Victor Bowers , M.D, FACS

Current Issues And Future Directions In Renal Transplantation

DisclosuresI HAVE NO FINANCIAL

RELATIONSHIP(S) RELEVANT TO THE CONTENT OF THIS

CME ACTIVITY.

Disclosures

I WILL NOT DISCUSS OFF-LABEL USE OF MEDICATIONS.

Renal Transplantation

• True or False-The Number of kidney transplants performed in 2013 was greater than

the entire kidney transplant waiting list in June of 1989.

UNOS Patient Waiting ListThe UNOS national patient waiting list for organ transplant contains

more than 17,000 names.*

ORGAN NUMBER

Kidney 15,045

Kidney/Pancreas 267

Heart 1,216

Liver 763

TOTAL 17,291

UNOS 6/1989

Recent Facts

2003 2008 2010 2013

Deceased Donors

5,752 7,188 7,241 7,547

Deceased Donor Transplant

8,668 10,553 10,622 11,163

Living Donors

6,470* 5,968 6,278 5,732

Total Renal Transplants

15,138 16,521 16,900 16,895

Chronic Kidney Disease

Any Condition That Causes Reduced Kidney Function, GFR Less 60 Ml/Min For More Than 3 Months or When a

Patients Urine Albumin-to- Creatinine Ratio Over 30mg of Albumin to Each

Gram of Creatinine.

One In 10 American Adults Have a Diagnosis of CKD.

(CKD)

Chronic Kidney Disease

Stages 1- GFR > 90 Ml/Min (per 1.73m2) 2- GFR 60-89 Ml/Min (per 1.73m2) 3a-GFR 45-59 Ml/Min 3b-GFR 30-44 Ml/Min 4- GFR 15-29 Ml/Min 5- GFR <15Ml/Min or Treatment on

Dialysis

Adjusted Incident Rates Of ESRD & Annual Change

USRD 2013

Adjusted Prevalent Rates of ESRD & Annual Percent Change

USRD 2013

USRD 2013

USRD 2013

Incident & prevalent patient counts (USRDS), by modality

USRDS 2013

Figure 1.1 (Volume 2)

Renal Transplant OutcomesProbability of Graft Survival

Adult

1 Year 3 Year

TGH 94.9 90.3

Nat’l Expected 94.9 87.1

SRTR 03/20/2014

Deceased t ½ 9.5 yearsLiving t ½ 12.4 years

Adjusted all-cause mortality in the ESRD & general populations, by age, 2011

USRDS 2013

Figure 5.2 (Volume 2)

(PER 1 ,000 PATIENT YEARS AT RISK)

Adjusted All- Cause Mortality in the ESRD & General

Populations,2011

USRD 2013

Total Medicare Expenditures per person/year

Hemodialysis $87,945

Peritoneal Dialysis $71,630

Transplant $32,922

Wait Listed Patients Receiving a Deceased Donor Transplant in 3 years - Listing (2010)

Blood Type %TGH

%Nat’l

“O” 43 21.1

“A” 57.7 33.0

“B” 56.9 20.8

“AB” 65.8 45.8

USRDS 2013

Kidney Transplant:Supply and Demand

Kidney Transplant is Routinely successfulCost EfficientImproves Patient Survival and Quality of LifeLimited Only by donor Availability

Medicare Act Signed into Law July 30, 1965

ESRD Act Signed into Law 1972

10 ,000 NEW PATIENTS PER YEARTOTAL BENEFICIARIES WILL LEVEL AT 35 ,000

Estimated ESRD Program(Klar 1972)

Reality

1978- 14,000

1986- 32,000

1998- 75,000

2011- 115,643

US Healthcare Cost $• 2.8 Trillion Dollars

• 18% GDP (15.1 Trillion)

• Projected to 21% by 2020

• Distinct Threat to our Government’s Fiscal Stability

Institute of Medicine Report

September 6th, 2012

“It’s A Mess”

US Healthcare

30 % Healthcare Spending is WASTED (750 Billion)

Unnecessary Services Defensive Medicine/ Futile Care

Excess Administrative Costs

Fraud

Contractual Value Clinical

Medical Devices

US Healthcare

Single Largest Payer-Medicare Uncapped Entitlement

Fee for Service

Accelerate Use of Alternatives to Fee for Service Comprehensive “Fee for Event”

“Bundled Payments”

Payment/ Health Reform

Transplant Centers

Multidisciplinary Approach• All Facets of Care-“Under One Roof”• Identify Processes for Improving Communication• Protocols for All Areas of Care Including

Community Physicians• Dedicated Specialists • Physician Extenders

Survival Guide

David and Goliath

Waitlist vs. TransplantedNational

2014 2013 2003 1989

Waitlist 108,314 103,131 59,080 15,045

Transplanted

2,676* 16,894 15,138 8,656

*As of May 30, 2014 OPTN

Kidney

Donor

Profile

Index

KDPI

Score is Associated with How Long Kidney is Likely to Function Compared to Other KidneysRange 0 to 100

KDPI ScoreAgeHeightWeightEthnicityDid Donor Die Due To

Loss of Heart or Brain Function

CVA Cause of DeathHistory of

HypertensionHistory of DiabetesPositive Serology for

Hepatitis CSerum Creatinine

KDPI: Kidney Donor Profile Index

Estimated Graft Half Lives (Years)

Score of 20 Means That The Kidney is

Likely to Function Longer Than 80%

of

“Available Kidneys”

Score of 60 Means That This Kidney is

Likely to Function Longer Than 40%

of “Available Kidneys”

Estimated

Post

Transplant

Survival

EPTS

Each Kidney Transplant Candidate Will Get An Individual ScoreRange 0 to 100

EPTS Score

Calculated on 4 Variables Age Length of Time On Dialysis Having a Previous Transplant

(Of any Organ) Current Diagnosis of Diabetes

EPTS of 20% Indicates That You Will Need a

Kidney Longer Than 80% of the Other

Candidates

EPTS of 55 Means That One Will Need A

Kidney Longer Than 45% of Other

Candidates

KDPI/EPTSAllocation

KDPI- Score Of 20 or Less Will First Be Off ered to Patients Likely to Need A Transplant The

Longest-Those With An EPTS Score of 20 or Less.

If Not Accepted by One of These Individuals, It ’s Off ered to Any Other Person Who Would Match on

the Transplant List.

KDPI/EPTSAllocation

Children & Teenagers(Age <18) Will Receive Priority for Kidneys With a KDPI Score of 35% or Lower

Blood Group A2 B

Highly Sensitized Candidates Also get Priority (> 98% PRA)

Current Renal Allocation

Deceased Donor 21 year old male MVA passenger Multi-organ Donor

Recipient Profile No pediatric compatible recipients 72 year old male Dialysis 2 years Type II DM, HTN

PROPOSEDEPTS CALCULATION

45 years old 2 years dialysis No diabetes No previous

transplants

EPTS Score 16%

70 years old Pre-emptive No diabetes No previous

transplants

EPTS Score 55%

Proposed EPTS Calculation

65 years oldDialysis 5 yearsType II diabetes1 previous transplant

EPTS Score 97%

30 years oldPre-emptiveNo history of diabetesNo previous

transplants

EPTS Score 2%*

TRIVIA

Which event(s) took place in 1996?a) Derek Jeter named rookie of the yearb) Winter Olympics held in Lillehammer, Norwayc) “dolly” the sheep clonedd) Monica Lewinsky signs affidavit denying affair with

President Clintone) First crew arrives at the International Space

Station

We can’t solve problems by using the same kind

of thinking we used when we created them.Albert Einstein

Quote…

THE PAST 30 YEARS HAS SEEN THE EMERGENCE OF AN ENDEAVOR CALLED REGENERATIVE MEDICINE AND TISSUE

ENGINEERING. SCIENTISTS, ENGINEERS, AND PHYSICIANS APPLY BIOLOGICAL SUBSTITUTES

THAT CAN REPLACE OR HELP REGENERATE DISEASED OR INJURED TISSUES.

Regenerative Medicine/Tissue Engineering

REGENERATIVE MEDICINE IS OFTEN USED SYNONYMOUSLY WITH TISSUE ENGINEERING,

ALTHOUGH THOSE INVOLVED IN REGENERATIVE MEDICINE PLACE MORE

EMPHASIS ON THE USE OF STEM CELLS TO PRODUCE REPAIR TISSUE.

Regenerative Medicine

Regenerative

Medicine

TISSUE ENGINEERING IS THE USE OF A COMBINATION OF CELLS, ENGINEERING AND

MATERIAL METHODS, AND SUITABLE BIOCHEMICAL AND PHYSIO-CHEMICAL

FACTORS TO IMPROVE OR REPLACE BIOLOGICAL FUNCTIONS.

Tissue Engineering

Mammalian Development

ZygoteBlastomere (32-64 cell stage)MorulaBlastocyst

TrophoblastInner Cell Mass (Gastrula)

GASTRULA“GERM LAYERS”

3 Layers are responsible for all tissue within the human body.EndodermMesodermEctoderm

CAPABLE OF SELF-RENEWAL ABILITY OF CELLS TO PROLIFERATE WITHOUT LOSS OF DIFFERENTIATION WITHOUT

UNDERGOING SENESCENCE

CAPABILITY TO DIFFERENTIATE SYMMETRICAL OR ASYMMETRICAL (SELF GENERATION) OR

(DIFFERENTIATED CELL TYPES)

Stem Cells

Stem Cells

Pluripotent Cells – can make all cells of the embryo (can make any cell type of the body)

Multipotent Cells - Can only make cells from within a given germ layer.

Unipotent Cells – Can make cells of a single cell type within a specific germ layer

Stem Cells

Pluripotent cells were thought to be limited to cells derived from the inner cell mass of the blastocyst (7-10 days)

Cells cultured and cell lines established from these structures are called embryonic stem cells (ES)

Induced Pluripotent Stem Cells(iPSCs)

2006 Yamanaka Took genes of pluripotent ES cells and

introduced them into “mature cells”. A small number of mature cells reverted

back to a highly immature cell state that resembled an ES cell “reprogramming”.

Induced a pluripotent state in a previously differentiated cell type. (“Re-Programmed”)

“Unprecedented Opportunities”

CAN BE DIFFERENTIATED INTO MANY TISSUES

Hematopoietic precursorsOsteoclassPancreatic B-CellsCardiomyocytesHepatocytes and Biliary Epithelium

Human iPSCs

TWO METHODS OF “BUILDING”ORGANS/TISSUES

Utilization Tissue Scaffolds High porosity, pore size to facilitate

seeing/nutrition/waste removal “ghost organs”

Bioprinting Computer program is created, rather than

ink, cells are utilized

TISSUE INTEGRATION:

How effectively will these cells integrate into surrounding tissue and achieve physiologic function

ONCOGENESIS:

Pluripotent cells in vivo may form teratomas (neoplastic tumors with all three germ lines)

DIRECTED DIFFERENTIATION

Challenges in Clinical Use of Stem Cells

BIO PRINTER

Ghost Organ

Thank you!