in clinical
studies (in situ hybridization, TUNEL assays,
etc.) - Performing new protocol specific assays for same.
- Developing a tissue analysis database.
- Advancing tissue analysis assays such as biopsy
grading, laser-mediated capture dissection, etc. - Interested parties should visit ITN web
site http//www.immunetolerance.org
13Outline
- Major NIAID initiatives in transplantation.
- The importance of histology for understanding
mechanism, and relating this to practice. - The future endpoints for efficacy in clinical
trials structure and function. - Early changes and the importance of structure.
- What the transplant pathology community needs to
address.
14Major Clinical Goals in Renal Transplantation
- Reduce early (e.g., 1 year) graft and patient
losses (failure from acute rejection). - Reduce long term (e.g., 10 year) graft and
patient losses (loss from chronic rejection). - Achieve donor specific unresponsiveness so as to
make long-term immunosupression, with its
toxicities and expense, unnecessary. - Reduce other morbidity, improve quality of life,
reduce expense.
15Proposed Hard End Points for Clinical Trials in
Renal Transplantation
- Reduce graft loss to acute rejection Patient
and graft survival at one year - Reduce graft loss to chronic rejection Pt.
and graft survival over many years. - Induce tolerance ?Withdrawal of
immunosuppression? - Reduce cost and improve quality of life
Eliminate acute rejection episodes
16Difficulty of Studying Strategies to Improve 1
Year Graft Survival
- In 1997-1998, U.S. 1 year renal allograft
survival (all comers) was - 89.4 for cadaveric donor organs, and
- 94.5 for living donor organs.
- To have 80 power to detect a 30 improvement in
1 year cadaveric graft survival (p0.05) requires
2,627 patients. - The same study with living donor patients
requires 5,371 patients. - Studies with these endpoints are no longer
feasible.
17Proposed Hard End Points for Clinical Trials in
Renal Transplantation
- Reduce graft loss to acute rejection Patient
and graft survival at one year - Reduce graft loss to chronic rejection Pt.
and graft survival over many years. - Induce tolerance ?Withdrawal of
immunosuppression? - Reduce cost and improve quality of life
Eliminate acute rejection episodes
18Difficulty of Studying Strategies to Improve 5
Year Graft Survival
- Currently, 5 year graft survival for cadaveric
renal transplants is 65 - to detect a 30 reduction in graft loss (75
survival) requires 800 patients recruited over 2
years and followed for an additional 3 years. - However, about 50 of graft losses are due to
death.
19Difficulty of Studying Strategies to Improve 5
Year Graft Survival
- To detect a 30 reduction in graft loss due to
chronic rejection would take 1600 pts.
recruited over 4 years and followed for 3 more. - These endpoints are not feasible, either.
20Proposed Hard End Points for Clinical Trials in
Renal Transplantation
- Reduce graft loss to acute rejection Patient
and graft survival at one year - Reduce graft loss to chronic rejection Pt.
and graft survival over many years. - Induce tolerance ?Withdrawal of
immunosuppression? - Reduce cost and improve quality of life
Eliminate acute rejection episodes
21Drugs Approved by the FDA Based on Reduction of
Acute Rejection
- Chemical immunosuppressants
- mycophenolate mofetil
- sirolimus (rapamycin)
- Antibodies
- daclizumab
- basiliximab
- thymoglobulin
22Present Incidence of Acute Rejection in 1st 6
Months
- Recent sirolimus trials
- acute rejection rate within 6 months was 11 -
19. - Thymoglobulin induction trial
- acute rejection rate was 6. (Brennan et al.)
- Daclizumab 2 dose regimen in high risk patients
trial - acute rejection was 6. (Golconda et al.)
- Trials to reduce acute rejection are no longer
feasible.
23Proposed Alternative End Points for Clinical
Trials in Renal Transplantation
- Reduce graft loss to acute rejection Patient
and graft survival at one year - Reduce graft loss to chronic rejection Surroga
te endpoints for graft survival - Induce tolerance ?Withdrawal of
immunosuppression? - Reduce cost and improve quality of life
Eliminate acute rejection episodes
24Surrogate Endpoints for Late Renal Allograft
Failure
- Even when there is currently a strong
relationship between a surrogate endpoint and a
clinically meaningful endpoint, that
relationship may not persist following an
intervention. - For this reason, the FDA is very reluctant to
accept surrogate outcomes in clinical trials. - There may be an exception to this generality.
25Alternative Explanations for Correlation of
Outcomes
26On the Way Surrogate EndpointsThe Possible
Exception
27Proposal for Use of On the Way Surrogate
Endpoints for CAN
- Randomize patients at 6 months with high risk for
CAN and early graft failure. - Provisionally establish the impact of the
intervention using change of glomerular
filtration rate (6 month baseline to 2.5 years)
for FDA approval.
28Proposal for Use of On the Way Surrogate
Endpoints for CAN
- Estimate changes in histology from 6 months to
protocol biopsy at 2.5 years. - Confirm provisional findings with long term graft
outcomes, possibly using UNOS registry.
29Early Access to Drugs
- Subpart E in Section 312 of the Code of Federal
Regulations establishes procedures to expedite
the development, evaluation, and marketing of new
therapies intended to treat people with
life-threatening and severely-debilitating
illnesses, especially where no satisfactory
alternatives exist. (Federal Register, October
21, 1988). - Designed primarily in response to the demands of
HIV/AIDS advocates.
30Accelerated Development/Review
- Can be used under two special circumstances
- when approval is based on evidence of the
product's effect on a surrogate endpoint, and - when the FDA determines that safe use of a
product depends on restricting its distribution
or use.
31Accelerated Development/Review
- The fundamental element of this process is that
the manufacturers must continue testing after
approval to demonstrate that the drug indeed
provides therapeutic benefit to the patient. - May be an avenue for provisional approval of a
drug that requires very long trials for
definitive endpoints -- e.g. for treatment of
chronic renal allograft rejection.
32Outline
- Major NIAID initiatives in transplantation.
- The importance of histology for understanding
mechanism, and relating this to practice. - The future endpoints for efficacy in clinical
trials structure and function. - Early changes and the importance of structure.
- What the transplant pathology community needs to
address.
33Functions of the Glomerulus
- Filtration of water and small solutes
- Retention of larger elements
- plasma proteins
- formed elements (RBCs, platelets, etc.)
- Maintenance of near constancy of GFR
- short term autoregulation
- longer term compensatory hyperfiltration in
response to reductions in glomerular number or
filtration surface area.
34GLOMERULAR HEMODYNAMICS
Afferent
Efferent
Arteriole
Arteriole
Normal Pressure 105 mmHg
15 mmHg
50 mmHg
EFFECTS OF CHANGES IN ARTERIOLE TONE
Afferent arteriolar dilatation leads to
??Flow
? PGC
Efferent arteriolar dilatation leads to
? Flow
??PGC
35HYPOTHETICAL EFFECT OF ACE INHIBITION
ON GLOMERULAR FILTRATION AREA (GA) AND GFR IN
DIABETIC NEPHROPATHY
100
50
GA nl
GFR nl
Placebo
Ace. INH
0
0
10
20
Years
Intervention 1
Intervention 2
36CSG Trial of Captopril in Type I Diabetic
Nephropathy By Entry Scr
Lewis EJ et al N Engl J Med 1993 3291456-62
37Outline
- Major NIAID initiatives in transplantation.
- The importance of histology for understanding
mechanism, and relating this to practice. - The future endpoints for efficacy in clinical
trials structure and function. - Early changes and the importance of structure.
- What the transplant pathology community needs to
address.
38Requirements for Evaluation of Histological
Outcomes
- Consensus on methods for evaluation and grading
of biopsies -- the Banff process. - Demonstration of ability to achieve good intra-
and interobserver consistency in grading. - Determination of an appropriate baseline for
studies of progressive CAN. - Validation of correlation of histological changes
with longer term functional changes and hard
outcomes.
39Definition of a Standard Does Not Imply
Reproducibility
- Five experienced renal pathologists graded twice
each 25 biopsies of patients with lupus
nephropathy for Austin chronicity index (CI). - Grades
- low-risk 0 or 1
- intermediate-risk 2 or 3
- high risk gt 3
- Analyses examined range of mean values, and
intra- and interobserver variability using the
kappa statistic.
Wernick RM et al, Ann Int Med 1993 119805
40Wernick Study Results
- Range of average CI over readers
- 2.3 - 4.8
- Intraobserver consistency of reading low or
intermediate vs. high risk - Mean kappa (range) 0.62 (0.44 - 0.78)
- Interobserver consistency
- Range of agreement 44 - 72
- Mean kappa, first reading 0.53
- Mean kappa, second reading 0.48
Wernick RM et al, Ann Int Med 1993 119805
41Wernick Study Conclusions
- the incorporation of index scoring into patient
management may lead to erroneous decision making.
Small differences in chronicity index scoring
may profoundly alter risk group assignment
Wernick RM et al, Ann Int Med 1993 119805
42Wernick Study Conclusions
- Experienced reviewers from referral institutions
may benefit from mutual education, leading
to a more uniform standard of grading. - biopsy specimens should be scored by
pathologists working in a quality-controlled
reference center.
Wernick RM et al, Ann Int Med 1993 119805
43Reproducibility of the Banff Classification of
Renal Allograft PathologyMarcussen N et al.
Transplantation 1995 601083
- Five experienced transplant renal pathologists
scored 77 renal transplant biopsies for the
components of the 1995 Banff classification of
acute allograft rejection, including estimation
of volume fraction of inflammation. - Intraobserver kappa score for dx of ACR 0.38
- Interobserver kappa score for dx of ACR 0.40
44Some Possible Conclusions
- The Banff Consortium must go beyond defining a
standard method for the analysis of transplant
biopsies to establish the ability of the
definition to be used in a reproducible way. - The Banff Consortium should seek opportunities
for pathologists to experience joint reading
sessions with experts to improve consistency.
45Some Possible Conclusions
- Consideration should be given to development of
centralized Pathology Cores. - Consideration should be given to the use of
morphometry for things such as fibrosis.
46Requirements for Evaluation of Histological
Outcomes
- Consensus on methods for evaluation and grading
of biopsies -- the Banff process. - Demonstration of ability to achieve good intra-
and interobserver consistency in grading. - Determination of an appropriate baseline for
studies of progressive CAN. - Validation of correlation of histological changes
with longer term functional changes and hard
outcomes.
47Possible Etiologies of Chronic Allograft
Nephropathy
- Initial, but not ongoing, renal damage from ATN,
advanced donor age, etc. - Ongoing immunological damage
- Impact of HLA mismatching on long term outcomes
- Possibly antibody mediated - C4d staining
- Ongoing non-immunological damage
- calcinerurin inhibitor toxicity
- accelerated graft loss in hypertensive
African-Americans
48ALTERNATIVE MECHANISMS FOREARLY KIDNEY GRAFT
FAILURE
Good Function
GFR
Accelerated Slope
Reduced Intercept
GFR at return to dialysis
Time
49Implantation renal biopsy showing ATN, but
minimal interstitial fibrosis. Courtesy of
Lorraine Racusen
50Renal biopsy in the same patient 5 weeks after
transplant, showing extensive interstitial
fibrosis. Courtesy of Lorraine Racusen
51Nicholson ML et al, Transplantation 1999 68236
52What is the Basis for Fibrosis after (Transplant)
Kidney Damage?
- Progressive fibrosis might be due to
- overactivity of profibrotic mechanisms,
squeezing out recovery of normal tubules. - failure of recovery of normal tubular cells,
leading to tubular atrophy and filling in with
fibrous tissue. - Can the ultimate extent of baseline fibrosis be
predicted by analyses of - tubular cell apoptosis or mitosis rates?
- early overactivity of profibrotic cytokines?
53Requirements for Evaluation of Histological
Outcomes
- Consensus on methods for evaluation and grading
of biopsies -- the Banff process. - Demonstration of ability to achieve good intra-
and interobserver consistency in grading. - Determination of an appropriate baseline for
studies of progressive CAN. - Validation of correlation of histological changes
with longer term functional changes and hard
outcomes.
54Conclusions - 1
- NIH and the transplant community continue to need
consistent and reproducible consensus criteria
for the diagnosis of - acute rejection -- primarily for the testing of
new proposed surrogates of rejection and
tolerance. - chronic allograft nephropathy -- for the
performance of definitive therapeutic trials.
55Conclusions - 2
- The NIH is focusing major resources on
development of minimally and noninvasive
diagnostic tools. - The only way to be ready for this is to have
standardized histopathology AND be ready for the
landscape to change to more molecular and
bioimaging technologies.
56Conclusions - 3
- The Banff process permits consensus to develop.
- Now the Banff process has to be expanded to
maximize consistency of reading and answer new
questions raised about clinical interpretation.