Sum Scores and Scores of Individual Components in Clinical Practice and Clinical Trials

1. Sum Scores and Scores of Individual Components in Clinical Practice and Clinical Trials Lillian W. Gaber University of Tennessee

2. Semiquantitative Schema in the Analysis of Renal Allograft Biopsies • Standardize the evaluation and reporting of biopsies • Improve reproducibility for biopsy interpretation • Measure the severity of lesions • Identify correlates with prognosis • Guide treatment • Facilitate comparative analysis of morphologic features in clinical trials and research • Provide Meticulous evaluation of the morphologic features

3. Scores For Chronic Allograft Nephropathy

4. Chronic Scores • Diffuse interstitial fibrosis was consistently identified as a significant risk factor for graft loss • Proliferative vasculopathy is detrimental • What is the value of CAN before we get to endstage?

5. CAN Scores for Protocol Biopsies & Graft Function * P <0.05 Nicherson et al; 1997

6. 282 protocol biopsies at transplantation and at 3 months CAN and renal transplant vasculopathy were independent risk factors for graft failure Proteinuria and serum creatinine at time of biopsy, cholesterol level and donor age independently correlated with CAN Serum cholesterol levels prior to transplanation was the only predictor of RTV CAN Scores and Long Term Survival Seron et al; 2000

7. Protocol biopsies - CAN & Intervention Trials • Primary intervention trials • CAN with or without RTV in 15.7% donor biopsies and 38.3% protocol 3 M biopsies. Denovo CAN develops in 22.6% of patients in the first 3 M • Hypothetical trial to detect a 50% reduction in the incidence of denovo CAN from 38.3% to 27%; 285 patients in the control and treatment groups would be necessary • Secndary intervention trials • If selection is restricted to patients with RTV only, 72 patients in each arm would be necessary, to detect a 50% increase in graft survival from 55.1% to 77.5% • 217 patients in each group will be needed to detect a 50% survival increase from 81.1% to 90.5% in 5 years when all patients with CAN with or without RTV included

8. CAN scores in 3-month Protocol Biopsies Predicts Outcome of Grafts in Pediatric Renal Patients * p < 0.05 versus CCr of CAN at 3 M * * p < 0.05 versus CCr of CAN at 2 Y Fudjisawa et al, 2000

9. Chronic Allograft Damage Index (CADI) Isoniemi et al; 1994

10. CAN Scores: Potential Application • Scores for CAN can be used as a primary efficacy endpoint in trials aimed at prevention or treatment of CAN • CAN represents the collective effect of immunologic, hemodynamic, metabolic, baseline kidney status. It is an important tool to control the effect of therapeutic maneuvers • Estimation of CAN in protocol biopsies for enrolment in large intervention studies aimed at prevention or modification the natural history of CAN, may allow reduction in the time of follow up of patients and a significant reduction in sample size • Question the use of protocol biopsies in clinical practice

11. Grades and Scores in Clinical Practice

12. Components Scores and Sum Scores Correlate with Response to Steroids - University of Tennessee * ** * P= 0.04 ** P= 0.02 Gaber et al, 1996

13. Component Scores and Sum Correlate with Reversal of Acute Rejection- University of Tennessee ** * ** * * *significant from complete ** significant from partial and complete Gaber et al, 1996

14. Banff ‘93 Rejection Grades & Response to Anti-rejection Therapy- University of Tennessee Gaber et al, 1996

15. Validity of Banff ‘93 Schema in Clinical Practice- University of Tennessee • Sum scores correlate with rejection reversal • Mean Sum for complete reversal was 3.9, partial 6.0, irreversible 8.5 • Vascular scores were significantly higher in irreversible rejection compared to partial or completely reversed rejection (mean 3.0 versus 1.0) • Resolution of rejection by steroids versus the need for added OKT3 was correlated with low vascular score (0.65 versus 1.4) and low Sum (3.7 versus 5.2)

16. Validity of Banff ‘93 Schema in Clinical Practice- University of Tennessee • Correlation between the sum scores and grades of acute rejection • Borderline (Sum 1.6 + 0.5) • Grade I (Sum 3.3 + 0.4) • Grade II (Sum 4.2 + 0.3) • Grade III (Sum 8.5 + 0.4)

17. At and Av in Banff’ 97- University of Pittsburgh • Acute cellular rejection with mild or moderate tubulitis (Banff 97 IA) have better prognosis than acute cellular rejection with severe tubulitis (Banff 97 IB) • No differences between acute rejection with t3 (Banff IB) and rejection with mild vasculitis v 1(Banff IIA) in terms of rejection reversal, 12-month creatinine or graft loss • Rejection with moderate (Banff IIB) or severe intimal arteritis (Banff III) was associated with the worst outcome Randhawa, AST 2000

18. Acute Glomerulitis in Renal Allografts; Johns Hopkins Zachary, Racusen AST, 2000

19. Borderline Change: Understanding the ambiguous class- University of Chicago 65 untreated Bo Improve Cr to 110% of Baseline 46% Initial improvement followed by increase Cr 26% Increasing Creatinine 28% AR in 50% re-biopsies AR in 50% re-biopsies

20. Untreated Borderline lesions: University of Chicago • Incidence of BO: 17% • Common concomitant lesions • Nephrotoxicity • ATN • Urinary tract obstruction • CAN • Risk Factors for progression to rejection • Acute glomerulitis • Banff acute score >2

21. Sum Scores & Components’ Scores For Prognostic Studies

22. Efficacy Endpoints Conference on Acute Rejection in Kidney • 19 participating centers, each reported 50 consecutive rejection episodes • 320 out of 698 biopsies were graded according to Banff ‘93 • Banff Grades: Bo (3%), I (41%), II (38%), III (18%) • Clinical data collected: Demographic data, induction and maintenance immunosuppression, rejection agents, clinical signs (decreased urinary output, fever, creatinine), serum creatinine response to treatment over a period of time, morbidity, recurrent rejection, graft function at 1 year

23. Frequency of Clinical Signs During Rejection & Histologic Severity Schroeder et al, for the Efficacy Endpoint Conference

24. Scores in Assessment of Acute Rejection Gaber et al;1996

25. Is recurrent rejection the result of persistent subclinical rejection or a new acute relapse of immunologic intolerance? • Severity of acute rejection, quantitated by Banff, did not discriminate patients at risk for recurrent rejection • Trend for increase in Banff scores in recurrent rejections, which was statistically significant for the sum, and for the interstitial and tubular scores • Higher Peak PRA in patients with recurrent rejection

26. Scores of Rejection on Enrolment and Endpoint Biopsies Gaber et al,1999

27. Grades of Lesions in Post-treatment Biopsies Gaber et al, 1999

28. Changes In Acute Rejection Scores From Inclusion to Post-treatment Biopsies Gaber et al, 1999

29. Recurrent Rejection in Patients with Protocol Biopsies Primary response occurred in 35 and 65% of patients

30. Recurrent Acute Rejection • 31% of patients developed a second rejection • Sum scores for residual inflammation in the protocol post-treatment biopsies were significantly higher in cases with recurrent rejection (4.2 ± 0.6), versus no recurrence (2.2 ± 0.4) [P = 0.015]

31. 2-Year Protocol Biopsies From the U.S. Multicenter Trial Comparing Tacrotimus to Cyclosporine Solez for FK 506 Study Group, 1998

32. Histologic Improvement by Steroids According to Acute Rejection Severity Mazzucchi et al; 1999

33. Changes in Morphology Following Steroid Therapy Mazzucchi et al; 1999

34. Conclusions • Evidence to support the validity of grading and scoring of acute rejection to direct therapy choices as adjuncts to pathologic diagnosis • Grades and individual scores for acute and chronic lesions in the kidney correlate with graft survival • Potential of monitoring patients by protocol biopsies • Scores and Sum are an easy and cheap way to screen pathology reports • Force detailed analysis of lesions • Digitization of morphologic data for statistical analysis • Patients selection in clinical efficacy trials • Endpoint in large prospective clinical trials