L. G. Hunsicker, M.D. Professor of Internal Medicine Carver College of Medicine at

Six years since the BanffClinical Practice Guidelines:Practical reality comes crashing down on the pure thinking of Banff 1999 L. G. Hunsicker, M.D. Professor of Internal Medicine Carver College of Medicine at the University of Iowa

Outline • What were the “Clinical Practice Guidelines” that came out of Banff 1999? • How did we arrive at them? • A standard process for CPGs (K/DOQI): • Evolution of the K/DOQI process • CPGs vs. research recommendations • Where are we now? • Standard methods for kidney transplant pathology • Standards for when biopsies should be done • One possible road forward

Agreed upon clinical practice guidelines that need buy in from AST/ASTS/Eurotransplant: 1. Implantation biopsies. 2. Rapid paraffin (microwave) processing for rapid reading rather than frozen sections. 3. Routine (“protocol”) biopsies. 4. H&E, PAS (+/o silver), and trichrome or Sirius red stains.

Protocol (routine biopsies). Early and intermediate post-transplant protocol biopsies 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!

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!

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!

Motivation • From its inception, Banff has concerned itself with establishment of consensus on issues dealing with transplant pathology. • Up to 1999, this has dealt almost entirely with classification of histological findings. • BUT, many questions about interpretation of histological findings were confounded by lack of good quality biopsies taken at appropriate times. • In 1999 there was a sense that Banff should establish expectations for the provision of good histological materials.

Modus Operandi at a Quaker Meeting • A question is put to the meeting. • Unlimited (endless) discussion ensues. • At some point, the Stated Clerk of the Meeting announces his/her understanding of “the sense of the meeting.” • Return to step 2. • At a later point, exhaustion sets in and no-one stands up to object. (Or he/she is hushed by his/her friends.) • No vote is taken. The last summary of the Stated Clerk is recorded as “the sense of the meeting.”

Outcome of the Banff 1999 Process • The proposed CPGs for kidney transplant pathology were posted on the Banff web site. (How much discussion ensued?) • Little discussion at least within the AST/ASTS • At least one of the recorders of the Banff consensus seemed to have defected. • Most of the transplant community doesn’t even know that these CPGs exist.

K/DOQI Process • Topics are chosen by K/DOQI committee and ranked in importance for improving quality and consistency in clinical care. • Work Group appointed with experts familiar with various aspects of issue under review. • Thorough review of the literature done by outside consultant, with arranging and grading of evidence on specific questions put by Work Group. • Work Group writes proposed set of guidelines graded as to the strength of the evidence. • Three stage review process: • Work Group and K/DOQI Advisory Board and Support Group, both with representatives from all “plank holders.” • Representatives of key allied health and patient organizations • The public in general.

Evolution of the K/DOQI Process • Era of authority: • Large number of complicated CPGs proposed for each topic. • Often there was limited hard data supporting the opinions of the experts. A (to me) disconcertingly large fraction of proposed guidelines were based on “opinion” rather than on “evidence” of varying grades. • Moment of truth: • CMS proposes to embody one set of guidelines as “Clinical performance indicators!!” … followed by rapid NKF retreat. • More recent approach: • Propose a limited number of uncomplicated CPGs based on hard citable evidence. • Offer “suggestions” rather than CPGs where the data is soft. • Make strong recommendations for research to obtain hard data to permit further CPGs in the future.

One Person’s Evaluation of the Banff 1999 CPGs • These were more a statement of the consensus of the specific Banff 1999 participants than a properly formed CPG. • Two of the CPGs addressed primarily issues of histological technique where the pathology community are the proper experts. • The other two involved issues important to clinicians. It would probably have been wiser to formulate “proposals” concerning these topics for consideration of the broader community rather than to propose actual CPGs. • The clinical participant in this process was quite unwise in assuming that he understood where the rest of the community came down on this issue.

Agreed upon clinical practice guidelines that need buy in from AST/ASTS/Eurotransplant: 1. Implantation biopsies. 2. Rapid paraffin (microwave) processing for rapid reading rather than frozen sections. 3. Routine (“protocol”) biopsies. 4. H&E, PAS (+/o silver), and trichrome or Sirius red stains.

Rapid Paraffin Processing in Place of Frozen Section • I personally concur that no pathologist should ever have to read a frozen section kidney biopsy – transplant or native. • Many transplant kidney biopsies are “urgent.” Rarely occur when they can be included in the “morning run.” • Rapid processing used to require ~4 hours of technician overtime. Too expensive for Pathology Departments squeezed by US payment system. • Often it was reasonable simply to treat suspected rejection episodes empirically with steroids for one day so that it was hard to justify the cost of rush processing. • Salvation by technical advance: Equipment is now available for unattended, automated, rush processing. This issue is likely to become moot within a year or so.

What Proportion of CAN is due to Alloimmunity? • De novo GN (14%) • Recurrent GN (17%) • Chronic cyclosporine nephrotoxicity (15%) • Chronic rejection (21%) • Duplication of peritubular capillary basement membrane • Inflammation of endothelium, etc…. • 61% C4d and Donor Specific Antibody positive • Non-specific tubulointerstitial fibrosis (40%) • A proportion of these may be Polyoma/CNI/Alloimmune-mediated N=142 Biopsies Mauiyyedi et al, J Am Soc Nephrol (2001) 12: 574-582

1 0.8 0.6 Biopsy Control 0.4 0.2 0 Treatment of Early Subclinical Rejection:Decreases 6 Month Interstitial Fibrosis & Tubular Atrophy Chronic Score * p < 0.05 (Rush et al, J Am Soc Nephrol 1998;9:2129)

Prevalence of Subclinical Rejection:Inverse Correlation with Immunosuppressive Potency Baseline Immunosuppression CsA + Aza + Pred 1 Neoral CsA + MMF+ Pred 2 Anti-CD25+Neoral CsA+MMF+Pred 3 Anti-CD25/ATG (56%) + FK506 + MMF +Pred 4 1mo 43% 38% 14% No Bx 2mo 32% 25% 19% No Bx 3mo 27% 31% 7% 3% 6mo 15% 25% 7% No Bx (Rush et al, J Am Soc Nephrol (1998) 9:2129)1 (Nickerson et al, J Am Soc Nephrol (1999) 10:1801)2 (Jeffery et al, presented at ITS, Miami (2002)3 (Gloor et al, Transplantation (2002) 73:1965)4

Calcineurin Inhibitor Nephrotoxicity:Longitudinal Assessment by Protocol BiopsyNankivell BJ et al, Transplantation 2003; 76:552

Reasons for Not Doing Protocol Biopsies • Safety: Risk of complication in transplant needle biopsies was 8.7% and major complication 2.9% in one series. (Preda A et al, European Radiology 2003; 3:527) If there is no established benefit, this risk is too great. • Cost: Estimated cost of doing a Tp renal biopsy is $1,555. If this is not reimbursed (because “experimental”), this cost is prohibitive. • Patient/physician reluctance: Even when protocol biopsies have been part of formal research plans, paid for and with prior agreement of MDs and consent of patients, the fraction completed is low (< 50%). This argues strongly that the doctors/patients are not convinced of the utility of the information received. I.e.: no consensus “for.”

Protocol (routine biopsies). Early and intermediate post-transplant protocol biopsies 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!

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!

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!

Reasons for NOT Doing Implantation Renal Biopsies • Safety: The risk of bleeding following an implantation biopsy is thought to be greater than that of a subsequent biopsy because the kidney is not yet fibrosed into its site. Many patients on aspirin, etc. • Incidence of significant complications following implantation renal biopsies was 4% among 236 patients. (Duman S et al. Transplant Proc 2004; 36:137) • Cost: Only incremental cost is for processing the biopsy – about $475. • No issues of acceptability to patient. • Perception that there is a low yield of useful information.

Rationale for Doing Implantation Transplant Renal Biopsies • To determine baseline donor disease, facilitating accurate interpretation of subsequent biopsies: • Underlying incidental donor disease: vascular disease, global glomerulosclerosis, incidental GN, etc. Not frequently found in low risk donors. • Baseline fibrosis to be able to determine “delta” fibrosis in subsequent biopsies. • Baseline arteriolar disease to be able to detect early calcineurin inhibitor toxicity.

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

Current Status of Implantation Biopsies • In most US OPOs, kidneys from “extended donors” are biopsied prior to allocation to permit centers to judge organ “quality.” These biopsies are available for further clinical use. • Few centers perform implantation biopsies of low risk donor kidneys because of a combination of concern over risk and an experience of low yield of useful information. • There is as yet no consensus that it is standard of care to obtain routine implantation biopsies

K/DIGO CPGs for Care of the Kidney Transplant Recipient • Consensus conference to be held in Feb 2006. Chaired by Frank Delmonico. Will address all aspects of care of kidney transplant recipients. • Guideline Work Group to be created, cochaired by Hunsicker and European MD. • Will include representatives of AST/ASTS and other “plank holders.” • Will use accepted methods for development of CPGs.

L. G. Hunsicker, M.D. Professor of Internal Medicine Carver College of Medicine at