irwin.solid organ transplant 101

Solid Organ Transplant 101Dennis Irwin, MD

May 10, 2012

2

Learning objectives

• State indications and contraindications for solid organ transplant

• Discuss the pre-transplant evaluation process, strategies for managing patients on the transplant waiting list, and common immuno-suppressants used for transplant patients

• Review average billed charges for solid organ transplants

• Describe emerging trends in solid organ transplantation, including the role of alternative donors

Upon the completion of this program, participants should be able to:

Image source: thinkstockphotos.com

3

Solid organs transplanted

Image source: Innovations in Living Donor Kidney Transplantation, presented by David C. Mulligan, MD, FACS, NCC Conference 2009

4

History of solid organ transplantation

1954: First successful kidney transplant (Joseph Murray, Boston)

1962: First successful cadaveric (deceased) kidney transplant

1963: First successful lung transplant

1966: First successful pancreas transplant (Richard Lillehei and William Kelly, Minneapolis)

1967: First successful heart transplant (Christiaan Barnard, Cape Town) AND liver transplant (Thomas Starzl, Denver)

1968: Uniform Anatomical Gift Act

1950–1969

1972: End Stage Renal Disease Act

1981: First successful heart/lung transplant (Bruce Reitz, Palo Alto)

1983: First successful lung lobe transplant (Joel Cooper, Toronto); FDA approves cyclosporine

1984: National Organ Transplant Act (NOTA)

1986: First successful double lung transplant (Joel Cooper, Toronto)

1987: First successful whole lung transplant (Joel Cooper, St. Louis)

1988: First successful small intestine transplant; FDA approves Viaspan

1989: First successful living-related liver transplant

1970–1989

1990: First successful living-related lung transplant

1995: First successful laparo-scopic live-donor nephrectomy (Lloyd Ratner, Baltimore)

1998: First successful live-donor partial pancreas transplant (David Sutherland, Minneapolis)

1990–1998

5

Waiting list

• 114,029 unique patients registered on the wait list as of April 22, 2012

• Many listed on multiple waiting lists, resulting in over 123,588 total registrations; 98,050 are for kidney transplant (91,938 unique candidates. The difference is multiple listing)

U.S. Waiting List by Organ 2012

Source: optn.transplant.hrsa.gov/ Assessed April 22, 2012

Kidney 91,960 80.6%

Liver 16,074 14.1%

Pancreas 1,268 1.1%

Kidney/Pancreas 2,151 1.9%

Heart 3,166 2.8%

Lung 1,622 1.4%

Heart/Lung 52 < 0.1%

Intestine 278 0.2%

6

Living with a transplant

• At of the end of 2007, 183,222 persons were living with a functioning organ transplant in the United States

• Number reflects increase of 1.7 percent over the previous year; a 1.6-fold increase since 1999

Source: optn.transplant.hrsa.gov/ Assessed April 22, 2012

U.S. Transplants by Organ in 2011

Kidney 16,812 58.9%

Liver 6,341 35.0%

Pancreas 287 1.0%

Kidney/Pancreas 795 2.8%

Heart 2,332 8.2%

Lung 1,822 6.4%

Heart/Lung 27 < 0.1%

Intestine 129 0.5%

7

Long-term survival: recipient age = 35 – 49

Source: OPTN Data. Accessed May 16, 2011

One-, three-, and five-year survival rates

0

20

40

60

80

100

120

Kidney Liver K/P Heart Lung Intestine

Organ

% S

urvi

val

1 Year 3 Year 5 Year

8

Estimated utilization and cost for patients under 65 years of age (Milliman 2011)

Estimated U.S. average 2011 first-year transplant utilization for a commercial populationbilled charges and costs per member per month (PMPM)

TransplantEstimated number

of transplantsEstimated annual

utilization per 1,000,000Estimated first-year

billed chargesEstimated cost PMPM

Bone marrow — allogeneic 6,894 23.82 $805,400 $1.60

Bone marrow — autologous 13,263 40.82 $363,800 $1.22

Heart only 2,161 6.76 $997,700 $0.57

Intestine only 74 0.24 $1,208,800 $0.03

Kidney only 16,571 53.03 $262,900 $1.11

Liver only 5,898 19.79 $577,100 $0.94

Single lung only 734 1.73 $561,200 $0.08

Double lung only 1,050 3.29 $797,300 $0.22

Pancreas only 286 1.10 $289,400 $0.03

Heart–lung 30 0.11 $1,248,400 $0.01

Intestine with other organs 107 0.35 $1,343,200 $0.04

Kidney–heart 66 0.21 $1,296,500 $0.02

Kidney–pancreas 867 3.38 $474,700 $0.13

Liver–kidney 369 1.21 $1,026,000 $0.10

Other multi-organ 42 0.16 $1,707,500 $0.02

48,412 156.0 $471,861 $6.12

Source: Milliman “2011 U.S. Organ and Tissue Transplant Cost Estimates”

9

U.S. transplant activity

• In 2012 there are 249 centers in the United States performing one or more solid organ transplants

Source: http://optn.transplant.hrsa.gov/. Accessed April 22, 2012

U.S. Transplant Volume 1998 – January 31, 2012

10

Indications for solid organ transplant

• Death within 12–24 months in the absence of an organ transplant

• Unacceptable quality of life without transplant– Intractable pruritis in progressive sclerosing

cholangitis (PSC)

– Severe COPD

• Potentially lethal complications of the underlying illness

– Intractable cardiac arrhythmia

• Prevention of the manifestation of a genetic illness

– Familial Amyloid Polyneuropathy (FAP)

– Metabolic diseases of the liver

• All other forms of medical and surgical management have been tried and failed

In general, indications for organ transplant:


11

Typical indications: Kidney

• End-stage Renal Disease (ESRD) Stage 5: Creatinine Clearance less than 15 mls/min

• Anticipated ESRD within next 12 months (preemptive transplantation)

• Combined liver/kidney transplant in the presence of combined organ failure

• Combined heart/kidney transplant in the presence of combined organ failure

Image source: courtesy of: Johns Hopkins medicine

12

Frequent diagnoses: Kidney

Image source: courtesy of California Pacific Medical Center

Amyloidosis Polycystic disease

Congenital anomalies

Hypertension

Focal Segmental Glomerulo-sclerosis (FSGS)

IgA Nephropathy

Diabetes

Chronic Allograft

Nephropathy (CAN)

Analgesic nephropathy

13

Typical indications: Liver

• Transplantation is indicated for patients with End-Stage Liver Disease (ESLD) with a life expectancy < 12–24 months and who have developed life-threatening complications

• MELD score ≥ 15, either calculated or with additional MELD points awarded by Regional Review Board (RRB) following review

• Hepatocellular carcinoma within Milan criteria (based upon size and number of lesions), and no contraindications

• Additional considerations may be present where liver transplantation may be appropriate in other circumstances such as Familial Amyloid Polyneuropathy (FAP) or where quality of life considerations become paramount

Image source: A.D.A.M, derived from MyOptumHealth.com

hepatocellular carcinoma

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Frequent diagnoses: Liver

• Alcoholic cirrhosis

• Non-alcoholic steatohepatitis (NASH)

• Hepatitis C (HCV) with cirrhosis

• Progressive sclerosing cholangitis

• Primary biliary cirrhosis

• Hepatocellular Carcinoma (HCC) or hepatoblastoma

• Neuroendocrine tumors of the liver

• Metabolic abnormalities

• Fulminant hepatic failure

• Autoimmune hepatitis

• Biliary atresia Liver with Cirrhosis

Image source: A.D.A.M, derived from MyOptumHealth.com

15

Typical indications: Pancreas

• SPK (simultaneous pancreas-kidney) and PAK (pancreas after kidney):

– Qualifies for kidney transplant and the member is diabetic, type I or type II

• PTA (pancreas transplant alone):– Type I diabetes mellitus with

life-threatening hypoglycemic unawareness or inability to tolerate exogenous insulin

– Type II diabetes mellitus with similar but more strict criteria

Image source Clarian Transplant and Indiana University School of Medicine in Indianapolis, Indiana

16

Frequent diagnoses: Pancreas

Diabetes

Autologous islet cell transplants canbe done following total pancreatectomy(assuming sufficient residual islet cellmass to prevent the new onset of diabetes)

• Generally performed as part of procedure for nonmalignant indications for total pancreatectomy, e.g., chronic, refractory pancreatitis

Performing one of the first islet cell transplant surgeries in 2004

17

Typical indications: Intestine

• Dependent on TPN with cholestatic liver disease

• Recurrent sepsis as a result of either line sepsis or intestinal stasis

• Dependent on TPN with loss of or impending loss of (using last major vessel) vascular access

• Unable to meet fluid and/or nutritional needs through TPN, i.e., recurring dehydration, failure to thrive, etc.

Image source: Clarian Transplant and Indiana University School of Medicine in Indianapolis, Indiana

18

Typical indications: Multivisceral

Liver/small bowel/pancreas with or without addition of stomach or colon:

Liver/intestine:• One of the above AND irreversible cholestasis/

fibrosis secondary to TPN

Multivisceral:• All of the above under AND technically necessary

OR

• Desmoid tumors

Image source: Clarian Transplant and Indiana University School of Medicine in Indianapolis, Indiana.

19

Frequent diagnoses: Intestine

Image source: A.D.A.M compliments of MyOptumHealth.com

Transplant indicated: Intestinal failure from any cause following treatment in a comprehensive intestinal failure program and when it has been shown that all other medical and surgical modalities to manage the intestinal failure have been tried and failed

Vascular catastrophe

Failure on TPN

TraumaNecrotizing enterocolitis

in children

Inflammatory bowel

disease (Crohn's)

20

Typical indications: Heart

• Life expectancy of less than one year due to heart disease

• All therapy has been exhausted

21

Frequent diagnoses: Heart

• End stage heart disease (New York Heart Association Class III or IV)

• Severe systolic or diastolic ventricular dysfunction

• Valvular heart disease with left ventricular dysfunction (not correctable with valve replacement or repair)

• Life-threatening arrhythmias not otherwise correctable

• Intractable angina with coronary artery disease that is not amenable to revascularization

• Primary cardiac tumors without metastasis

• Other advanced irreversible cardiac disease, including refractory congestive heart failure

• Cardiomyopathy

• Congenital Heart Disease (CHD) that is not amenable to surgical therapy or that has failed previous surgical correction

22

Typical indications: Lung

Any ambulatory patient with end-stage pulmonary disease:

• Clinically and physiologically severe disease

• Medical therapy ineffective or unavailable

• Limited life expectancy, usually less than two to three years

• Ambulatory, with rehabilitation potential

• Acceptable nutritional status, usually 80 to 120 percent of ideal body weight

• Satisfactory psychosocial profile and support system

• Adequate coverage for the procedure and for post-transplantation care

23

Frequent diagnoses: Lung

• COPD

• Idiopathic pulmonary fibrosis

• Cystic fibrosis

• Sarcoidosis

• Scleroderma

• Idiopathic primary pulmonary hypertension

• May be single lung or double lung (sequential single lung) transplant:

– Varies by center

– Uninfected patients may get single lung (COPD, IPF, etc.)

– Infected patients will get double lung (CF)

24

Typical indications: Heart/lung

Patients with end-stage pulmonary vasculardisease with end-stage non-reversible cardiacdisease secondary to one of the following:

• Primary pulmonary hypertension

• Eisenmenger syndrome with a cardiac defect not correctable by surgical repair

• Patients who are appropriate for single or double lung transplantation and who have severe cardiac disease not otherwise treatable


25

Absolute contraindications

• Systemic and/or uncontrolled infection

• Active untreated or untreatable malignancy

• Post-transplant Lymphoproliferative Disease (PTLD) unless no active disease demonstrated by negative PET scan and resolved adenopathy on CT/MRI

• Active alcohol and/or other substance abuse Requires six months of documented abstinence through participation in a structured alcohol/substance abuse program with regular meeting attendance and negative random drug testing

• AIDS

• Inability to give informed consent

• Significant uncorrectable life-limiting medical conditions

• Irreversible severe brain damage

• History of non-compliance that has not been successfully remediated

26

Relative contraindications

• Recent graft loss

• Recent history of malignancy (treated) within five years

• Active psychiatric or behavioral disorder

• Remote history (more than six months in the past) of alcohol or substance abuse or occasional recreational use of marijuana

• Insufficient social (caregiver) support

• HIV infection without AIDS and with sustained CD4 counts > 200/mm3

• BMI ≥ 35 kg/m2

• Chronic peptic ulcer disease, GI bleeding, diverticulitis

• High dose systemic corticosteroid use (> 10mg prednisone/day or equivalent)

27

Pre-transplant evaluation

• Confirm appropriate indications

• Uncover contraindications

• Adequate organ function

– Heart

– Lungs

– Kidney

– Liver

• Adequate social/caregiver support

• Adequate financial support


28

Minimum patient evaluation requirements

• Psychosocial evaluation and clearance

• Echocardiogram or MUGA with LVEF > 40 percent OR cardiology clearance

• Colonoscopy (if indicated or > age 50) with removal of any polyps

• Liver function tests (LFT) with transaminases ≤ 3x upper limit of normal and total bilirubin < 2.5mg/dl

• HIV testing

• Hepatitis A, B and C serology

• Serum creatinine < 2.5 mg/dl (≤ 1.5 mg/dl in children) or GFR > 35 ml/min. If abnormal, may be eligible for a combined transplant

• Carotid Doppler ultrasound (with known coronary artery disease or > age 50) — abnormal findings evaluated further; intervention and/or clearance required for abnormal findings

Image source: A.D.A.M. Compliments of MyOptumHealth.com. Accessed September 21, 2009

Carotid Doppler ultrasound

29

Minimum patient evaluation requirements

• Ankle-Brachial Index (ABI) (if indicated or > age 50); ABI < 0.95 may indicate peripheral artery disease (PAD); intervention and/or clearance required

• Dental examination; required dental work completed prior to transplant

• Ophthalmology examination (for diabetics) — baseline

• Mammogram (if indicated or > age 40) — intervention and/or clearance required for abnormal findings

• GYN examination with Pap smear (if indicated or > age 18) — intervention and/or clearance required for abnormal findings

• Immunizations up to date when indicated: Hepatitis A, Hepatitis B, influenza and pneumonia


30

Organ procurement organization locations

Local

Regional

National

Source: UNOS.org. Accessed September 4, 2009.

31

UNOS regional map

Source: UNOS.org. Accessed September 4, 2009.

32

Organ allocation

• Children have priority over adults

• Body habitus

• Blood group

• Human leukocyte antigens (HLA) match

• High panel reactive antibody (PRA) score: highly sensitized recipients


33

Organ allocation by organ

• Adult: Model for end-stage liver disease (MELD) score; calculation based upon total bilirubin, INR, and creatinine

• Pediatric: pediatric end-stage liver disease (PELD) score; calculation based upon total bilirubin, INR, albumin, growth failure and age at listing

Liver

• Lung allocation score (LAS) ; calculation based on age, diagnosis and multiple PFT and physiologic variables

Lung

• Status 1 (A and B)

• Ventricular assist devices (VAD) as bridge to transplant

Heart

• Time on list

Kidney, pancreas, intestine

34

Transplant wait times by organ in 2011

5th percentile 10th percentile 25th percentile 50th percentile(median) 75th percentile

Kidney 1.8 3.9 13.2 50.0 >72

Liver 0.1 0.3 1.5 11.8 >72

Pancreas 0.4 0.9 3.9 20.7 >72

Kidney/pancreas 0.7 1.6 4.7 13.7 >72

Heart 0.2 0.4 1.2 5.3 >72

Lung 0.2 0.3 1.1 4.7 >72

Heart/lung 0.2 0.7 2.5 >72 >72

Intestine 0.2 0.4 1.2 5.8 >72

Months to transplant

Source: http://www.srtr.org. Accessed April 22, 2012

35

Strategies for managing long wait times

Living donation

Ventricular Assist Devices (VAD) for heart

transplant

Double list in two regions, one of which

has a low wait time

Move to region with

low wait time

Alternative donors

Ongoing caregiver

support and education

Excellent medical

management


36

Alternative donors

• Paired donation for kidney transplant

• Desensitization for highly sensitized kidney transplant

• Extended Criteria Donors (ECD)

• Donation after Cardiac Death (DCD)


37

Kidney-paired donation

• Over 90,000 Americans on kidney transplant waiting list

• Twelve die every day waiting for a kidney

• Mysteries of the immune system sometimes prevent willing living kidney donors from being able to donate to their loved ones.

However, there is hope…

• A recent breakthrough, called kidney-paired donation, matches one incompatible donor/recipient pair to another pair with a comple-mentary incompatibility, so the donor of the first pair gives to the recipient of the second, and vice versa

• In the end, this procedure adds ~$25,000 to the average kidney transplant cost

Source: OPTN. Accessed July 10, 2011; Image source: thinkstockphotos.com

38

Action takenThe desensitization protocols as well as donor exchange programs are effective. Using either of these techniques can increase the life expectancy of the highlysensitized patients by 10+ years:

• Early transplantation of highly sensitized patients can save over $500,000 in expenses over the lifetime of a patient

• Transplanting 50% of highly sensitized patients could save over $140 million per year in medical expense

Desensitization of highly sensitized recipient

Panel reactive antibodies (PRAs) are preformed antibodies against human leukocyte antigens (HLA), and develop in patients who have been exposed to HLA from blood products, pregnancy and prior transplantation

39

Deceased Donor Population by Donor Type and Year

Increased ECD and DCD

Source: 2010 OPTN/SRTR Annual Report, Table 2.2; *includes DCD that meet ECD kidney criteria., Data as of October 31, 2010. Accessed April 22, 2012

4040

Changing donor pool

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

Don

ors

Deceased Donor

Living Donor Number of ECD in Deceased Donors

Number of DCD in Deceased Donors

Forecast Number of ECD and DCD

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Source: 2010 OPTN/SRTR Annual Report, Table 2.2; *includes DCD that meet ECD kidney criteria., Data as of October 31, 2010 and http://optn.transplant.hrsa.gov/. Accessed: April 22, 2012.

2010 2011

* projected

* *

http://optn.transplant.hrsa.gov/

41

Commonly used immunosuppressant drugs

• Immunosuppressant drugs, also called anti-rejection drugs, are used to prevent the body from rejecting a transplanted organ

• Major categories of immunosuppressant drugs:

– Calcineurin inhibitors: cyclosporine A (Neoral, Sandimmune, SangCya) and tacrolimus (Prograf)

– Azathioprine: (Imuran)

– Monoclonal antibodies: including basiliximab (Simulect), daclizumab (Zenapax), and muromonab (Orthoclone, OKT3)

– Corticosteroids: prednisolone (Medrol), prednisone (Deltasone, Orasone)

– Mycophenolate: (CellCept, Myfortic)

– mTOR inhibitors: rapamycin (Sirolimus)

Source: http://www.surgeryencyclopedia.com/Fi-La/Immunosuppressant-Drugs.html. Accessed Monday, August 24, 2009.

http://www.surgeryencyclopedia.com/Fi-La/Immunosuppressant-Drugs.html

42

Post-transplant management

• Immediate post-hospital management (up to 90 days)

• Intermediate term management (up to one year)

• Long-term management (over one year)

• At all stages:COMPLIANCE


43





• At all stages:COMPLIANCECOMPLIANCE


44





• At all stages:COMPLIANCECOMPLIANCECOMPLIANCE


45

Five year graft survival – living and deceased donors

*Source: SRTR DATA, June 30, 2009. Accessed September 18, 2009.

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

6-10 Years 11-17 Years 18-34 Years 35-49 Years 50-64 Years 65+ Years

Age

Deceased Donor ECD Deceased Donor Non-ECD Living Donor

46

Long-term consequences

• Malignancy:– Post-transplant lymphoproliferative

disease (PTLD)

– Skin cancers

– Leukemia

• Diabetes

• Hypertension

• Hyperlipidemia

• Coronary artery disease

• Opportunistic infections

• Calcineurin Associated Nephropathy (CAN)

• Osteoporosis (steroids)

• Social costs: employability, health insurance, family issues


Transplant Costs are Significant• U.S. average billed charges for 180 days post-

transplant is $471,857

On average, 64% of a transplant’s total cost equals the hospital and

the physician

15–20% of ALL patient events are transplant

related and cost more than $100,000

Outpatient Immunosuppressant’s and other RX

180 days post transplant admission

Physician during transplant

Hospital transplant admission

Procurement

30 days pre-transplant

Estimated 2011 U.S. Average First Year Billed Charges Per Transplant

Co

st

Milliman estimated U.S. average billed charges related to 30 days prior and 180 days after transplant for the commercial population under age 65. Milliman 2011

Transplant Type

$-

$200,000

$400,000

$600,000

$800,000

$1,000,000

$1,200,000

$1,400,000

$1,600,000

$1,800,000

BMT A

llo

BMT A

uto

Heart

Inte

stine

Kidney

Liver

Lung

Sing

le

Lung

Dou

ble

Pancr

eas

Heart-

Lung

Inte

stine

w/ O

ther

Kidney

-Hea

rt

Kidney

-Pan

crea

s

Liver

-Kidn

ey

Other

Mult

i-Org

an

48

Emerging technology and trends

The evolution of paired exchange:

• Organ allocation cost is an increasingly large component of overall cost

• Paired kidney donation

RR R

D

R

D

R

D

Traditional Paired Exchange

Two Pair Exchange Three Pair Exchange

D

R

R

R

D

D

D

R

R

D

D

R

R

D

Etc.

Chains

Non-directed altruistic donor

Clu

ste

r #

1C

lus

ter

#2

Clu

ste

r #

3Image source: Innovations in Living Donor Kidney Transplantation, presented by David C. Mulligan, MD, FACS. NCC Conference 2009.

DD

49


Source: Axelrod 2007



• ECD/DCD and the clinical and financial implications

0

10

20

30

40

50

60

0-10 11-20 21-30 31-35 > 35MELD Score Category

Leng

th o

f Sta

y

0.0-1.0

1.0-1.5

1.5-2.0

2.0-2.5

2.5+

50





• Nonalcoholic steatohepatitis (NASH) as an increasingly frequent cause of liver disease


51


2010$1,212,790 Average billed per kidney/liver transplant

$592,910 Average paid per kidney/liver transplant




• NASH as an increasingly frequent cause of liver disease

• Combined organ transplants (i.e., liver/kidney, liver/heart, kidney/heart, liver/intestine, multivisceral, etc.)

52







• Belatacept as cyclosporine-free immunosuppression


53








• Islet cell transplant

Performing one of the first islet cell transplant surgeries in 2004

Image source: Hub Pages: Cure for Diabetes — Islet Cell Transplants; accessed August 2011

54








• Islet cell transplant

• Xenografts


55

Summary

• Indications:– Death within 12–24 months in the absence

of an organ transplant

– Unacceptable quality of life without transplant

– Potentially lethal complications of the underlying illness

– Prevention of the manifestation of a genetic illness

– All other forms of medical and surgical management have been tried and failed

• Wait times vary by organ and region

• Organ allocation varies by organ

• Average billed charges are $480,000 and rising

• While life-saving, ECD and DCD organs add to the overall cost of transplantation

• A good pretransplant evaluation, good recipient and donor matching, close managed in the pre-and post-transplant periods are essential for success

• A well motivated and educated caregiver is vitally important

• There are serious post-transplant complications not directly related to the transplant surgery that require careful long-term follow-up

• There are a number of important trends to watch in the future including multi-organ transplants and newer immunosuppressive drugs

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