kim solez chronic rejection

Chronic rejection- current concepts and newer perspectives

Kim Solez, M.D.

Mentor influences: Smelling the FlowersMeetings – 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.

Number of CAN Articles Per Year

Elaborate Schemes Explaining CAN At The Height of Its Popularity

Elaborate Schemes Explaining CAN At The Height of Its Popularity

In the early post-transplant biopsy, many specific lesions which provide evidence of clinically significant processes. Biopsy is helpful. Tubulitis – Rejection Intimal arteritis – Rejection Transmural arteritis – Rejection Hyaline arteriolar change – Calcineurin

inhibitor toxicity Glomerulitis, peritubular capillary cell

accumulation, C4d positivity – Antibody-mediated rejection

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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.

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Sclerosing Rejection: “neo-media” formation super-

imposed on donor disease (0.9 years post grafting)

PAS stain

Elastic stain

Transplant Glomerulitis and Glomerulopathy 4.5 years post transplantation

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INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA) IN RENAL ALLOGRAFTS

IFTA WITH INFLAMMATION – MENGEL ET AL.

INFILTRATES IN AREAS OF FIBROSIS AND TUBULAR ATROPHY

SUBCAPSULARperivascular

NODULAR INFILTRATES

i-score total i-score

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BANFF I- AND TOTAL I-SCORE AND DIAGNOSIS: INTERSTITIAL INFILTRATES ARE NOT DISEASE SPECIFIC

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INFILTRATES IN BIOPSIES FOR CAUSE ARE TIME DEPENDENT

3 months

8 months

27 months

79 months

246 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 the Non-Specificity of Interstitial Infiltrates at the Beginning “So The Message Will Reach Even Those 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.

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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 Mouse similar genes and similar development

The Cell 2002.

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

TABLE 1: CORRELATIONS BETWEEN INFILTRATE TYPES AND PATHOGENESIS BASED TRANSCRIPT SETS (PBTS)

Paula Blanco – Superiority of Virtual Microscopy

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Virtual vs. Virtual slides

Observer 1 Observer 2 Observer 3

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9CHANGES NOT CONSIDERED TO BE DUE TO REJECTION:

Post-transplant lymphoproliferative disorder 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

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POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD): WHO 2008

Early lesions

a. plasmacytic hyperplasia,

b. infectious mononucleosis type

Polymorphic PTLD

Monomorphic PTLD

c. B-cell neoplasms

d. T-cell neoplasms

Classic Hodgkin lymphoma-type PTLD

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.