Transcript Importance of Formal Classification of Rejection for

Importance 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
Outline
• 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.
NIH Program in Transplantation
• NIH provides > $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).
NIH/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
NIH/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)
Other 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
Standardization 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!
Outline
• 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.
Current 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;
342:605) 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
Current 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.
Surrogate- 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.
Today’s gold standard is still classic
histopathology!
Immune Tolerance Network
Tissue 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
Outline
• 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.
Major 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.
Proposed “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
Difficulty 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 (p=0.05) requires 2,627
patients.
• The same study with living donor patients requires 5,371
patients.
Studies with these endpoints are no longer
feasible.
Proposed “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
Difficulty 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.
Difficulty 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.
Proposed “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
Drugs Approved by the FDA Based
on Reduction of Acute Rejection
• Chemical immunosuppressants
– mycophenolate mofetil
– sirolimus (rapamycin)
• Antibodies
– daclizumab
– basiliximab
– thymoglobulin
Present 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.
Proposed 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”:
Surrogate endpoints for graft survival
• Induce tolerance:
?Withdrawal of immunosuppression?
• Reduce cost and improve quality of life:
Eliminate acute rejection episodes
“Surrogate 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.
Alternative Explanations for
Correlation of Outcomes
Sequential Causes
Immunological
Disparity
leads to
Acute Rejection
Episodes
leads to
Chronic Rejection
and Graft Loss
Collateral Causes
Immunological
Disparity
leads to
Acute Rejection
Episodes
Chronic Rejection
with Graft Loss
“On the Way” Surrogate Endpoints:
The Possible Exception
Sequential Causes
Immunological
or nonimmunological
injury leads to
Graft fibrosis
and loss of GFR
leads to
Chronic Allograft
Nephropathy and
Graft Loss
Proposal 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.
Proposal 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.
Early 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 lifethreatening 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.
Accelerated 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.”
Accelerated 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.
Outline
• 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.
Functions 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.
GLOMERULAR HEMODYNAMICS
Afferent
Arteriole
Efferent
Arteriole
Normal Pressure: 105 mmHg
50 mmHg
15 mmHg
EFFECTS OF CHANGES IN ARTERIOLE TONE
Afferent arteriolar dilatation leads to:
Flow
 PGC
Efferent arteriolar dilatation leads to:
 Flow
PGC
HYPOTHETICAL EFFECT OF ACE INHIBITION ON
GLOMERULAR FILTRATION AREA (GA) AND GFR
IN DIABETIC NEPHROPATHY
100
GA % nl
50
GFR % nl
Placebo
Ace. INH
0
0
Intervention 1
10
Years
20
Intervention 2
CSG Trial of Captopril in Type I
Diabetic Nephropathy: By Entry Scr
Lewis EJ et al
N Engl J Med
1993;
329:1456-62
Outline
• 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.
Requirements for Evaluation of
Histological Outcomes
• Consensus on methods for evaluation and
grading of biopsies -- the Banff process.
• Demonstration of ability to achieve good intraand 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.
Definition 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:
– intermediate-risk:
– high risk:
0 or 1
2 or 3
>3
• Analyses examined range of mean values, and
intra- and interobserver variability using the
kappa statistic.
Wernick RM et al, Ann Int Med 1993; 119:805
Wernick 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; 119:805
Wernick 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; 119:805
Wernick 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; 119:805
Reproducibility of the Banff Classification of
Renal Allograft Pathology
Marcussen N et al. Transplantation 1995; 60:1083
• 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
Some 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.
Some 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.
Requirements for Evaluation of
Histological Outcomes
• Consensus on methods for evaluation and
grading of biopsies -- the Banff process.
• Demonstration of ability to achieve good intraand 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.
Possible 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 AfricanAmericans
ALTERNATIVE MECHANISMS FOR
EARLY KIDNEY GRAFT FAILURE
Good Function
GFR
Accelerated
Slope
Reduced
Intercept
GFR at return to dialysis
Time
Implantation renal biopsy showing ATN, but minimal
interstitial fibrosis. Courtesy of Lorraine Racusen
Renal biopsy in the same patient 5 weeks after transplant, showing
extensive interstitial fibrosis. Courtesy of Lorraine Racusen
Nicholson ML et al,
Transplantation
1999; 68:236
What 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?
Requirements for Evaluation of
Histological Outcomes
• Consensus on methods for evaluation and
grading of biopsies -- the Banff process.
• Demonstration of ability to achieve good intraand 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.
Conclusions - 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.
Conclusions - 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.
Conclusions - 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.