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Importance of Formal Classification of Rejection for Collaborative Studies in Transplantation

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Title: Importance of Formal Classification of Rejection for Collaborative Studies in Transplantation


1
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

2
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.

3
NIH 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).

4
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

5
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)

6
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

7
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!

8
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.

9
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
    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

10
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.

11
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.
  • Todays gold standard is still classic
    histopathology!

12
Immune 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

13
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.

14
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.

15
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

16
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 (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.

17
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

18
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.

19
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.

20
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

21
Drugs Approved by the FDA Based on Reduction of
Acute Rejection
  • Chemical immunosuppressants
  • mycophenolate mofetil
  • sirolimus (rapamycin)
  • Antibodies
  • daclizumab
  • basiliximab
  • thymoglobulin

22
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.

23
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 Surroga
    te endpoints for graft survival
  • Induce tolerance ?Withdrawal of
    immunosuppression?
  • Reduce cost and improve quality of life
    Eliminate acute rejection episodes

24
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.

25
Alternative Explanations for Correlation of
Outcomes
26
On the Way Surrogate EndpointsThe Possible
Exception
27
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.

28
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.

29
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
    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.

30
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.

31
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.

32
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.

33
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.

34
GLOMERULAR 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
35
HYPOTHETICAL 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
36
CSG Trial of Captopril in Type I Diabetic
Nephropathy By Entry Scr
Lewis EJ et al N Engl J Med 1993 3291456-62
37
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.

38
Requirements 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.

39
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 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
40
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 119805
41
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 119805
42
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 119805
43
Reproducibility 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

44
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.

45
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.

46
Requirements 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.

47
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
    African-Americans

48
ALTERNATIVE MECHANISMS FOREARLY KIDNEY GRAFT
FAILURE
Good Function
GFR
Accelerated Slope
Reduced Intercept
GFR at return to dialysis
Time
49
Implantation renal biopsy showing ATN, but
minimal interstitial fibrosis. Courtesy of
Lorraine Racusen
50
Renal biopsy in the same patient 5 weeks after
transplant, showing extensive interstitial
fibrosis. Courtesy of Lorraine Racusen
51
Nicholson ML et al, Transplantation 1999 68236
52
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?

53
Requirements 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.

54
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.

55
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.

56
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.
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