Standardization in Renal Allograft Standardization in Renal Allograft Biopsy Interpretation: Biopsy Interpretation: The Banff ClThe Banff Classificationassification

Kim Solez, M.D.Kim Solez, M.D.

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Two future phases in the relationship between Two future phases in the relationship between renal biopsies and management of the renal renal biopsies and management of the renal allograft recipient:allograft recipient:

In the short term the rigorous quantitation and In the short term the rigorous quantitation and internationally-agreed-upon evaluation of renal internationally-agreed-upon evaluation of renal biopsies via the Banff Classification which has biopsies via the Banff Classification which has proven itself quite useful in the early post-proven itself quite useful in the early post-transplant period will be extended to apply fully transplant period will be extended to apply fully to late graft biopsies.to late graft biopsies.

In the long term – perhaps decades away – the In the long term – perhaps decades away – the processes of acute and chronic rejection will be processes of acute and chronic rejection will be so well understood mechanistically that a test for so well understood mechanistically that a test for specific markers in blood or urine will completely specific markers in blood or urine will completely replace the percutaneous biopsy as a means of replace the percutaneous biopsy as a means of diagnosing these conditions.diagnosing these conditions.

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Introduction:Introduction:

Acute renal failure in the transplant kidney is Acute renal failure in the transplant kidney is a high stakes situation. Many different a high stakes situation. Many different entities present the same clinically – ATN, entities present the same clinically – ATN, acute rejection, CsA toxicity – and acute rejection, CsA toxicity – and misdiagnosis can rapidly lead to loss of the misdiagnosis can rapidly lead to loss of the graft or sometimes the patient.graft or sometimes the patient.

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Introduction:Introduction:

In 1990 all standard textbooks were In 1990 all standard textbooks were incorrect in interpretation of kidney incorrect in interpretation of kidney transplant biopsies, suggesting for transplant biopsies, suggesting for example that arteritis meant that the example that arteritis meant that the kidney was doomed and antirejection kidney was doomed and antirejection treatment should be abandoned. It treatment should be abandoned. It became imperative for the field to became imperative for the field to correct this and standardize correct this and standardize interpretation.interpretation.

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Banff ClassificationBanff ClassificationMilestonesMilestones 1991 First Conference1991 First Conference

1993 First Kidney International paper.1993 First Kidney International paper.

1995 Integration with CADI - identical scoring1995 Integration with CADI - identical scoring

1997 Integration with CCTT classification.1997 Integration with CCTT classification.

1999 Second KI paper. Clinical practice 1999 Second KI paper. Clinical practice guidelines. Implantation biopsies, microwave.guidelines. Implantation biopsies, microwave.

2001 Classification of antibody-mediated 2001 Classification of antibody-mediated rejection. Regulatory agencies participating.rejection. Regulatory agencies participating.

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Banff Classification - Subjects in Banff Classification - Subjects in Aberdeen mtg June 14-18 2003Aberdeen mtg June 14-18 2003 Updates of Schemas for Diagnosis and Treatment Updates of Schemas for Diagnosis and Treatment

of Allograft Rejectionof Allograft Rejection

Chronic transplant nephropathyChronic transplant nephropathy

Genomics of RejectionGenomics of Rejection

Antibody-mediated rejection/C4d Antibody-mediated rejection/C4d

Monocyte/MacrophagesMonocyte/Macrophages

Tolerance/Accomodation/ImmunodepletionTolerance/Accomodation/Immunodepletion

Continued Development/Consensus Generation via Continued Development/Consensus Generation via Internet CommunicationInternet Communication

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Table 11: Quantitative Criteria for Table 11: Quantitative Criteria for Arteriolar Hyaline ThickeningArteriolar Hyaline Thickening

0 = 0 = No PAS-positive hyaline thickening.No PAS-positive hyaline thickening.

1 =1 = Mild-to-moderate PAS-positive hyaline Mild-to-moderate PAS-positive hyaline thickening in at least one arteriole.thickening in at least one arteriole.

2 = 2 = Moderate-to-severe PAS-positive hyaline Moderate-to-severe PAS-positive hyaline thickening in more than one arteriole.thickening in more than one arteriole.

3 = 3 = Severe PAS-positive hyaline thickening in Severe PAS-positive hyaline thickening in many arterioles.many arterioles.

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Changes not considered to be due to rejection:Changes not considered to be due to rejection:

Post-transplant lymphoproliferative disorderPost-transplant lymphoproliferative disorder

Non-specific changesNon-specific changes

a)a) Focal interstitial inflammation without tubulitis: Nodular infiltrates, parivasular Focal interstitial inflammation without tubulitis: Nodular infiltrates, parivasular infiltrates.infiltrates.

b)b) Vascular changes: endothelial reactive changes, vacuolization, venulitis. Vascular changes: endothelial reactive changes, vacuolization, venulitis.

Acute tubular injuryAcute tubular injury

Acute Interstitial nephritisAcute Interstitial nephritis

Cyclosporine-associated changes, acute or chronicCyclosporine-associated changes, acute or chronic

Subcapsular injurySubcapsular injury

Pre-transplant acute endothelial injuryPre-transplant acute endothelial injury

Papillary necrosisPapillary necrosis

De novo glomerulonephritisDe novo glomerulonephritis

Recurrent diseaseRecurrent disease

Pre-existing diseasePre-existing disease

Other-viral infection (CMV), obstruction and refluxOther-viral infection (CMV), obstruction and reflux

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Table 1 - Specimen Adequacy – Table 1 - Specimen Adequacy – (Banff ’97) – Minimum Sampling(Banff ’97) – Minimum Sampling

Unsatisfactory – No glomeruli or arteriesUnsatisfactory – No glomeruli or arteries

Marginal – 7 glomeruli with an arteryMarginal – 7 glomeruli with an artery

Adequate – 10 or more glomeruli with at least two Adequate – 10 or more glomeruli with at least two arteriesarteries

Minimum Sampling: 7 slides – 3 H&E, 3 PAS or Minimum Sampling: 7 slides – 3 H&E, 3 PAS or silver stains, and 1 trichromesilver stains, and 1 trichrome

We are victims of our own success:We are victims of our own success:Rigid application of “possible clinical approach”: Rigid application of “possible clinical approach”:

In Table 5 of original paper, In Table 5 of original paper, “The Banff Schema Simplified”.“The Banff Schema Simplified”.

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Standardization of tx biopsy Standardization of tx biopsy interpretation.Banff Classificationinterpretation.Banff Classification Classification begun at 1991 Banff meeting has become Classification begun at 1991 Banff meeting has become

the worldwide standard, and the consensus process has the worldwide standard, and the consensus process has now extended to all solid organs. Meetings continue every now extended to all solid organs. Meetings continue every two years. Next meeting in Banff, Scotland (Aberdeen) two years. Next meeting in Banff, Scotland (Aberdeen) June 14-18, 2003!June 14-18, 2003!

Future meetings planned every two years through 2009.Future meetings planned every two years through 2009.

Standardization principles now being extended from Standardization principles now being extended from biopsy reporting to tissue typing, imaging, all the other biopsy reporting to tissue typing, imaging, all the other elements in transplant care.elements in transplant care.

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Standardization of tx biopsy Standardization of tx biopsy interpretation.Banff Classificationinterpretation.Banff Classification Lesion quantitation.Lesion quantitation.

Reproducibility and clinical validation studies.Reproducibility and clinical validation studies.

Involvement of pathologists, clinicians, surgeons, Involvement of pathologists, clinicians, surgeons, scientists, registries, and regulatory agencies in scientists, registries, and regulatory agencies in consensus generation.consensus generation.

Meetings have large amount of unstructured time for Meetings have large amount of unstructured time for deliberation and consensus generation.deliberation and consensus generation.

Most content online at Most content online at http://cnserver0.nkf.med.ualberta.ca/Banffhttp://cnserver0.nkf.med.ualberta.ca/Banff

Linked from http://www.cybernephrology.orgLinked from http://www.cybernephrology.org

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Hansen and Olsen, 1997Actuarial Graft Survival (%) According

to Most Severe Banff Grade

Max. Banff Grade N 1y 2y 5y

0 51 100 98 98

Bo 26 100 100 76

1 17 100 88 67

2 53 80 72 56

3 29 45 41 32

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Banff Standardization of tx biopsy Banff Standardization of tx biopsy interpretation. - Recent Commentsinterpretation. - Recent Comments Hass et al. Kidney International 61:2002, 2002 “The Hass et al. Kidney International 61:2002, 2002 “The

distinction between types 2A and 2B in the Banff ‘97 distinction between types 2A and 2B in the Banff ‘97 classification has significant prognostic value with regard classification has significant prognostic value with regard to both short term and long term clinical outcomes.” to both short term and long term clinical outcomes.”

Palomar et al. Trans. Proc. 34:349, 2002 “The 1997 Banff Palomar et al. Trans. Proc. 34:349, 2002 “The 1997 Banff classification is an excellent tool to graduate acute rejection classification is an excellent tool to graduate acute rejection severity and to predict short- and mid-term graft survival.”severity and to predict short- and mid-term graft survival.”

McCarthy and Roberts: Transplantation 73:1518, 2002 McCarthy and Roberts: Transplantation 73:1518, 2002 “There is likely to be significant under-diagnosis and under-“There is likely to be significant under-diagnosis and under-grading of acute rejection if the Banff ‘97 guidelines for grading of acute rejection if the Banff ‘97 guidelines for slide preparation are not implemented.”slide preparation are not implemented.”

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Banff Standardization of tx biopsy Banff Standardization of tx biopsy interpretation. - Recent Commentsinterpretation. - Recent Comments

Quiroga et al. Trans. Proc. 35:1154, 2001. “The Banff 97 Quiroga et al. Trans. Proc. 35:1154, 2001. “The Banff 97 classification has had an unforeseen and significant impact classification has had an unforeseen and significant impact on clinical practice.”on clinical practice.”

Howie AJ: The Problems with BANFF, Transplantation Howie AJ: The Problems with BANFF, Transplantation 73:1383, 2002 “…other approaches should be tried such as 73:1383, 2002 “…other approaches should be tried such as morphometry” morphometry”

Financially and technically impractical for most centers.Financially and technically impractical for most centers.

Banff classification is based on semiquantitative Banff classification is based on semiquantitative assessment. Quantitative assessment would ultimately be assessment. Quantitative assessment would ultimately be better, just as the molecular biology/genomics alternative better, just as the molecular biology/genomics alternative would be. But they much be made practical!would be. But they much be made practical!

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Promising New Developments:Promising New Developments:

Sirius red quantitiation of interstitial fibrosis.Sirius red quantitiation of interstitial fibrosis.

Immunostaining for C4d as a marker for antibody Immunostaining for C4d as a marker for antibody mediated rejection and chronic rejection.mediated rejection and chronic rejection.

Protocol (routine biopsy) prediction of chronic Protocol (routine biopsy) prediction of chronic rejection.rejection.

Implantation biopsy (hyaline arteriolar change, Implantation biopsy (hyaline arteriolar change, fibrous intimal thickening, glomerulosclerosis, fibrous intimal thickening, glomerulosclerosis, glomerular size) prediction of graft loss.glomerular size) prediction of graft loss.

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Agreed upon clinical practice Agreed upon clinical practice guidelines that need buy in generally.guidelines that need buy in generally.

Implantation biopsies.Implantation biopsies.

Rapid paraffin (microwave) processing for rapid Rapid paraffin (microwave) processing for rapid reading rather than frozen sections.reading rather than frozen sections.

Routine (“protocol”) biopsies.Routine (“protocol”) biopsies.

H&E, PAS (+/o silver), and trichrome or Sirius red H&E, PAS (+/o silver), and trichrome or Sirius red stains.stains.

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Perioperative (Implantation) BiopsyPerioperative (Implantation) Biopsy

Core vs wedgeCore vs wedge

Adequacy of sampleAdequacy of sample

Preimplantation vs. postimplantationPreimplantation vs. postimplantation

Consensus: Perioperative biopsy (? core, ? Consensus: Perioperative biopsy (? core, ? wedge) is sufficiently safe to be recommended wedge) is sufficiently safe to be recommended for any reasonable defined objective.for any reasonable defined objective.

STANDARD OF CARE!STANDARD OF CARE!

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Protocol (routine biopsies).Protocol (routine biopsies).

Early and intermediate post-transplant protocol Early and intermediate post-transplant protocol biopsies.biopsies.

Consensus: These biopsies, generally done Consensus: These biopsies, generally done under ultrasound guidance, have very low under ultrasound guidance, have very low morbidity. They are safe enough to be requested morbidity. They are safe enough to be requested of consenting patients for research purposes of consenting patients for research purposes when the objectives are clearly formulated and when the objectives are clearly formulated and stated.stated.

STANDARD OF SCIENCE!STANDARD OF SCIENCE!

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Routine biopsies to detect Routine biopsies to detect “subclinical rejection”! Kidney“subclinical rejection”! Kidney

Value is not unequivocally proven, but many felt Value is not unequivocally proven, but many felt the evidence to be sufficient to justify at least a the evidence to be sufficient to justify at least a biopsy at 6 months (or earlier), with treatment of biopsy at 6 months (or earlier), with treatment of subclinical rejection if detected.subclinical rejection if detected.

Further studies are required to confirm the value Further studies are required to confirm the value of this approach in a wider setting.of this approach in a wider setting.

FUTURE STANDARD OF CARE!FUTURE STANDARD OF CARE!

Pathology ExpertisePathology Expertise

Renal Pathology Society includes all pathologists Renal Pathology Society includes all pathologists with mentored training in renal pathology and who with mentored training in renal pathology and who considered themselves primarily renal considered themselves primarily renal pathologists. Only 163 RPS members in USA. 70% pathologists. Only 163 RPS members in USA. 70% of renal biopsies in the US are read by individuals of renal biopsies in the US are read by individuals self taught and/or lacking a primary interest in self taught and/or lacking a primary interest in renal pathology. In other countries situation is renal pathology. In other countries situation is even worse. even worse.

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11BrazilBrazil

11South AmericaSouth America

33AustraliaAustralia

22TurkeyTurkey

11KoreaKorea

44JapanJapan

77AsiaAsia

1313CanadaCanada

66The NetherlandsThe Netherlands

11SwedenSweden

22SpainSpain

33NorwayNorway

11ItalyItaly

11IcelandIceland

11GreeceGreece

22GermanyGermany

22FranceFrance

22EnglandEngland

11DenmarkDenmark

11AustriaAustria

2323EuropeEurope

163163USAUSA

211211RPS Membership (total)RPS Membership (total)

Pathology Expertise cont.Pathology Expertise cont.

Furness et al. International variation in the Furness et al. International variation in the interpretation of renal transplant biopsies. Kidney interpretation of renal transplant biopsies. Kidney International 60:1998, 2001.International 60:1998, 2001.

Lack of reproducibility of local readings in Europe Lack of reproducibility of local readings in Europe and have recommended central reading of and have recommended central reading of biopsies from clinical trials, already the standard biopsies from clinical trials, already the standard via the Banff classification. Concluded:via the Banff classification. Concluded:

“It is obvious that evaluation of biopsies in “It is obvious that evaluation of biopsies in multicenter studies must be done in one center.”multicenter studies must be done in one center.”

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To join Renal Pathology SocietyTo join Renal Pathology Society

http://www.renalpathsoc.orghttp://www.renalpathsoc.org

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Future Banff Meetings:Future Banff Meetings:

2005 - Edmonton, Alberta, CANADA.2005 - Edmonton, Alberta, CANADA.

2007 - Edinburgh, Scotland.2007 - Edinburgh, Scotland.

SEE YOU THERE!!SEE YOU THERE!!

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Close:Close:

Banff ’97 Classification is the new universal Banff ’97 Classification is the new universal classification of kidney transplant pathology.classification of kidney transplant pathology.

Future improvements involve participation in Future improvements involve participation in Banff meetings via physical presence or Banff meetings via physical presence or contributions via Internet.contributions via Internet.

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