Standardization in Renal Allograft Biopsy Interpretation The Banff

Standardization in Renal Allograft Biopsy Interpretation: The Banff Classification Kim Solez, M. D.

2 Two future phases in the relationship between renal biopsies and management of the renal allograft recipient: n In the short term the rigorous quantitation and internationally-agreed-upon evaluation of renal biopsies via the Banff Classification which has proven itself quite useful in the early posttransplant period will be extended to apply fully to late graft biopsies. n In the long term – perhaps decades away – the processes of acute and chronic rejection will be so well understood mechanistically that a test for specific markers in blood or urine will completely replace the percutaneous biopsy as a means of diagnosing these conditions.

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

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

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8 Banff Classification Milestones n 1991 First Conference n 1993 First Kidney International paper. n 1995 Integration with CADI - identical scoring n 1997 Integration with CCTT classification. n 1999 Second KI paper. Clinical practice guidelines. Implantation biopsies, microwave. n 2001 Classification of antibody-mediated rejection. Regulatory agencies participating.

9 Banff Classification - Subjects in Aberdeen mtg June 14 -18 2003 n Updates of Schemas for Diagnosis and Treatment of Allograft Rejection n Chronic transplant nephropathy n Genomics of Rejection n Antibody-mediated rejection/C 4 d n Monocyte/Macrophages n Tolerance/Accomodation/Immunodepletion n Continued Development/Consensus Generation via Internet Communication

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19 Table 11: Quantitative Criteria for Arteriolar Hyaline Thickening 0= No PAS-positive hyaline thickening. 1 = Mild-to-moderate PAS-positive hyaline thickening in at least one arteriole. 2 = Moderate-to-severe PAS-positive hyaline thickening in more than one arteriole. 3 = Severe PAS-positive hyaline thickening in many arterioles.

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21 Changes not considered to be due to rejection: n Post-transplant lymphoproliferative disorder n Non-specific changes a) Focal interstitial inflammation without tubulitis: Nodular infiltrates, parivasular infiltrates. b) Vascular changes: endothelial reactive changes, vacuolization, venulitis. n Acute tubular injury n Acute Interstitial nephritis n Cyclosporine-associated changes, acute or chronic n Subcapsular injury n Pre-transplant acute endothelial injury n Papillary necrosis n De novo glomerulonephritis n Recurrent disease n Pre-existing disease n Other-viral infection (CMV), obstruction and reflux

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23 Table 1 - Specimen Adequacy – (Banff ’ 97) – Minimum Sampling n Unsatisfactory – No glomeruli or arteries n Marginal – 7 glomeruli with an artery n Adequate – 10 or more glomeruli with at least two arteries n Minimum Sampling: 7 slides – 3 H&E, 3 PAS or silver stains, and 1 trichrome

We are victims of our own success: Rigid application of “possible clinical approach”: In Table 5 of original paper, “The Banff Schema Simplified”.

25 Standardization of tx biopsy interpretation. Banff Classification n Classification begun at 1991 Banff meeting has become the worldwide standard, and the consensus process has now extended to all solid organs. Meetings continue every two years. Next meeting in Banff, Scotland (Aberdeen) June 14 -18, 2003! n Future meetings planned every two years through 2009. n Standardization principles now being extended from biopsy reporting to tissue typing, imaging, all the other elements in transplant care.

26 Standardization of tx biopsy interpretation. Banff Classification n Lesion quantitation. n Reproducibility and clinical validation studies. n Involvement of pathologists, clinicians, surgeons, scientists, registries, and regulatory agencies in consensus generation. n Meetings have large amount of unstructured time for deliberation and consensus generation. n Most content online at http: //cnserver 0. nkf. med. ualberta. ca/Banff n Linked from http: //www. cybernephrology. org

27 Hansen and Olsen, 1997 Actuarial Graft Survival (%) According to Most Severe Banff Grade Max. Banff Grade N 1 y 2 y 5 y 0 51 100 98 98 Bo 26 100 76 1 17 100 88 67 2 53 80 72 56 3 29 45 41 32

28 Banff Standardization of tx biopsy interpretation. - Recent Comments n Hass et al. Kidney International 61: 2002, 2002 “The distinction between types 2 A and 2 B in the Banff ‘ 97 classification has significant prognostic value with regard to both short term and long term clinical outcomes. ” n Palomar et al. Trans. Proc. 34: 349, 2002 “The 1997 Banff classification is an excellent tool to graduate acute rejection severity and to predict short- and mid-term graft survival. ” n Mc. Carthy and Roberts: Transplantation 73: 1518, 2002 “There is likely to be significant under-diagnosis and under-grading of acute rejection if the Banff ‘ 97 guidelines for slide preparation are not implemented. ”

29 Banff Standardization of tx biopsy interpretation. - Recent Comments n Quiroga et al. Trans. Proc. 35: 1154, 2001. “The Banff 97 classification has had an unforeseen and significant impact on clinical practice. ” n Howie AJ: The Problems with BANFF, Transplantation 73: 1383, 2002 “…other approaches should be tried such as morphometry” n Financially and technically impractical for most centers. n Banff classification is based on semiquantitative assessment. Quantitative assessment would ultimately be better, just as the molecular biology/genomics alternative would be. But they much be made practical!

30 Promising New Developments: n Sirius red quantitiation of interstitial fibrosis. n Immunostaining for C 4 d as a marker for antibody mediated rejection and chronic rejection. n Protocol (routine biopsy) prediction of chronic rejection. n Implantation biopsy (hyaline arteriolar change, fibrous intimal thickening, glomerulosclerosis, glomerular size) prediction of graft loss.

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36 Agreed upon clinical practice guidelines that need buy in generally. n Implantation biopsies. n Rapid paraffin (microwave) processing for rapid reading rather than frozen sections. n Routine (“protocol”) biopsies. n H&E, PAS (+/o silver), and trichrome or Sirius red stains.

37 Perioperative (Implantation) Biopsy Core vs wedge Adequacy of sample Preimplantation vs. postimplantation Consensus: Perioperative biopsy (? core, ? wedge) is sufficiently safe to be recommended for any reasonable defined objective. STANDARD OF CARE!

38 Protocol (routine biopsies). n Early and intermediate post-transplant protocol biopsies. n Consensus: These biopsies, generally done under ultrasound guidance, have very low morbidity. They are safe enough to be requested of consenting patients for research purposes when the objectives are clearly formulated and stated. STANDARD OF SCIENCE!

39 Routine biopsies to detect “subclinical rejection”! Kidney Value is not unequivocally proven, but many felt the evidence to be sufficient to justify at least a biopsy at 6 months (or earlier), with treatment of subclinical rejection if detected. Further studies are required to confirm the value of this approach in a wider setting. FUTURE STANDARD OF CARE!

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

41 RPS Membership (total) 211 USA 163 Europe 23 Austria 1 Denmark 1 England 2 France 2 Germany 2 Greece 1 Iceland 1 Italy 1 Norway 3 Spain 2 Sweden 1 The Netherlands 6 Canada 13 Asia 7 Japan 4 Korea 1 Turkey 2 Australia 3 South America 1 Brazil 1

Pathology Expertise cont. Furness et al. International variation in the interpretation of renal transplant biopsies. Kidney International 60: 1998, 2001. Lack of reproducibility of local readings in Europe and have recommended central reading of biopsies from clinical trials, already the standard via the Banff classification. Concluded: “It is obvious that evaluation of biopsies in multicenter studies must be done in one center. ”

43 To join Renal Pathology Society http: //www. renalpathsoc. org

44 Future Banff Meetings: n 2005 - Edmonton, Alberta, CANADA. n 2007 - Edinburgh, Scotland. SEE YOU THERE!!

45 Close: n Banff ’ 97 Classification is the new universal classification of kidney transplant pathology. n Future improvements involve participation in Banff meetings via physical presence or contributions via Internet.

46 To subscribe to Nephrol (it’s free): Send an E-mail message to majordomo@ualberta. ca with the message “subscribe Nephrol” (or Nephrol-digest) Or contact Kim. Solez@UAlberta. ca or Michele. Hales@UAlberta. ca