Renal Transplant Pathology (The Rest of the Story Beyond Rejection) and Future Perspectives 

Kim Solez, MD

Michael Mengel gave a TTS webinar on rejection on October 20th 2015. In this presentation I will talk about the remaining issues in transplant pathology, general approaches, and the future.

The Importance of Rooms and Places in the Generation of Important Ideas and Actions.

Pathology Library, Johns Hopkins Hospital

Importance of Rooms and Places (Paris!) in Generation of Important Ideas and Actions.

Objectives of this Presentation One hundred and thirty year history of

transplant pathology, 100 years back, 30 years forward.

To present a general approach to transplant pathology, special stains, and adjunctive procedures.

To introduce you to the concept of tissue engineering pathology and show its evolution from and relation to transplant pathology.

To present transplant pathology and tissue engineering pathology in an accessible way so people who do not regularly think about anatomical pathology like aviator Charles Lindberg (1902-1974) could understand it.

To introduce you to prototypical people from the future your offspring may resemble someday (in 2045)!

Alexis Carrel/Charles Lindberg

In February 2002, theMedical University of South Carolina at Charleston in celebration of Lindberg’s 100th birthday established the Lindberg-Carrel Prize, given to major contributors to “development of perfusion and bio reactor technologies for organ preservation and growth”. M. E. DeBakey and nine other scientists received the prize, a bronze statuette expressly created for the event by the Italian artist C. Zoli and named “Elisabeth”, after Elisabeth Morrow, who died as a result of heart disease. Lindberg was disappointed that contemporary medical technology could not provide an artificial heart pump that would allow for for heart surgery on Elisabeth and that led to the first contact between Carrel and Lindberg.

Alexis Carrel

In 1902, Alexis Carrel started the modern field of transplantation by describing surgical vascular anastomoses for transplantation, work that eventually resulted in his receiving the Nobel Prize. The first transplant pathology paper was published 13 years later: Hesselberg C: A comparison of autoplastic and homeoplastic transplantation of thyroid tissue in the guinea pig, J. Exp. Med. 1915 Feb 1:21(2):164-178.2015 is the centennial of this first publication in transplantation pathology

Robert Heptinstall/Ken PorterMy mentor was Robert Heptinstall. In the early editions of his iconic textbook Kendrick Porter wrote the chapters on transplantation pathology. Porter collaborated for more than thirty years with transplant pioneer Thomas Starzl.

24 years ago Kim Solez and Lorraine Racusen Directed the First Banff Meeting Which Created the Banff Classification of Transplant Pathology

BANFF CLASSIFICATION STANDARD FOR TRANSPLANT BIOPSY INTERPRETATIONBegan in kidney (Solez et al. 1993), and was then

extended to liver, pancreas, composite tissue grafts etc. Meetings also consider heart, lung, small bowel.

Uses semiquantitative lesion scoring 0-3+ and diagnostic categories. A pathologic classification of all pathologic changes, not just rejection.

Polys in peritubular capillaries in antibody-mediated rejection.

The Banff Classification Deals with All Pathologic Conditions, Not Just Rejection. For Genomic Approaches to Take Off They Also Need to Deal with All Conditions, Be Affordable, and Capable of Being Standardized.

At present the Banff Classification uses mainly techniques from 30-60 years ago. More modern approaches would be welcomed!(Experts in pathology can skip next 12 slides, next 12 minutes.)

Affymetrix GeneChip® probe array. Image courtesy of Affymetrix.

Diseases Which Commonly Recur Following Transplantation

FSGSMembranous GlomerulopathyIgA NephropathyMPGN IMPGN II (Dense Deposit Disease, C3 Glomerulopathy)SLE

Diseases Which Commonly Appear De Novo Following Transplantation

Diabetic Nephropathy Anti-GBM Nephritis in Alport SyndromeIgA NephropathyMembranous NephropathyFSGSPost-Infectious GN

Transplanted Kidney is Still A Kidney, Can Be Affected By Any of the Diseases that Affect Native Kidneys Such As Post-Infectious Glomerulonephritis

Transplanted Kidney is Still A Kidney, All Four Compartments Should Be Described, With Number of Glomeruli and Vessels.

TubulesInterstitiumGlomeruliVessels

Light microscopy, electron microscopy, and immunofluorescence are standard.

Transplanted Kidney is Still A Kidney, Standard Special Stains Should Be Employed.

H&E, PAS,Silver Stain, Trichrome.Martius Scarletfor Fibrin.

Membranous GNThis case shows “spikes” on silver stain.

BV Virus Nephropathy, Nuclear Inclusions, SV40 stain. http://ndt.oxfordjournals.org/content/15/3/324/F1.expansion

The Influences Shaping This Presentation

Kim Solez, Korey C. Fung, Khouloud Saliba, Victoria Sheldon, James F. Burdick, William H. Fissell, Anthony J. Demetris, and Lynn D. Cornell - Authors of the tissue engineering pathology manuscript in preparation.

Jason Wertheim, Harald Ott, and Shuvo Roy, regenerative medicine experts who teach in my Technology and Future of Medicine course LABMP 590 http://www.singularitycourse.com

Stem Cell Technologies on Google Trends – News Headlines and Forecast

Current transplant protocols reach fewer than 10% of those in need.

Worldwide 1.2 million people are in need of transplantation for end stage organ failure. Current transplant protocols reach fewer than 10% of this number. Regenerative medicine can save the remaining 90%, over one million people annuallly!

ViaCyte Announces Highly Anticipated Encapsulation Clinical

Trial Site Expansion into Canada JDRF-funded researcher, Dr. James Shapiro

will be the lead investigator at the Canadian site. TORONTO, July 29, 2015 -- ViaCyte, Inc. announced the opening of a second site in its Phase 1/2 trial for Type I Diabetes which utilizes PEC-01™ pancreatic progenitor cells and the proprietary Encaptra® drug delivery system which is designed to protect the transplanted cells from a patient’s immune system.

Regenerative Medicine Already Here! Viacyte Trial for Diabetes Therapy.

Double Think: Stem Cells are Greatest Hope and Greatest Hype, Stem Cell Tourism Estimated to be $3 Billion a Year Industry and Growing, with More than 700 Clinics Worldwide

Mason C et al. Regen Med. 2011 May;6(3):265-72. doi: 10.2217/rme.11.28. Cell therapy industry: billion dollar global business with unlimited potential.

Timothy Caulfield - Stem Cell Tourism June 2015https://www.youtube.com/watch?v=B0r89nMtg10

Channel the Energy of the Regret Felt About Stem Cell Hype, Stem Cell Tourism, and Stem Cell Fraud into Support for the Enormous Benefit for Humanity that Can Come from Well-Conducted Stem Cell Research.

My Avoca Central School high school graduation speech “Youth Rebellion” many years ago talked about sublimation, rechanneling the raw energy of primitive instincts into productive pursuits. The same concept applies here. Channel the emotional energy we feel about stem cells into support of high quality stem cell research.

The Positive Aspects of Stem Cell Therapies,The True Hope, Has Potential to Reverse Three Looming Problems in Medicine:

1. The loss of “luster” in transplantation.2. Workforce problems in nephrology due to lack of appeal to young people/potential trainees worldwide.

3. Technological unemployment in medicine due to replacement of human workers by machines.

Nephrologists & Renal Pathologists May Be Only People Still Employed in 2045!

Sina Marzoughi Found An Image Showing What 2045 Will Look Like

What Human Beings Will Look Like in 2045!

Banff Classification of Kidney Transplant Pathology

Histologic criteria for the diagnosis of rejection and other conditions in the transplanted kidney, began 1991, updated and expanded every two years in consensus meeting.

Significance of ‘Banff papers’• More than 5,000 citations of the 14 Banff meeting reports• 915 Banff / Transplantation papers in PubMed• Banff 2003 meeting report (ABMR criteria) = most cited AJT

paper• 3 Banff meeting reports are among the top 4 cited AJT articles

Tissue Engineering Pathology Added Soon!•

The World is Changing Rapidly!

The World is Changing Rapidly!

The World is Changing Rapidly!

The World is Changing Rapidly!

Canadian Data on Public Interest in Regenerative Medicine

The Technological Singularity

Podocytes go wandering into the interstitium! Song et al.

Many problems with stem cell generate organs not being discussed. Do not exclude yourself from the conversation in this area!

Many problems with stem cell generate organs not being discussed. Need to get those conversations to happen.

The recellularized organ clots like crazy, impossible to regenerate more than 80% of endothelial surface. Artificial heparinized surface not fenestrated. Cell traffic abnormal.

Hard to get right types of cells to right places. Podocytes seems to be terminally differentiated cells,

when attempt to culture them they turn into different type of cell.

Kidney progenitor stem cell difficult to identify, kidney work has lagged behind.

Easy to make stem cell generated kidneys that lack loop of Henle. Could produce lethal polyuria. What is “function”?

Many old fashioned questions of physiology about how the stem cell generated organ works, not just true for kidney, true for every organ. Logo still works for future!

Banff Foundation for Allograft Pathology and Banff Meetings Must Adapt to Future Changes in Field of Transplantation

Transplant pathologists will also become tissue engineering pathologists, pathologists who analyze organs grown from stem cells. This is not something beyond us, we can adapt to a work life that includes stem cells. Someone needs to cross the disciplines.

It is OK to Allow the Natural Resistance to Change and Nostalgia for the Past to Motivate You!

Many of the questions that need to be posed about stem cell generated organs are old fashioned questions, intact nephron hypothesis, cell regeneration, stunned myocardium, contraction band necrosis etc. Use your nostalgia! Stimulate conversations between stem cell researchers and transplant physicians.

Beginning at the Very Beginning! “We are at the very beginning of time for the

human race. It is not unreasonable that we grapple with problems. But there are tens of thousands of years in the future. Our responsibility is to do what we can, learn what we can, improve the solutions, and pass them on.” - Richard P. Feynman, (1918-1988) Physicist, Nobel Prize Winner

"The sense of the future is behind all good policies. Unless we have it, we can give nothing either wise or decent to the world." - Snow CP, (1905-1980) Novelist and Philosopher.

"To a large extent, the future lies before us like a vast wilderness of unexplored reality. The God who created and sustained the evolving universe through eons of progress and development has not placed our generation at the tag end of the creative process. God has placed us at a new beginning. We are here for the future." - Sir John Templeton (1912-2008 ), Financial Analyst

Beginning at the Very Beginning!

Like 1851 when the first International Classification of Diseases was presented in the Grand Exhibition of Technology at London’s Crystal Palace

Emphasis was on cause of death

Classification focus is on sustaining life. Native and transplanted organ diseases can also

occur in tissue engineered organs. Includes ex vivo repair.

The classification focus of the new pathology discipline of Regenerative Medicine/Tissue Engineering Pathology is exactly the opposite of traditional classification of disease which starts with causes of death. In Regenerative Medicine/Tissue Engineering Pathology the emphasis is on the degree of normality necessary to sustain life: 

Normal,  Abnormalities of unknown functional significance,  Abnormalities which will impair the main functions

of the organ,  Abnormalities leading to severe organ dysfunction

where function may not be great enough to sustain life. 

Song et al. Interstitium, vessels, and glomeruli with missing cells. Disordered tubule formation with multiple interconnecting lumina of differing sizes. “Can you really call this a kidney?” (Yes!)

Song et al. In addition to missing cells and disordered structures,you have cells in the wrong places. Podocytes in the interstitium.

Focus of Tissue Engineering Pathology The specific questions become: 1. Are too many

cells missing, 2. Are too many cells in in the wrong places? 3. Are too many structures missing (long loops of Henle)? 4. Is there too much endothelial disruption for the organ to be properly perfused? 5. What are the risks of neoplastic transformation?

Classification categories should be not one-off, but reproducible, generalizable.

Tissue engineering pathology has been up to now really dull (articles since 1967), since most reports were of scaffolds with no inflammatory reaction "Move along, nothing to see here" pathology, but from today becomes really exciting with novel morphological changes and lives hanging in the balance, clinical trials starting!

Banff Classification of Tissue Engineering Pathology major focus 2017 meeting in Spain and 2019 in Turkey.

In our original location we had mule deer poking their heads into the meeting rooms! We’ve come a

long way! Please help us transition to the future!

We are grateful to the Roche Organ Transplantation Research

Foundation for funding the establishment of the Banff

Foundation for Allograft Pathology from 2013-2016, our

infrastructure.