Chronic rejection- currentconcepts and newer perspectives Kim Solez, M.D.
Mentor influences: Smelling the Flowers Meetings – Not A Waste of Time! “You should take time to smell the flowers.” (1972) “Medical meetings are just social events. Nothing important happens at them. They are a waste of time. You should avoid organizing medical meetings.” - Robert H. Heptinstall, M.D. I did not follow the latter advice. Physicians need to be socialized, humanized. Organized my first Acute Renal Failure Symposium in 1982, published as a book in 1984 Acute Renal Failure: Correlations Between Morphology and Function. Many other meetings since then. Banff meetings began 1991, continued every two years since then. Technology and Future of Medicine course began 2011, mixes science and humanities, technological Singularity, futurism, exponential change. High impact education changes human behavior, like advertising does. In the area of late biopsies and the scarred allograft in Banff consensus process we have been working to change behavior for some time. Evolution of thinking from chronic rejection, to chronic allograft nephropathy, to interstitial fibrosis and tubular atrophy.
An Evolution in Which We Find Evidence of the Human Tendency to Try to Believe in Specific Entities There Is No Evidence For! Originally all late scarring processes in the transplanted kidney were called “chronic rejection”. In order to stop perpetuating the idea that everything was chronic rejection we coined the term “chronic allograft pathology” – “CAN” for these nonspecific chronic changes. People seized on CAN as a new entity, devised strategies to prevent it, animal models for it etc. Soon there were hundreds of articles about CAN. To stop this artificial glorification of nonspecific changes as a new entity we eliminated the phrase CAN and used the descriptive terms interstitial fibrosis and tubular atrophy instead - IFTA.
In the late post-transplant biopsy, many non-specific lesions. Often biopsy is not helpful. Interstitial fibrosis, tubular atrophy – Non-specific. Fibrous intimal thickening – Non-specific Chronic transplant glomerulopathy – Antibody-mediated rejection, or thrombotic microangiopathy or MPGN (hepatitis related) True chronic rejection vascular changes, with intimal arteritis, elastica breaks etc. – rare. Peritubular capillary multilayering on electron microscopy – usually chronic antibody mediated rejection.
BANFF I- AND TOTAL I-SCORE AND DIAGNOSIS: INTERSTITIAL INFILTRATES ARE NOT DISEASE SPECIFIC * i-score total i-score *p<0.05 * *% cortex with infiltrate * * *
INFILTRATES IN BIOPSIES FOR CAUSE ARE TIMEDEPENDENT 100 fibrosis/atrophy 90 i-Banff i-IFTA 80 70 % cortex involved 60 50 40 30 20 10 0 1 6 11 16 21 26 31 36 41 46 51 56 61 66 71 76 81 86 91 96 101 106 111 116 121 126 3 8 27 79 246 months months months months months 129 biopsies ordered by time post TX Mengel et al. Am J Transplant. 2009 Jan;9(1):169-78.
Coming Full Circle – In the Original Banff Paper .The Editor Insisted We Put Everything About theNon-Specificity of Interstitial Infiltrates at theBeginning “So The Message Will Reach EvenThose Who Only Read The First Page!” Solez, K., Axelsen, R.A., Benediktsson, H., Burdick, J.F., Cohen, A.H., Colvin, R.B.,Croker, B.P., Droz, D., Dunnill, M.S., Halloran, P.F., Hayry, P., Jennette, J.C., Keown, P.A., Marcussen, N., Mihatsch, M.J., Morozumi, K., Myers, B.D., Nast, C., Olsen, S., Racusen, L.C., Ramos, E.L., Rosen, S., Sachs, D.H., Salomon, D.R., Sanfilippo, F., Verani, R., von Willebrand, E., and Yamaguchi, Y.: International standardization of nomenclature and criteria for the histologic diagnosis of renal allograft rejection : the Banff working classification of kidney transplant pathology. Kidney Int. 44:411-422, 1993.
CURRENT RESEARCH Microarray analysis of both human & mouse kidney transplants with rejection and other complications Correlate with Clinical data & Banff lesions. Common entities like glomerulonephritis, bacterial infection, and calcineurin inhibitor toxicity have no genomics signature at present.
Human and Mousesimilar genes and similar development The Cell 2002.
TABLE 1: CORRELATIONS BETWEEN INFILTRATE TYPESAND PATHOGENESIS BASED TRANSCRIPT SETS (PBTS) Gene sets*# i-Banff t-score i-IFTA IFTA nodular perivascular T-cell associated (CATs) 0.534 0.484 0.284 0.246 0.298 ns γ-Interferon dependent (GRITs) 0.532 0.441 0.258 0.211 0.241 ns Kidney parenchyma associated (KTs) -0.296 -0.303 -0.199 -0.156 ns ns Injury and repair associated (IRITs) 0.379 0.355 0.246 0.206 ns ns Immunoglobulin associated (IGTs) 0.174 ns 0.434 0.398 0.336 ns B-cell associated (BATs) 0.281 0.279 0.423 0.387 0.355 ns # given is the highest r-value revealed for one PBT of each particular biological process *Spearman correlation, p<0.001
Paula Blanco – Superiority of Virtual MicroscopyA BC D
Figure 2. Average intra-observer reproducibility of 3 observers 0.90 all comparisons p>0.05 0.80 0.70 (overall kappa values) 0.60 0.50 Virtual Slide 0.40 Glass Slide 0.30 0.20 0.10 0.00 g i t v ptc cg ci ct cv ah mm Diagnosis v ah cv t cg c ct m i sis g ci pt m no g ia D
Figure 3. Inter-observer reproducibility among 3 observers 0.90 p=0.04 0.80 0.70 p=0.03 (overall kappa values) p=0.08 0.60 p=0.03 0.50 p=0.08 Virtual Slide p=0.08 p=0.05 NS p=0.08 Glass Slide 0.40 p=0.03 NS 0.30 NS 0.20 0.10 0.00 g i t v ptc cg ci ct cv ah mm Diagnosis t ci v cg ah i ct m g c cv is pt s m g no ia D
Figure 4. p = 0.29 p = 0.11 A. B. 100% 100% Virtual vs. Virtual slidesAgreement rate in diagnosis 90% 90% Glass vs. Glass slides 80% 80% Virtual vs. Glass slides 70% 70% 60% 60% Virtual vs. Virtual slides 50% 50% Glass vs. Glass slides 40% 40% Virtual vs. Glass slides 30% 30% 20% 20% 10% 10% 0% 0% Observer 1 Observer 2 Observer 3
CHANGES NOT CONSIDERED TO BE DUE TO REJECTION: Post-transplant lymphoproliferative disorder Slide 39 Non-specific changes a) Focal interstitial inflammation without tubulitis: Nodular infiltrates, parivasular infiltrates. b) Vascular changes: endothelial reactive changes, vacuolization, venulitis. Acute tubular injury Acute Interstitial nephritis Cyclosporine-associated changes, acute or chronic Subcapsular injury Pre-transplant acute endothelial injury Papillary necrosis De novo glomerulonephritis Recurrent disease Pre-existing disease Other-viral infection (CMV), obstruction and reflux
DIFFERENTIAL DIAGNOSIS OF PTLD T-cell rich PTLDs occur in 10-30% of cases EBV negative PTLDs occur in 10-30% of cases Endarteritis may be PTLD associated. PTLD is not associated with edema.
MY PRESENTATION TOMORROW “BANFF AND BEYOND”CONTINUES THIS DISCUSSION, SO STAY TUNED! The pathologic spectrum of chronic allograft injury is very broad, and we should keep all entities in mind, even the rare ones. Technology is advancing in some areas much more quickly than you think, and in other areas not at all. Further conclusions (big and small!) tomorrow.