Immunosuppression

Prof. Ileana Constantinescu

Immunosuppression
Immunosuppressive protocols in
transplantation include the targeting of
IL-2/IL-2R axis that are considered to be
the most important pathway for Tcell
proliferation.

Immunosuppressants
classification
Calcineurin
inhibitors:
Cyclosporine, Tacrolimus
Antimetabolites:
Mycophenolat mofetil,
Azathioprine
Corticosteroids
Proliferation inhibitors (mTOR
inhibitors/mammalian target of rapamycin):
Sirolimus, Everolimus

IMMUNOSUPPRESSION
The consideration of the various factors affecting transplant
outcome now turns to a discussion of a subject of tremendous
importance not only to recipient selection but also to longterm
transplant recipient care and management, namely the issue
of often associated immunosuppression.
Since graft rejection is provoked by an undesirable but
healthy immune response on the part of the host, it is
imperative for favorable transplant outcome that the
transplant recipient be in some way immunosuppressed.
Immunosuppression of the transplant recipient falls into one
of two categories, either suppression targeted specifically
toward donor antigen or targeted nonspecifically, resulting in
broader immunocompromise of the transplant recipient. Means
of
achieving
both
antigen-nonspecific
and
specific
immunosuppression.
Total lymphoid irradiation, while infrequently used today,
effectively eliminates the host immune response, resulting in
graft survival, albeit profound immunosuppression.
5

 More frequent approaches to cripple the transplant

recipient's immune system have included the use of antilymphocyte globulins, such as OKT-3, directed against
T cell-mediated responses. CD3 component of the
human T cell receptor, antimetabolite drugs, such as
azathioprine, inhibit nucleotide synthesis and result in
suppressing the proliferative capacity of rapidly dividing
cells, such as lymphocytes recently recruited to participate
in an immune response.
Such drugs are frequently used in combination with
steroids, such as prednisone, which is broadly
immunosuppressive by inhibiting lymphocyte function, as
well as a drugs called Cyclosporine A or Tacrolimus
(FK506) which more specifically inhibits T cell expression
of cytokine effector molecules. A triple regimen consisting
of azathioprine, prednisone, and cyclosporine A is
commonly used post-transplant to manage heart and
kidney transplant recipients.
7

 Such effective immunosuppressive measures, due to their

broad impact on the host's immune system, as well as frequent
adverse side effects, have raised the issue of identifying means
of suppressing the transplant rejection response in a more
antigen-specific way. It is hoped that such antigen-specific
means of immunosuppression, though still in their infancy, will
impact less on the host's immune system and result in fewer
side effects associated with multiple drug use.
One strategy considered in antigen-specific
immunosuppression is to employ antibodies directed against
graft antigens, such as MHC alloantigens, which results in a
prolongation of graft survival known as enhancement.
The mechanism by which anti-graft antibodies promote
transplant survival is currently under investigation. Another
donor antigen-specific approach to immunsuppression, still in
an experimental phase of study, is the use of anti-T cell
receptor (TCR) antibodies to block host T cells specific for
allogeneic MHC.

 This kind of therapy implies a detailed knowledge not

only of which MHC alloantigens are expressed on each
graft, but also which antigen epitopes are critical for
generating host T cell help during the alloimmune
response.
Antibody therapy, whether donor antigen-specific or
nonspecific, due to its passive nature, usually requires
chronic administration. Associated with long-term
antibody therapy is the adverse sensitization of the
individual receiving these antibodies, which are usually
raised in nonhuman species.
These antibodies, therefore, act as alloantigens due to
foreign isotope sequences and as such have the
potential to provoke anti-antibody responses in the
recipient. Clearly, such a situation renders antibody
therapy of limited longterm value.
9

 In the face of these therapeutic difficulties, an appealing strategy

aimed at inducing donor antigen specific immunosuppression is the
concept of tolerance, defined here as specific, acquired, long
lasting immunological unresponsiveness. Tolerance to self antigens
occurs very early in life, during fetal and neonatal development.
Self-tolerance or central tolerance is principally acquired by
negative selection or elimination of potentially self-reactive T cell
clones during thymic development. Negative selection in the
thymus is characterized by programmed cell death in a process
referred to as clonal deletion.
Tolerance to prospective donor alloantigens, however, raises
the issue of how to achieve tolerance in the adult transplant
recipient long after central or self-tolerance has been achieved.
Issues surrounding how to establish peripheral (nonthymic)
tolerance form the basis of many experimental studies in the fields
of transplantation and autoimmunity today. While still at their
inception, these studies aim to elucidate how prior oral or
intravenous administration of donor allo MHC antigens, in the case
of transplantation, sometimes achieves a tolerant state in the
transplant recipient.
10

 Also under investigation are the doses of antigen required

to induce tolerance, described as either low zone or high
zone, depending upon the relative doses of antigen needed
to achieve it. Route of administration and antigen dose
aside, experimental observations published to date have
indicated that tolerance to donor allo MHC antigens
may be established by a combination of active
suppression of the recipient immune response
and/or failure to respond to foreign antigen
mediated by either T cell clonal deletion or anergy.
Anergy may be defined as the absence of an immune
response due to loss of cell function or "immune paralysis"
and may be reversible. Future transplant therapy awaits
clarification of these issues.

Immunosupression
Cyclosporin A: MEIA Axsym/TDx,
HPLC
Tacrolimus: MEIA IMx, HPLC
Sirolimus: MEIA IMx, HPLC
Methotrexat: MEIA TDx

Sadimmun. Concentrate for I.v. infusion

Immunosuppressive agent
Composition
Active component

Sandimmun Neoral
1 soft gelatin capsule

Sandimmun Neoral
oral solution

Sandimmun
concentrate
for I.v.infusion

Ciclosporin

10 mg; 25 mg
100 mg/mL
50 mg/mL
50 mg; 100 mg
Sandimmun Neoral is a new pharmaceutical form of the active ingredient ciclosporin based on the microemulsion principle,
which reduces the variability of pharmacokinetic parameters, and provides dose linearity of ciclosporin exposure with a more
consistent absorption profile and less influence from concomitant food intake. The formulation is a microemulsion
preconcentrate which in pharmacokinetic and clinical studies has demonstrated that the correlation between trough
concentration and exposure to ciclosporin is much stronger when ciclosporin is given as Sandimmun Neoral than when it is
given as Sandimmun. The formation of the microemulsion itself takes place in the presence of water, either in the form of a
beverage or in the form of the gastric fluid.
Therapeutic indications
Transplantation indications
Solid organ transplantation
Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung, or pancreas allogeneic transplantations.
Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.
Bone marrow transplantatiom
Prevention of graft rejection following bone marrow transplantation.
Prevention or treatment of graft-versus-host disease (GVHD)

Challenges in Immunosuppression

Cyclosporin complex pharmacokinetics impact clinical outcomes1

Neoral Absorption Profiling demonstrates CsA absorption monitoring can result in more effective
immunosuppression2

Optimising immunosuppression requires individualisation of Neoral doses4

C-2 monitoring is validated as the most effective and practical single sampling point for Neoral
monitoring3

Cyclosporin blood level monitoring is standard practice for Neoral management of the transplant
recipient4

1. Lindholm A, Kahan BD. Clin Pharmacol Ther. 1993;55:205-218. 2. Mahalati K et al. Transplantation.1999;68:55-62.
3. Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S. 4. Kahan BD. N Engl J Med. 1989;321:1725-1738.

Improving Patient Outcomes in Transplantation

The importance of the absorption phase in Neoral pharmacokinetics1

AUC0-4 monitoring in renal transplantation2
C-2 monitoring in liver transplantation3
Application of C-2 monitoring to all transplant recipients4

1. Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S. 2. Mahalati K et al. Transplantation. 1999;68:55-62. 3. Levy G
et al. Transplantation. 2000;69:S387. 4. Belitsky P et al. Transplant Proc. 2000;32(suppl 3A):45S-52S.

Neoral C-2 MonitoringWhy the Need?

Issue
C-0 (trough) monitoring was introduced to minimise toxicity1
C-0 monitoring does not optimise the clinical benefits of Neoral2-4
AUC monitoring is cumbersome and expensive as a routine
management tool5

1. Uchida K et al. Dev Toxicol Environ Sci. 1986;14:163-166. 2. Mahalati R et al. Transplantation.
1999;68:55-62. 3. Johnston A et al. Transplant Proc. 2000;32(suppl 3A) 53S-56S. 4. Mahalti K et al.
Transplantation. 2000;69:S114. 5. Amante AJ et al. Clin Chem. 1996;42:1294-1295.

Greatest Degree of Intra-subject Variability

Occurs 1 to 2 Hours Post-Dose
50
45
40
35
30
25
20
15
10
5
0
0

0.33 0.66

1.5

2.5

12

Hours Post-Dose
Stable Cardiac Transplant Recipients: 1, 12, 52 Weeks Intrasubject Variability
in CsA Mean Concentration Values
Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S.

Interpatient Variability of CsA Absorption Not

Captured by C-0
1400

AUC0-4

Cyclosporin Concentration
(ng/mL)

1200

AUC0-4

1000
800
600
400
200
0

0
C-0

2
C-2

Hours Post-Dose

10

12

Extent and rate of absorption are highly variable.

Patient differences are highlighted in the absorption phase.
Adapted from Johnston A et al. Transplant Proc. 2000;32:53S-56S.

Incidence of Rejection (%)

Incidence of Rejection (%)

C-0 Does Not Predict Acute Rejection: Cmax Does

60

54.5%
45.5%

40

34%

38%

20

80

<250

250-300
301-400
C-0 (ng/mL)

>400

71%

60
44%
40

36%

34%

20
0

<600

601-850
851-1200
Cmax (ng/mL)
Grant D et al. Transplantation. 1999;67:1133-1137.

>1200

C-2 Is a Surrogate Marker of Cmax

Cmax requires multiple blood samples and subsequent

extrapolation of cyclosporin concentration-time curve
A single sampling point is the ideal monitoring tool
C-2 has the best correlation with Cmax in liver
transplant patients

Grant D et al. Transplantation. 1999;67:1133-1137.

Choice of C-2 for Neoral Monitoring

Pharmacokinetic evidence for C-2
The region of highest pharmacokinetic variability1
The single sampling point that defines CsA absorption2

Pharmacodynamic evidence for C-2

Correlates with the period of maximum calcineurin inhibition 3
More extensive and consistent IL-2 suppression compared with C-04

1. Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S. 2. Belitsky P et al. Transplant Proc.
2000;32(suppl 3A):45S-52S. 3. Halloran PF et al. Transplantation. 1999;68:1356-1361. 4. Sindhi R et al.
Transplantation. 2000;69:432-436.

100
Calcineurin
Inhibition (%)

80
60
40
20
0
0
1
2
4
C-0
C-2
Hours Post-Dose

Adapted from Halloran P et al.

Transplantation.1999;68:13561361.

CD4+ IL-2 + Lymphocytes

< Baseline (%)

Calcineurin Inhibition Maximal and IL-2

Suppression Most Consistent at 2 Hours
Post-Dose
50
40
30
20
10
0

C-0

C-2

Sampling Point

Sindhi R et al. Transplantation.

2000;69:432-436.

C-2: A Sensitive Indicator of Risk for Subclinical

Rejection
P=.04
0.04

C-2 Level (g/ mL)

1.25
1.20
1.15
1.10
1.05

0.03

1.00
0.95

1.2

1.0

0.90
Mean C-2 in Patients Mean C-2 in Patients
With No ScRj
With ScRj

Mean C-2 in Patients Without Subclinical Rejection (No ScRj) or With Subclinical
Rejection (ScRj) at Biopsy 6 to 9 Months Post-Transplant
Barama A et al. Transplantation. 2000;69:S225.

Kidney Transplant
Cyclosporinemia (ng/ml)
C0

Determination at 12 hours after administration:

Month 1
Month 2 Month 3
Month 4 Month 12
After 1 year

C2

250-350 ng/ml (preferably min 300 ng/ml)

250-300 ng/ml
250 ng/ml
200-250 ng/ml

Determination at 2 hours after administration:

Month 1
Month 2
Month 3
After 1 year

1600-1800 ng/ml
1400-1600 ng/ml
1200-1400 ng/ml
700-800 ng/ml

TACROLEMIA
(ng/ml)

Day 1 - Day 7
Day 8 Day 30
Day 31 Day 60
Day 61 Day 90
After 90 Days

15 - 20 ng/ml
10 20 ng/ml
5 10 ng/ml
5 - 10 ng/ml
5 ng/ml

SIROLIMUS: 6 7 ng/ml

Adverse reactions in
immunosuppressant drugs

When immunosuppressant drugs weaken the immune system, the body becomes
less resistant to infection. Any infections that develop will be more difficult to
treat because of this. These drugs also increase the likelihood of uncontrolled
bleeding due to injury or infection.
People taking immunosuppressant drugs should be careful to avoid catching an
infection. Precautions include:
frequent hand washing
avoiding sports in which injuries occur
extra care when using sharp objects such as knives or razors
avoiding close contact with people who have infections or colds

A physician should be notified immediately when the following symptoms

occur:
fever or chills
pain in the lower back, on the sides
pain or difficulty urinating
unusual bruising or bleeding
blood in your urine
stools that are bloody or black

Immunosuppressant drugs can cause adverse reactions and birth defects.

Physicians should be made aware of the following conditions before
immunosuppressant drugs are prescribed:

allergies

pregnancy

lactation

shingles or chickenpox

kidney or liver disease

intestinal problems

The most significant side effect of immunosuppressant drugs is an increased risk of

infection. The drugs can also put you at a higher risk for cancer because the immune
system also protects you from this disease.

Other, less serious side effects can include loss of appetite, nausea, vomiting,
increased hair growth, and hand trembling. These effects typically subside as the
body adjusts to the immunosuppressant drugs.
The following side effects indicate the need for immediate attention:

a feeling of being unusually tired or weak

fever or chills

frequent urination

Immunosuppressant drugs can interact with many other medications. This can cause
dangerous effects in which the immunosuppressants may lose or even increase their
effect. The primary caregiver should be made aware of any prescription or over-thecounter medications their patients are taking while on immunosuppressant therapy.

Conclusions
Transplantation immunology is complex.
Our Immunogenetic Centre provide expanded
immunological monitoring together with virological
and drug monitoring of the transplanted patients.
Our goal is to offer complete integrated monitoring
data and to fulfil EFI Standards.
We are open for collaborative work and research
projects within EFI.
Clinical and laboratory scientists should work
together as a team in order to have a complete
overview of the transplanted patients.

Posttransplant
management in solid
organ transplantation
(SOT)
Prof. Ileana
Constantinescu

What means post transplant management of

the patient

Management of skin cancer in solid organ transplant recipients

Renal function and nonrenal solid organ transplantation
Treatment and prevention of post-transplant lymphoproliferative disor
ders
Long-term management of adult liver transplant recipients
Clinical manifestations, diagnosis, and treatment of cytomegalovirus in
fection in lung transplant recipients
Prevention of cytomegalovirus infection in lung transplant recipients
Development of malignancy following solid organ transplantation
Infection in the solid organ transplant recipient
Osteoporosis after solid organ or stem cell transplantation
Systemic treatment of advanced cutaneous squamous and basal cell
carcinomas
Overview of care of the adult kidney transplant recipient
Solid organ transplantation in HIV-infected individuals
Management of the hematopoietic cell transplant recipient in
the immediate posttransplant period
Treatment and prognosis of cutaneous squamous cell carcinoma
ESOT - http://www.esot.org

Management of skin cancer in solid organ tran

splant
recipients
INTRODUCTION

Solid organ transplant recipients are at increased risk for cutaneous malignancies, a
finding related to the long-term use of immunosuppression. Because some skin cancers
demonstrate aggressive biologic behavior in the setting of immunosuppression, care
must be taken to identify and treat early lesions appropriately. In addition to treatments
that directly target cutaneous malignancies, modulation of immunosuppression and
preventive measures often play an important role in the management of these patients.
Organ transplant recipients with a history of skin cancer should be followed closely for
the development of new lesions, locally recurrent lesions, and metastatic disease.

The management of skin cancers in organ transplant recipients will be reviewed here.
The epidemiology and risk factors for skin cancers in organ transplant recipients, as well
as a summary of other malignancies that develop with increased frequency after solid
organ transplantation, are discussed separately.
SQUAMOUS CELL CARCINOMA

Squamous cell is carcinoma (SCC) is the most common cutaneous malignancy in solid
organ transplant recipients . As in the immunocompetent population, cutaneous SCC is
most likely to occur in patients with fair skin.

In comparison to SCC in immunocompetent patients, SCC in organ transplant recipients

is more likely to manifest as aggressive disease . The prognosis is poor for the 5 to 8
percent of patients who develop metastases; in a retrospective study that included 58
organ transplant recipients with distant or systemic metastases of cutaneous SCC, the
three-year disease-specific survival rate was 29 percent . Thus, once detected, prompt,
appropriate management of early SCC is essential.
Patient evaluationAll lesions that are suspicious for SCC should be pathologically
examined to confirm the diagnosis and to evaluate for features associated with
aggressive disease. Biopsies of papular or nodular lesions should extend at least into the
deep reticular dermis.

Renal function and nonrenal solid organ trans

plantation
INTRODUCTION

As outcomes following nonrenal solid organ transplantation have improved, chronic kidney
disease (CKD) has become an increasingly prevalent complication in this population . CKD
occurs despite advancements in immunosuppression and perioperative management, as well
as attention to cardiovascular risk factors and infectious complications .
The development of CKD is associated with enhanced morbidity and mortality .

PREOPERATIVE EVALUATION OF KIDNEY FUNCTION

As a general rule, the preoperative evaluation of kidney function in nonrenal solid organ
transplantation candidates should focus upon establishing the likelihood of being left with
adequate kidney function posttransplant and the chance of progression to end-stage renal
disease (ESRD). Patients who are likely to have stage 4 or stage 5 chronic kidney disease
(CKD) after the early posttransplant periodand/orthose with established primary renal disease
that is likely to progress at a rapid pace (thereby requiring chronic kidney replacement therapy
shortly after transplant) should be listed for combined organ transplant. It should be noted
that, in an era of ever-increasing organ shortage, in which waiting times for kidneys are
lengthening, combined nonrenal and renal organ transplantation should be considered very
judiciously.
The vast majority of patients with normal or mild impairment in kidney function should receive
a nonrenal solid organ transplant alone. However, normal or near-normal serum creatinine
levels do not necessarily reflect normal kidney function, especially in states of heart failure or
liver disease, where affected patients frequently have poor nutritional status, low muscle
mass, weight loss, and edema.

Treatment and prevention of post-transplant lympho

proliferative disorders
(PTLD)
INTRODUCTION

Post-transplant lymphoproliferative disorders (PTLD) are lymphoidand/orplasmacytic

proliferations that occur in the setting of solid organ or allogeneic hematopoietic cell
transplantation as a result of immunosuppression. They are among the most serious
and potentially fatal complications of transplantation. While the majority appears to be
related to the presence of Epstein-Barr virus (EBV), EBV-negative disease does occur.

Three general types of PTLD have been described in transplant recipients:

Early lesion(plasmacytic hyperplasia and infectious mononucleosis-like PTLD) This

presents as an infectious mononucleosis-type acute illness characterized by polyclonal
B cell proliferation with no evidence to suggest malignant transformation.

Polymorphic PTLD Polymorphic PTLD are polyclonal or monoclonal lymphoid

infiltrates that demonstrate evidence of malignant transformation but do not meet all
of the criteria for one of the B cell orT/NKcell lymphomas recognized in
immunocompetent patients.

Monomorphic PTLD Monomorphic PTLD are monoclonal lymphoid proliferations

that meet the criteria for one of the B cell orT/NKcell lymphomas recognized in
immunocompetent patients.

These conditions lie along a continuum of disease and are categorized by the 2008
WHO classification system as PTLD . Of importance, small B cell lymphoid
neoplasms (eg, follicular lymphomas, small lymphocytic lymphoma) and
marginal zone (MALT) lymphomas arising in the post-transplant setting
arenotconsidered PTLD.

Long-term management of adult liver transplan

t recipients
INTRODUCTION
Liver transplantation is the treatment of choice for appropriately
selected patients with end-stage liver disease. With improved long-term
survival, more patients are being cared for outside of a transplant
center, requiring more widespread familiarity with the complications
seen in this patient population. Several medical problems are routinely
encountered by clinicians caring for patients after liver transplantation.
These include:
Acute or chronic rejection
Complications of immunosuppression including hypertension, renal
insufficiency, infection, malignancy, a variety of dermatologic
conditions, and metabolic diseases such as diabetes mellitus, obesity,
hyperlipidemia, and bone disease
Biliary complications
Recurrence of the primary liver disease

Clinical manifestations, diagnosis, and treatm

ent of cytomegalovirus infection in lung trans
INTRODUCTION
plant
recipients

Cytomegalovirus (CMV), a member of the betaherpesvirus group, remains an important cause of

morbidity and mortality in lung transplant recipients. It is the second most common infection among lung
transplant recipients, after bacterial pneumonia.

While the development and availability of potent antiviral agents has decreased CMV-related mortality,
there is a growing body of evidence that the indirect effects of CMV may be equally important or even
more important than its direct effects of tissue injury and infection . CMV-induced immunosuppression
may lead to infection with other opportunistic organisms. In addition, CMV infection and disease have
been associated with acute and chronic rejection (bronchiolitis obliterans syndrome) in some, but not all
studies.

The approach to the diagnosis and treatment of CMV infections in lung transplant recipients continues to
evolve as transplant specialists gain experience using molecular diagnostic techniques and the potent
oral antiviral agent, valganciclovir. The epidemiology, clinical features, diagnosis, and treatment of CMV
infection in lung transplant recipients will be discussed here. Prevention of CMV infection in lung
transplant recipients, as well as infectious complications due to pathogens other than CMV, are discussed
elsewhere.
EPIDEMIOLOGY

Primary cytomegalovirus (CMV) infection is acquired through close physical contact involving direct
inoculation with infected cells or body fluids. Following primary infection, CMV infection persists for life.
Population studies document a gradual increase in CMV seropositivity through young adulthood.
Although there is considerable variability, more than one-half of adults in the United States have
serologic evidence of previous infection.

CMV infection following transplantation can be acquired in one of several ways

Prevention of cytomegalovirus infection in lun

g transplant recipients
INTRODUCTION

Cytomegalovirus (CMV), a member of the betaherpesvirus group, remains an important

cause of infection, resulting in substantial morbidity and increased mortality in lung
transplant recipients. It is the second most common infection among lung transplant
recipients after bacterial pneumonia.

While the development and availability of potent antiviral agents has decreased CMVrelated mortality, there is a growing body of evidence that the indirect effects of CMV
may be equally important or even more important than its direct effects of tissue injury
and infection . CMV-induced immunosuppression may lead to infection with other
opportunistic organisms. In addition, CMV infection and disease have been associated
with acute and chronic rejection (bronchiolitis obliterans syndrome) in some but not all
studies.

The approach to prevention of CMV infections in lung transplant recipients continues to

evolve as transplant specialists gain experience using molecular diagnostic techniques
and the potent oral antiviral agent valganciclovir. The prevention of CMV infection in
lung transplant recipients will be discussed here. The clinical manifestations, diagnosis,
and treatment of CMV infection in lung transplant recipients and infectious
complications due to agents other than CMV are discussed elsewhere.
EPIDEMIOLOGY

Primary CMV infection is acquired through close physical contact involving direct
inoculation with infected cells or body fluids. Following primary infection, CMV infection
persists for life. Population studies document a gradual increase in CMV seropositivity
through young adulthood. Although there is considerable variability, more than one-half
of adults in the United States have serologic evidence of previous infection.

CMV infection following transplantation can be acquired in one of several ways

Development of malignancy following solid organ t

ransplantation
INTRODUCTION AND OVERVIEW

The chronic use of immunosuppressive agents to prevent allograft rejection increases

the long-term risk of malignancy, compared with that of the general population. This
topic will review the general issue of malignancy following solid organ transplantation.
The problems of second malignancies following bone marrow transplantation and the
development of lymphoproliferative disorders following solid organ transplantation are
discussed separately.
GENERAL EPIDEMIOLOGY

There is an increased risk of a wide range of cancers associated with solid organ
transplantation. The most extensive data come from a cohort study that analyzed the
frequency of malignancy in over 175,000 solid organ transplant recipients during the
period 1987 to 2008 . The most common organs transplanted included kidney, liver,
heart, and lung (in 58, 22, 10, and 4 percent of cases, respectively).

Overall, malignancy was identified in over 10,656 cases, which correlated with a
standardized incidence ratio (SIR) of 2.10 (95% CI 2.06-2.14), compared with the general
population, and an excess absolute risk (EAR) of 719 cases per 100,000 person-years.

A significantly increased risk of malignancy was associated with more than 30 different
primary sites. The tumor sites with a fivefold or greater increase, compared with the
general population, included the following:

Kaposi sarcoma (KS; SIR 61 and EAR 15)

Infection in the solid organ transplant recipien

t

INTRODUCTION

Solid organ transplantation has increased worldwide since the first successful human kidney
transplant was performed in 1954. As immunosuppressive agents and graft survival have
improved, infection and malignancy have become the main barriers to disease-free survival
after organ transplantation. As a result of the growing population of immunosuppressed patients
with prolonged survival, an increased incidence and spectrum of opportunistic infections is
observed . Guidelines for the diagnosis and treatment of infection in transplant recipients have
been developed .

The risks of infection and an overview of specific infections in the solid organ transplant
recipient will be reviewed here. The pretransplant evaluation for solid organ and hematopoietic
cell transplant (HCT) recipients, prophylaxis of infections in solid organ transplant and HCT
recipients, and an overview of infections following HCT are discussed separately.
GENERAL PRINCIPLES

When infection occurs, early and specific diagnosis and rapid and aggressive
treatment are essential to good clinical outcomes.

Potential etiologies of infection in these patients are diverse, including common, communityacquired bacterial and viral diseases and uncommon opportunistic infections of clinical
significance only in immunocompromised hosts . Pulmonary processes can progress rapidly and
may constitute medical emergencies . These include infections due toPneumocystis
jirovecii(formerlyP. carinii),Nocardia asteroides,Aspergillusspp,Cryptococcus
neoformans, cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza,
respiratory syncytial virus (RSV),Rhodococcus equi, andLegionellaspp.

Inflammatory responses associated with microbial invasion are impaired by

immunosuppressive therapy, which results in diminished symptoms and muted clinical and
radiologic findings. As a result, infections are often advanced (disseminated) at the time of
clinical presentation.

Osteoporosis after solid organ or stem cell tr

ansplantation
INTRODUCTION

Transplantation has become an established therapy for end-stage kidney, heart, lung,
and liver diseases, as well as for several hematologic disorders. Improved survival of
transplant recipients has raised awareness of post-transplant complications, such as
osteoporosis. Post-transplant osteoporosis and fracture occur in a substantial
proportion of patients.

The pathogenesis, clinical manifestations, and management of bone loss after solid
organ (with the exception of renal transplant) or stem cell transplantation will be
reviewed here. Management of bone loss after renal transplantation is discussed
elsewhere.
PATHOGENESIS

Transplant-related osteoporosis and fracture are due to both pretransplant and posttransplant factors
Pretransplant bone statusMany patients undergoing transplantation already have
low bone mineral density (BMD).
The mechanism appears to vary with the underlying disease:

In patients with severe heart failure (New York Heart Association [NYHA] classes III
and IV) who are candidates for cardiac transplantation, chronic kidney disease,
vitamin D deficiency, secondary hyperparathyroidism, hypogonadism,
chronic use of heparinand/orloop diuretics, and reduced physical activity
may contribute to low BMD.

Systemic treatment of advanced cutaneous squam

ous and basal cell carcinomas
INTRODUCTION
Basal cell carcinoma and squamous cell carcinoma of the skin, together referred to
as nonmelanoma skin cancer (NMSC), are the most commonly diagnosed malignant
neoplasms in the Caucasian population of the United States. Because many
patients are treated as outpatients in an office setting, reliable statistics are difficult
to obtain. Nonetheless, the National Cancer Institute estimates that approximately
two million new cases occurred in 2012 .
The vast majority of patients can be successfully managed with a variety of simple
procedures, such as cryotherapy, curettage and electrodesiccation, topical
treatments (5-fluorouracil, imiquimod), or simple surgical excision. When lesions are
more advanced, Mohs micrographic surgery, more extensive surgical resection, or
radiation therapy generally are generally sufficient to control locoregional disease.
Despite their high prevalence, these nonmelanoma skin cancers are rarely fatal. It
is estimated that in 2012, approximately 1000 patients died of the disease.
Squamous cell carcinomas are biologically more aggressive, and neglected lesions
can be life threatening due to local extension or metastasis. In contrast, basal cell
carcinoma is only very rarely life threatening.
The use of systemic therapy is limited to patients with distant metastases or locally
advanced disease that cannot be adequately managed with surgical or
radiotherapeutic techniques.
Systemic chemotherapy for basal cell and squamous cancers of the skin could be a
solution. The treatment of localized basal cell and squamous cell carcinomas is an
issue to be discussed.

Overview of care of the adult kidney transplan

t recipient
INTRODUCTION
Kidney transplantation is the treatment of choice for end-stage renal disease . A
successful kidney transplant improves the quality of life and reduces the mortality
risk for most patients when compared with maintenance dialysis. However,
patients require close follow-up after transplantation since they are on complex
immunosuppressive regimens that render them susceptible to infection,
malignancy, and cardiovascular disease (CVD). In addition, patients often have
multiple comorbidities due to, or as a cause of, their underlying end-stage renal
disease.

Whereas patients are generally followed by a transplant specialist for the first
three to six months following transplant, thereafter they may be seen primarily by
a general nephrologist or internist, who is often able to address existing
comorbidities. Whether a patient is followed by a transplant nephrologist, general
nephrologist, or internist often depends upon the availability of services in
proximity to the patient. While many believe that transplant nephrologists should
be directly involved in care of transplant recipients for the life of the graft, this is
often not practical. Communication between the internist or community-based
nephrologist and the transplant center is important for optimal care of the patient,
however.

This topic reviews the general medical care of the kidney transplant recipient
including recommendations for monitoring allograft function and minimizing the
risk of infections, malignancies, bone disease, CVD, and diabetes. These are
common medical problems encountered after transplantation are also discussed.

Solid organ transplantation in HIV-infected ind

ividuals
INTRODUCTION

Liver, kidney, and heart transplantation are the current treatments of choice for
advanced organ failure. However, human immunodeficiency virus (HIV) infection was
traditionally considered anabsolutecontraindication for transplantation . One of the
principal concerns was that immunosuppression would accelerateHIV/acquiredimmune
deficiency syndrome (AIDS), resulting in increased mortality and a "waste" of organs.

Since highly active antiretroviral therapy (HAART) became widely available in 1996, the
prognosis of HIV infection has dramatically improved. There have been significant
decreases in morbidity and mortality, and, for many individuals with well-controlled viral
replication,HIV/AIDSis now a chronic, manageable disease.

Previously, HIV-infected individuals with very advanced disease frequently died from
opportunistic infections (OIs). Among such individuals, the presence of chronic diseases,
such as renal insufficiency, coronary artery disease, diabetes mellitus, or liver failure
(associated with hepatitis B [HBV] or C virus [HCV] coinfection), were not significant
causes of mortality. The situation is currently quite different as these comorbidities, as
well as others, are real medical problems for many individuals with well-controlled HIV
replication.

Such improvements in the long-term prognosis of those with HIV infection have
prompted many transplant programs to reevaluate their policies regarding the exclusion
of patients with HIV infection. A review of the issues surrounding solid organ
transplantation in HIV-infected patients is presented here.
OUTCOMES BEFORE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)

Prior to the availability of a reliable diagnostic test for HIV infection, some individuals
unknowingly infected with HIV underwent solid organ transplantation . Others acquired
HIV infection by receiving an organ from a HIV-positive individual.

Management of the hematopoietic cell transpla

nt recipient in the immediate posttransplant
INTRODUCTION
period

Among patients undergoing hematopoietic cell transplantation (HCT), advances in

hematopoietic support; improvements in antibiotics, antifungal agents, and antiviral drugs;
and better medications to control side effects of treatment such as nausea, vomiting, diarrhea
and pain have all had a major impact on the clinical course.

In terms of decreased morbidity and mortality after autologous transplantation, probably the
single most important advance has been the introduction of mobilized peripheral blood
progenitor cells (PBPCs) as the source of hematopoietic stem cells. This approach results in
more rapid recovery, which has significantly reduced the duration of antibiotic therapy, the
degree of mucositis, the length of hospitalization, and the risk of the transplant procedure
itself. These positive developments have resulted in a marked decline in the discomfort that
patients experience in the transplant setting.

The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a
general term to cover transplantation of progenitor cells from any source (eg, bone marrow,
peripheral blood, umbilical cord blood). Otherwise, the source of such cells will be specified
(eg, autologous PBPC transplantation).

General supportive care measures for patients following HCT and long term complications of
HCT will be reviewed here . Hematopoietic support after HCT and the prevention and
treatment of acute and chronic graft versus host disease are discussed separately.

The diagnosis and treatment of pulmonary, renal, and infectious complications following HCT
are also presented separately.

Treatment and prognosis of cutaneous squamous ce

ll carcinoma
INTRODUCTION

Cutaneous squamous cell carcinoma (SCC) is a common cancer arising from malignant
proliferation of the keratinocytes of the epidermis. Treatment of cutaneous SCC is indicated
since progression of the tumor may lead to local tissue destruction or metastasis resulting in
significant morbidity or death. Early treatment provides the best opportunity to cure cutaneous
SCC.

In contrast to basal cell carcinoma (BCC), which rarely metastasizes, around 2 to 5 percent of
cutaneous SCCs metastasize to regional lymph nodes or more distant sites. The approach to
treatment is dependent upon the presence or absence of tumor features and patient
characteristics that portend an increased risk for aggressive tumor behavior. Cutaneous SCCs
that do not have high-risk features have low frequencies of recurrence and metastasis.

The treatment of cutaneous SCCswithoutfeatures associated with aggressive behavior (lowrisk cutaneous SCC) and the prognosis of cutaneous SCC will be reviewed here. The
management of high-risk and metastatic cutaneous SCCs, the treatment of keratoacanthomas,
and the risk factors, clinical features, and diagnosis of cutaneous SCC are reviewed separately.
APPROACH TO TREATMENT

The risk of locoregional recurrence and regional or distant metastasis is the most important
factor for determining the approach to the treatment for cutaneous squamous cell carcinoma
(SCC). Examples of characteristics that impact the risk for recurrence and metastasis include
the site, size, and histologic features of a tumor, as well as patient comorbidities . "High-risk"
SCCs are tumors that exhibit characteristics that are associated with an elevated risk for
aggressive tumor behavior.

A consensus on the specific characteristics that define high-risk SCC has not been established
and major entities such as the National Comprehensive Cancer Network (NCCN) and the
American Joint Committee on Cancer (AJCC) have described dissimilar "high-risk" criteria . We
follow the NCCN criteria when categorizing tumors as high-risk or low-risk for determining the
approach to treatment . The features of high-risk cutaneous SCC are reviewed in greater detail
separately.

Organ donation
Transplant coordination

Prof. Ileana
Constantinescu

Types of transplant

Autograft
Allograft and allotransplantation
Xenograft and xenotransplantation
Split transplants
Domino transplants
ABO-incompatible transplants
Transplantation in obese individuals

Autograft

Autografts are the transplant of tissue to the same person. Sometimes this is done with
surplus tissue, tissue that can regenerate, or tissues more desperately needed elsewhere
(examples include skin grafts,vein extractionforCABG, etc.). Sometimes an autograft is done to
remove the tissue and then treat it or the person before returning it (examples include
stem cell autograft and storing blood in advance of surgery). In arotationplasty, adistal joint
is used to replace a more proximal one; typically a foot or ankle joint is used to replace a knee
joint. The person's foot is severed and reversed, the knee removed, and thetibiajoined with the
femur.
Allograft and allotransplantation

An allograft is a transplant of an organ or tissue between two genetically non-identical

members of the samespecies. Most human tissue and organ transplants are allografts. Due
to the genetic difference between the organ and the recipient, the recipient'simmune system
will identify the organ as foreign and attempt to destroy it, causing transplant rejection. The risk
of transplant rejection can be estimated by measuring thePanel reactive antibody (PRA)level.
Isograft

A subset of allografts in which organs or tissues are transplanted from a donor to a

genetically identical recipient (such as an identical twin). Isografts are differentiated from
other types of transplants because while they are anatomically identical to allografts, they
do not trigger animmune response .
Xenograft and xenotransplantation

A transplant of organs or tissue from one species to another. An example is porcine heart
valve transplant, which is quite common and successful. Another example is attemptedpiscineprimate(fishto non-human primate) transplant of islet (i.e. pancreatic or insular tissue) tissue. The
latter research study was intended to pave the way for potential human use if successful.
However, xenotransplantion is often an extremely dangerous type of transplant because of the
increased risk of non-compatibility, rejection, and disease carried in the tissue.

Split transplants

Sometimes a deceased-donor organ, usually a liver, may be divided between two recipients,
especially an adult and a child. This is not usually a preferred option because the transplantation of a
whole organ is more successful.

Domino transplants
In people withcystic fibrosis, where both lungs need to be replaced, it is a technically easier
operation with a higher rate of success to replace both the heart and lungs of the recipient with
those of the donor. As the recipient's original heart is usually healthy, it can then be transplanted
into a second recipient in need of a heart transplant.Another example of this situation occurs with a
special form of liver transplant in which the recipient suffers from
familial amyloidotic polyneuropathy , a disease where the liver slowly produces aproteinthat
damages other organs. The recipient's liver can then be transplanted into an older person for whom
the effects of the disease will not necessarily contribute significantly to mortality.

This term also refers to a series of living donor transplants in which one donor donates to the highest
recipient on the waiting list and the transplant center utilizes that donation to facilitate multiple
transplants. These other transplants are otherwise impossible due toblood typeor antibody barriers
to transplantation. The "Good Samaritan " kidney is transplanted into one of the other recipients,
whose donor in turn donates his or her kidney to an unrelated recipient. Depending on the person on
the waiting list, this has sometimes been repeated for up to six pairs, with the final donor donating
to the person at the top of the list. This method allows all organ recipients to get a transplant even if
their living donor is not a match to them. This further benefits people below any of these recipients
on waiting lists, as they move closer to the top of the list for a deceased-donor organ.
Johns Hopkins Medical Center in Baltimore andNorthwestern University 's
Northwestern Memorial Hospital have received significant attention for pioneering transplants of this
kind.
In February 2012, the last link in a record 60-person domino chain of 30 kidney transplants was
completed.

ABO-incompatible transplants

Because very young children (generally under 12 months, but often as old as 24 months) do
not have a well-developed immune system, it is possible for them to receive organs from
otherwise incompatible donors. This is known as ABO-incompatible (ABOi) transplantation.
Graft survival and peoples mortality is approximately the same between ABOi and ABOcompatible (ABOc) recipients. While focus has been on infant heart transplants, the principles
generally apply to other forms of solid organ transplantation.

The most important factors are that the recipient not have producedisohemagglutinins , and
that they have low levels of Tcell-independentantigens. United Network for Organ Sharing (UNOS)
regulations allow for ABOi transplantation in children under two years of age if
isohemagglutinin titers are 1:4 or below, and if there is no matching ABOc recipient. Studies
have shown that the period under which a recipient may undergo ABOi transplantation may
be prolonged by exposure to nonself A and B antigens. Furthermore, should the recipient (for
example, type B-positive with a type AB-positive graft) require eventual retransplantation, the
recipient may receive a new organ of either blood type.

Limited success has been achieved in ABO-incompatible heart transplants in adults, though
this requires that the adult recipients have low levels of anti-A or anti-B antibodies.Kidney
transplantation is more successful, with similar long-term graft survival rates to ABOc
transplants.

Transplantation in obese individuals

Until recently, people labeled asobesewere not considered appropriate candidates for renal
transplantation. In 2009, the physicians at theUniversity of Illinois Medical Center performed
the first robotic kidney transplantation in an obese recipient and have continued to transplant
people withBody Mass Index(BMI)s over 35 usingrobotic surgery. As of January 2014, over
100 people that would otherwise be turned down because of their weight have successfully
been transplanted.

Organs and tissues transpl

anted
Chest
Abdomen
Tissues, cells and fluids

Chest

Heart(deceased-donor only)
Lung(deceased-donor and living-related lung transplantation)
Heart/Lung(deceased-donor and domino transplant)

Abdomen

Kidney(deceased-donor and living-donor)

Liver(deceased-donor and living-donor)
Pancreas(deceased-donor only)
Intestine(deceased-donor and living-donor)
Stomach(deceased-donor only)
Testis

Tissues, cells and fluids

Hand(deceased-donor only), see the first recipientClint Hallam

Cornea(deceased-donor only) see theophthalmologistEduard Zirm
Skin, includingface replant(autograft) andface transplant(extremely rare)
Islets of Langerhans(pancreas islet cells) (deceased-donor and living-donor)
Bone marrow/Adultstem cell(living-donor and autograft)
Blood transfusion/Blood Parts Transfusion (living-donor and autograft)
Blood Vessels(autograft and deceased-donor)
Heart Valve(deceased-donor, living-donor and xenograft [porcine/bovine])
Bone(deceased-donor and living-donor)

Types of donor
Living donor
Deceased donor

Organ donors may be living or may have died of brain death or circulatory death. Most
deceased donors are those who have been pronounced brain dead. Brain dead means
the cessation of brain function, typically after receiving an injury (either traumatic or
pathological) to the brain, or otherwise cutting off blood circulation to the brain (
drowning,suffocation, etc.). Breathing is maintained viaartificial sources, which, in turn,
maintains heartbeat. Once brain death has been declared the person can be considered
for organ donation. Criteria for brain death vary. Because less than 3% of all deaths in
the U.S. are the result of brain death, the overwhelming majority of deaths are ineligible
for organ donation, resulting in severe shortages.

Organ donation is possible after cardiac death in some situations, primarily when the
person is severely brain injured and not expected to survive without artificial breathing
and mechanical support. Independent of any decision to donate, a person's next-of-kin
may decide to end artificial support. If the person is expected to expire within a short
period of time after support is withdrawn, arrangements can be made to withdraw that
support in an operating room to allow quick recovery of the organs after circulatory death
has occurred.

Tissue may be recovered from donors who die of either brain or circulatory death. In
general, tissues may be recovered from donors up to 24 hours past the cessation of
heartbeat. In contrast to organs, most tissues (with the exception of corneas) can be
preserved and stored for up to five years, meaning they can be "banked." Also, more
than 60 grafts may be obtained from a single tissue donor. Because of these three factors
the ability to recover from a non-heart beating donor, the ability to bank tissue, and
the number of grafts available from each donortissue transplants are much more
common than organ transplants. TheAmerican Association of Tissue Banksestimates
that more than one million tissue transplants take place in the United States each year.

Living donor

In living donors, the donor remains alive and donates a renewable tissue, cell, or fluid
(e.g., blood, skin), or donates an organ or part of an organ in which the remaining
organ can regenerate or take on the workload of the rest of the organ (primarily
single kidney donation, partial donation of liver, lung lobe, small bowel).
Regenerative medicine may one day allow for laboratory-grown organs, using
person's own cells via stem cells, or healthy cells extracted from the failing organs.

Deceased donor

Deceased donors (formerly cadaveric) are people who have been declared brain-dead
and whose organs are kept viable byventilatorsor other mechanical mechanisms
until they can be excised for transplantation. Apart from brain-stem dead donors, who
have formed the majority of deceased donors for the last 20 years, there is increasing
use of donation-after-circulatory-death-donors (formerly non-heart-beating donors) to
increase the potential pool of donors as demand for transplants continues to grow.
Prior to the recognition of brain death in the 1980s, all deceased organ donors had
died of circulatory death. These organs have inferior outcomes to organs from a
brain-dead donor; however, given the scarcity of suitable organs and the number of
people who die waiting, any potentially suitable organ must be considered.

Allocation of organs

In most countries there is a shortage of suitable organs for transplantation. Countries often have formal
systems in place to manage the process of determining who is an organ donor and in what order organ
recipients receive available organs.
The overwhelming majority of deceased-donor organs in the United States are allocated by federal
contract to theOrgan Procurement and Transplantation Network (OPTN), held since it was created by the
Organ Transplant Act of 1984 by theUnited Network for Organ Sharing or UNOS. (UNOS does not handle
donor cornea tissue; corneal donor tissue is usually handled by various eye banks.) Individual regional
organ procurement organizations (OPOs), all members of the OPTN, are responsible for the identification
of suitable donors and collection of the donated organs. UNOS then allocates organs based on the
method considered most fair by the scientific leadership in the field. The allocation methodology varies
somewhat by organ, and changes periodically. For example, liver allocation is based partially on MELD
score (Model of End-Stage Liver Disease), an empirical score based on lab values indicative of the
sickness of the person from liver disease. In 1984, the National Organ Transplant Act (NOTA) was passed
which gave way to the Organ Procurement and Transplantation Network that maintains the organ
registry and ensures equitable allocation of organs. The Scientific Registry of Transplant Recipients was
also established to conduct ongoing studies into the evaluation and clinical status of organ transplants.
In 2000 the Childrens Health Act passed and required NOTA to consider special issues around pediatric
patients and organ allocation (Services).
Experiencing somewhat increased popularity, but still very rare, is directed or targeted donation, in
which the family of a deceased donor (often honoring the wishes of the deceased) requests an organ be
given to a specific person. If medically suitable, the allocation system is subverted, and the organ is
given to that person. In the United States, there are various lengths of waiting times due to the different
availabilities of organs in different UNOS regions. In other countries such as theUK, only medical factors
and the position on the waiting list can affect who receives the organ.
One of the more publicized cases of this type was the 1994 Chester and Patti Szuber transplant. This was
the first time that a parent had received a heart donated by one of their own children. Although the
decision to accept the heart from his recently killed child was not an easy decision, the Szuber family
agreed that giving Patti's heart to her father would have been something that she would have wanted.
Access to organ transplantation is one reason for the growth ofmedical tourism .

Reasons for donation and ethic

al issues

Living related donors

Good Samaritan
Financial compensation
Forced donation

Living related donors

Living related donors donate to family members or friends in whom they have an emotional investment. The risk of surgery is
offset by the psychological benefit of not losing someone related to them, or not seeing them suffer the ill effects of waiting on a
list.

Paired exchange

Diagram of an exchange between otherwise incompatible pairs

A "paired-exchange" is a technique of matching willing living donors to compatible recipients using serotyping. For example a
spouse may be willing to donate a kidney to their partner but cannot since there is not a biological match. The willing spouse's
kidney is donated to a matching recipient who also has an incompatible but willing spouse. The second donor must match the
first recipient to complete the pair exchange. Typically the surgeries are scheduled simultaneously in case one of the donors
decides to back out and the couples are kept anonymous from each other until after the transplant.
Paired exchange programs were popularized in theNew England Journal of Medicine article "Ethics of a paired-kidney-exchange
program" in 1997 by L.F. Ross.It was also proposed by Felix T. Rapport in 1986 as part of his initial proposals for live-donor
transplants "The case for a living emotionally related international kidney donor exchange registry" in Transplant Proceedings. A
paired exchange is the simplest case of a much larger exchange registry program where willing donors are matched with any
number of compatible recipients. Transplant exchange programs have been suggested as early as 1970: "A cooperative kidney
typing and exchange program.
The first pair exchange transplant in the U.S. was in 2001 atJohns Hopkins Hospital . The first complex multihospital kidney
exchange involving 12 person was performed in February 2009 by The Johns Hopkins Hospital, Barnes-Jewish Hospital inSt. Louis
and Integris Baptist Medical Center inOklahoma City. Another 12-person multihospital kidney exchange was performed four
weeks later bySaint Barnabas Medical Center inLivingston, New Jersey ,Newark Beth Israel Medical Center and
New York-Presbyterian Hospital . Surgical teams led by Johns Hopkins continue to pioneer in this field by having more complex
chain of exchange such as eight-way multihospital kidney exchange. In December 2009, a 13 organ 13 recipient matched kidney
exchange took place, coordinated through Georgetown University Hospital and Washington Hospital Center, Washington DC.
Paired-donor exchange, led by work in theNew England Program for Kidney Exchange as well as at Johns Hopkins University and
the Ohio OPOs may more efficiently allocate organs and lead to more transplants.

Good Samaritan

Good Samaritan or "altruistic" donation is giving a donation to someone not well-known to the donor. Some people
choose to do this out of a need to donate. Some donate to the next person on the list; others use some method of
choosing a recipient based on criteria important to them. Web sites are being developed that facilitate such donation. It
has been featured in recent television journalism that over half of the members of theJesus Christians, anAustralian
religious group, have donated kidneys in such a fashion.
Forced donation

There have been concerns that certain authorities are harvesting organs from people deem undesirable, such as prison
populations. The World Medical Association stated that prisoners and other individuals in custody are not in a position to
give consent freely, and therefore their organs must not be used for transplantation.

According to the Chinese Deputy Minister of Health, Huang Jiefu, approximately 95% of all organs used for transplantation
are from executed prisoners. The lack of public organ donation program in China is used as a justification for this practice.

In July 2006, theKilgour-Matas report stated, "the source of 41,500 transplants for the six year period 2000 to 2005 is
unexplained" and "we believe that there has been and continues today to be large scale organ seizures from unwilling
Falun Gongpractitioners". Investigative journalistEthan Gutmannestimates 65,000 Falun Gong practitioners were killed
for their organs from 2000 to 2008.

In December 2006, after not getting assurances from the Chinese government about allegations relating to Chinese
prisoners, the two major organ transplant hospitals in Queensland, Australia stopped transplant training for Chinese
surgeons and banned joint research programs into organ transplantation with China.

In May 2008, two United Nations Special Rapporteurs reiterated their requests for "the Chinese government to fully
explain the allegation of taking vital organs from Falun Gong practitioners and the source of organs for the sudden
increase in organ transplants that has been going on in China since the year 2000".

People in other parts of the world are responding to this availability of organs, and a number of individuals (including U.S.
and Japanese citizens) have elected to travel to China or India asmedical tourists to receive organ transplants which may
have been sourced in what might be considered elsewhere to be unethical manner.

Usage

According to theCouncil of Europe,Spainthrough theSpanish Transplant Organization shows

the highest worldwide rate of 35.1 donors per million population in 2005 and 33.8 in 2006. In
2011, it was 35.3.

In addition to the citizens waiting for organ transplants in the U.S. and other developed
nations, there are long waiting lists in the rest of the world. More than 2 million people need
organ transplants in China, 50,000 waiting in Latin America (90% of which are waiting for
kidneys), as well as thousands more in the less documented continent ofAfrica. Donor bases
vary in developing nations.

Traditionally, Muslims believe body desecration in life or death to be forbidden, and thus many
reject organ transplant. However most Muslim authorities nowadays accept the practice if
another life will be saved.

In Latin America the donor rate is 40100 per million per year, similar to that of developed
countries. However, in Uruguay, Cuba, and Chile, 90% of organ transplants came from
cadaveric donors. Cadaveric donors represent 35% of donors in Saudi Arabia. There is
continuous effort to increase the utilization of cadaveric donors in Asia, however the popularity
of living, single kidney donors in India yields India a cadaveric donor prevalence of less than 1
pmp.

Organ transplantation in Chinahas taken place since the 1960s, and China has one of
the largest transplant programmes in the world, peaking at over 13,000 transplants a
year by 2004. Organ donation, however, is against Chinese tradition and culture, and
involuntary organ donation is illegal under Chinese law. China's transplant programme
attracted the attention of internationalnews mediain the 1990s due to ethical
concerns about theorgansandtissueremoved from the corpses of executed criminals
being commercially traded fortransplants.

In 2006 it became clear that about 41,500 organs had been sourced from Falun Gong
practitioners in China since 2000. With regard toorgan transplantation in Israel, there
is a severe organ shortage due to religious objections by some rabbis who oppose all
organ donations and others who advocate that a rabbi participate in all decision
making regarding a particular donor. One third of all heart transplants performed on
Israelis are done in the Peoples' Republic of China; others are done in Europe. Dr. Jacob
Lavee, head of the heart-transplant unit, Sheba Medical Center, Tel Aviv, believes that
"transplant tourism" is unethical and Israeli insurers should not pay for it. The
organization HODS (Halachic Organ Donor Society) is working to increase knowledge
and participation in organ donation among Jews throughout the world.

Transplantation rates also differ based on race, sex, and income. A study done with
people beginning long term dialysis showed that the sociodemographic barriers to
renal transplantation present themselves even before patients are on the transplant
list. For example, different groups express definite interest and complete pretransplant
workup at different rates. Previous efforts to create fair transplantation policies had
focused on people currently on the transplantation waiting list.

Transplantation of organs in different regions

Kidney(pm Liver(pm Heart(pm

p*)
p*)
p*)
USA

52

19

Europa

27

10

Africa

11

3.5

0.3

0.03

13

1.6

0.5

Asia
Latin America
*All numbers per million
population

Some estimates of the number of transplants performed in various regions of the world
have been derived from the Global Burden of Disease Study

History

Successful humanallotransplantshave a relatively long history of operative skills that

were present long before the necessities for post-operative survival were discovered.
Rejectionand the side effects of preventing rejection (especially infection and
nephropathy) were, are, and may always be the key problem.
Several apocryphal accounts of transplants exist well prior to the scientific
understanding and advancements that would be necessary for them to have actually
occurred. TheChinesephysicianPien Chi'aoreportedly exchangedheartsbetween a
man of strong spirit but weak will with one of a man of weak spirit but strong will in an
attempt to achieve balance in each man.Roman Catholicaccounts report the 3rdcentury saintsDamianandCosmasas replacing thegangrenousorcancerousleg of the
Roman deaconJustinianwith the leg of a recently deceasedEthiopian.[87][88]Most
accounts have the saints performing the transplant in the 4th century, many decades
after their deaths; some accounts have them only instructing living surgeons who
performed the procedure.
The more likely accounts of early transplants deal with skin transplantation. The first
reasonable account is of theIndiansurgeonSushrutain the 2nd century BC, who used
autografted skin transplantation in nose reconstruction, arhinoplasty. Success or failure
of these procedures is not well documented. Centuries later, theItaliansurgeon
Gasparo Tagliacozziperformed successful skin autografts; he also failed consistently
withallografts, offering the first suggestion of rejection centuries before that mechanism
could possibly be understood. He attributed it to the "force and power of individuality" in
his 1596 workDe Curtorum Chirurgia per Insitionem.
Alexis Carrel: 1912's Nobel Prize for his work on organ transplantation.

The first successful corneal allograft transplant was performed in 1837 in agazellemodel; the first
successful human corneal transplant, akeratoplastic operation, was performed byEduard Zirm at
Olomouc Eye Clinic , nowCzech Republic , in 1905. The first transplant in the modern sense the
implantation of organ tissue in order to replace an organ function was athyroidtransplant in 1883. It
was performed by theSwisssurgeon and laterNobel laureate Theodor Kocher . In the preceding
decades Kocher had perfected the removal of excess thyroid tissue in cases ofgoiterto an extent that
he was able to remove the whole organ without the person dying from the operation. Kocher carried
out the total removal of the organ in some cases as a measure to prevent recurrent goiter. By 1883,
the surgeon noticed that the complete removal of the organ leads to a complex of particular symptoms
that we today have learned to associate with a lack of thyroid hormone. Kocher reversed these
symptoms by implanting thyroid tissue to these perople and thus performed the first organ transplant.
In the following years Kocher and other surgeons used thyroid transplantation also to treat thyroid
deficiency that appeared spontaneously, without a preceding organ removal. Thyroid transplantation
became the model for a whole new therapeutic strategy: organ transplantation. After the example of
the thyroid, other organs were transplanted in the decades around 1900. Some of these transplants
were done in animals for purposes of research, where organ removal and transplantation became a
successful strategy of investigating the function of organs. Kocher was awarded hisNobel Prize in 1909
for the discovery of the function of the thyroid gland. At the same time, organs were also transplanted
for treating diseases in humans. The thyroid gland became the model for transplants ofadrenal and
parathyroid glands , pancreas,ovary,testiclesand kidney. By 1900, the idea that one can successfully
treat internal diseases by replacing a failed organ through transplantation had been generally
accepted. Pioneering work in the surgical technique of transplantation was made in the early 1900s by
theFrenchsurgeonAlexis Carrel , withCharles Guthrie , with the transplantation ofarteriesorveins.
Their skillfulanastomosis operations and the new suturing techniques laid the groundwork for later
transplantsurgeryand won Carrel the 1912Nobel Prize in Physiology or Medicine . From 1902, Carrel
performed transplant experiments ondogs. Surgically successful in movingkidneys,hearts, and
spleens, he was one of the first to identify the problem ofrejection, which remained insurmountable for
decades. The discovery of transplant immunity by theGerman surgeonGeorg Schne , various
strategies of matching donor and recipient, and the use of different agents for immune suppression did
not result in substantial improvement so that organ transplantation was largely abandoned afterWWI.

Major steps inskin transplantation occurred during the First World War, notably in the work of
Harold Gillies atAldershot. Among his advances was the tubed pedicle graft, which maintained a
flesh connection from the donor site until the graft established its ownbloodflow. Gillies'
assistant,Archibald McIndoe , carried on the work intothe Second World War as
reconstructive surgery . In 1962, the first successful replantation surgery was performed reattaching a severed limb and restoring (limited) function and feeling.
Transplant of a singlegonad(testis) from a living donor was carried out in early July 1926 in
Zajear,Serbia, by aRussianemigrsurgeon Dr. Peter Vasil'evi Kolesnikov. The donor was a
convicted murderer, one Ilija Krajan, whose death sentence was commuted to 20 years
imprisonment, and he was led to believe that it was done because he had donated his testis to an
elderly medical doctor. Both the donor and the receiver survived, but charges were brought in a
court of law by the public prosecutor against Dr. Kolesnikov, not for performing the operation, but
for lying to the donor.[90]
The first attempted human deceased-donor transplant was performed by theUkrainiansurgeon
Yuri Voronoy in the 1930s;[91][92] rejection resulted in failure.Joseph Murray andJ. Hartwell Harrison
performed the first successful transplant, a kidney transplant between identicaltwins, in 1954,
because noimmunosuppression was necessary for genetically identical individuals.
In the late 1940sPeter Medawar , working for theNational Institute for Medical Research ,
improved the understanding of rejection. Identifying the immune reactions in 1951, Medawar
suggested thatimmunosuppressive drugs could be used.Cortisonehad been recently discovered
and the more effectiveazathioprine was identified in 1959, but it was not until the discovery of
cyclosporine in 1970 that transplant surgery found a sufficiently powerful immunosuppressive.
Joseph Murray's success with the kidney led to attempts with other organs. There was a
successful deceased-donorlungtransplant into alung cancersufferer in June 1963 by
James Hardy inJackson, Mississippi . The person survived for eighteen days before dying of
kidney failure .Thomas Starzl ofDenverattempted a liver transplant in the same year, but he was
not successful until 1967.

The heart was a major prize for transplant surgeons. But over and above rejection issues, the heart
deteriorates within minutes of death, so any operation would have to be performed at great speed. The
development of theheart-lung machinewas also needed. Lung pioneer James Hardy attempted a human heart
transplant in 1964, but when a premature failure of the recipient's heart caught Hardy with no human donor, he
used achimpanzeeheart, which failed very quickly. The first success was achieved on 3 December 1967, by
Christiaan BarnardinCape Town,South Africa.Louis Washkansky, the recipient, survived for eighteen days amid
what many saw as a distasteful publicity circus. The media interest prompted a spate of heart transplants. Over
a hundred were performed in 19681969, but almost all the people died within 60 days. Barnard's second
patient,Philip Blaiberg, lived for 19 months.
It was the advent ofcyclosporinethat altered transplants from research surgery to life-saving treatment. In
1968 surgical pioneerDenton Cooleyperformed 17 transplants, including the firstheart-lung transplant.
Fourteen of his patients were dead within six months. By 1984 two-thirds of all heart transplant patients
survived for five years or more. With organ transplants becoming commonplace, limited only by donors,
surgeons moved on to riskier fields, including multiple-organ transplants on humans and whole-body transplant
research on animals. On 9 March 1981, the first successful heart-lung transplant took place at
Stanford UniversityHospital. The head surgeon,Bruce Reitz, credited the patient's recovery tocyclosporine-A.
As the rising success rate of transplants and modernimmunosuppressionmake transplants more common, the
need for more organs has become critical. Transplants from living donors, especially relatives, have become
increasingly common. Additionally, there is substantive research intoxenotransplantation, or transgenic
organs; although these forms of transplant are not yet being used in humans, clinical trials involving the use of
specificcelltypes have been conducted with promising results, such as usingporcineislets of Langerhansto
treattype1 diabetes. However, there are still many problems that would need to be solved before they would
be feasible options in people requiring transplants.
Recently, researchers have been looking into means of reducing the general burden of immunosuppression.
Common approaches include avoidance of steroids, reduced exposure tocalcineurininhibitors, and other means
of weaning drugs based on patient outcome and function. While short-term outcomes appear promising, longterm outcomes are still unknown, and in general, reduced immunosuppression increases the risk of rejection
and decreases the risk of infection.
Many other new drugs are under development for transplantation.The emerging field ofregenerative medicine
promises to solve the problem of organ transplant rejection by regrowing organs in the lab, using person's own
cells (stem cells or healthy cells extracted from the donor site).

Timeline of successful transplants

1823: First skin autograft-transplantation of skin tissue from one location on an individual's body to another location (Germany) In 1823 Carl
Bunger, a German surgeon documents the first modern successfulskin graft on a person. Bunger was repairing a person with a nose also
destroyed bysyphilis . He grafted a small chunk of full thickness flesh from the inner thigh to the nose successfully, in a method very
reminiscent ofSushrutha s.
1905: First successful cornea transplant byEduard Zirm (Czech Republic )
1908: First skin allograft-transplantation of skin from a donor to a recipient (Switzerland)
1933: First successful cadaveric AB-0 incompatible kidney transplant (donor was B(III) and the recipient has 0(I)) by Yuriu Yu. Voronoy (USSR)
1950: First successful kidney transplant by Dr. Richard H. Lawler (Chicago, U.S.A.)
1954: First living related kidney transplant (identical twins ) (U.S.A.)
1955: Firstheart valve allograft into descendingaorta(Canada)
1962: First kidney transplant from a deceased donor (U.S.A.)
1965:Australia 's first successful (living) kidney transplant (Queen Elizabeth Hospital ,SA, Australia)
1966: First successful pancreas transplant by Richard Lillehei and William Kelly (Minnesota , U.S.A.)
1967: First successful liver transplant byThomas Starzl (Denver, U.S.A.)
1967: First successful heart transplant byChristian Barnard (Cape Town, South Africa)
1981: First successful heart/lung transplant byBruce Reitz (Stanford, U.S.A.)
1983: First successful lung lobe transplant byJoel Cooperat theToronto General Hospital (Toronto, Canada)
1984: First successful double organ transplant byThomas Starzl and Henry T. Bahnson (Pittsburgh , U.S.A.)
1986: First successful double-lung transplant (Ann Harrison ) byJoel Cooperat theToronto General Hospital (Toronto, Canada)
1995: First successfullaparoscopic live-donor nephrectomy by Lloyd Ratner and Louis Kavoussi (Baltimore , U.S.A.)
1997: First successful allogeneic vascularized transplantation of a fresh and perfused humankneejoint byGunther O. Hofmann
1997: Illinois' first living donor kidney-pancreas transplant and first robotic living donor pancreatectomy in the U.S.A.
University of Illinois Medical Center
1998: First successful live-donor partialpancreas transplant by David Sutherland (Minnesota, U.S.A.)
1998: First successful hand transplant by Dr.Jean-Michel Dubernard (Lyon, France)
1998: United States' first adult-to-adult living donor liver transplantUniversity of Illinois Medical Center
1999: First successful tissue engineeredbladdertransplanted byAnthony Atala (Boston Children's Hospital , U.S.A.)
2000: First robotic donor nephrectomy for a living-donor kidney transplant in the worldUniversity of Illinois Medical Center
2004: First liver and small bowel transplants from same living donor into same recipient in the world University of Illinois Medical Center

2005: First successful ovarian transplant by Dr. P. N. Mhatre (Wadia Hospital,Mumbai,India)

2005: First successful partialface transplant(France)
2005: First robotic hepatectomy in the United StatesUniversity of Illinois Medical Center
2006: Illinois' first paired donation for ABO incompatible kidney transplantUniversity of Illinois Medical Center
2006: Firstjawtransplant to combine donorjawwithbone marrowfrom the patient, byEric M. Genden(
Mount Sinai Hospital,New York City, U.S.A.)
2006: First successful humanpenistransplant (later reversed after 15 days due to 44-year-old recipient's wife's
psychological rejection) (Guangzhou,China)
2008: First successful complete full doublearmtransplant by Edgar Biemer, Christoph Hhnke and Manfred
Stangl (Technical University of Munich, Germany)
2008: First baby born from transplanted ovary. The transplant was carried out by Dr Sherman Silber at the
Infertility Centre of St Louis in Missouri. The donor is her twin sister.
2008: First transplant of ahuman windpipeusing a patient's own stem cells, byPaolo Macchiarini(Barcelona,
Spain)
2008: First successful transplantation of near total area (80%) offace, (includingpalate,nose,cheeks, andeyelid)
byMaria Siemionow(Cleveland Clinic, U.S.A.)
2009: Worlds' first robotic kidney transplant in an obese patientUniversity of Illinois Medical Center
2010: First full facial transplant by Dr. Joan Pere Barret and team (Hospital Universitari Vall d'Hebron on 26 July
2010, inBarcelona,Spain)
2011: First double leg transplant by Dr. Cavadas and team (Valencia's Hospital, La Fe, Spain)
2012: First Robotic Alloparathyroid transplant. University of Illinois Chicago
2013: First successful entire face transplantation as an urgent life-saving surgery at
Maria Skodowska-Curie Institute of Oncologybranch inGliwice,Poland.
2014: First successful uterine transplant resulting in live birth (Sweden)
2014: First successful penis transplant. (South Africa)
2014: First neonatal organ transplant. (U.K.)

Society and culture

Comparative costs
Safety
Transplant laws
Ethical concerns
Artificial organ transplantation

Comparative costs

One of the driving forces for illegal organ trafficking and for "transplantation tourism" is the price
differences for organs and transplant surgeries in different areas of the world. According to the New
England Journal of Medicine, a human kidney can be purchased in Manila for $1000$2000, but in urban
Latin America a kidney may cost more than $10,000. Kidneys in South Africa have sold for as high as
$20,000. Price disparities based on donor race are a driving force of attractive organ sales in South Africa,
as well as in other parts of the world.
In China, a kidney transplant operation runs for around $70,000, liver for $160,000, and heart for
$120,000. Although these prices are still unattainable to the poor, compared to the fees of the United
States, where a kidney transplant may demand $100,000, a liver $250,000, and a heart $860,000,
Chinese prices have made China a major provider of organs and transplantation surgeries to other
countries.
In India, a kidney transplant operation runs for around as low as $5000.

Safety

In the United States of America, tissue transplants are regulated by the U.S. Food and Drug Administration
(FDA) which sets strict regulations on the safety of the transplants, primarily aimed at the prevention of
the spread of communicable disease. Regulations include criteria for donor screening and testing as well
as strict regulations on the processing and distribution of tissue grafts. Organ transplants are not regulated
by the FDA.
In November 2007, theCDCreported the first-ever case ofHIVandHepatitis Cbeing simultaneously
transferred through an organ transplant. The donor was a 38-year-old male, considered "high-risk" by
donation organizations, and his organs transmitted HIV and Hepatitis C to four organ recipients. Experts
say that the reason the diseases did not show up on screening tests is probably because they were
contracted within three weeks before the donor's death, so antibodies would not have existed in high
enough numbers to detect. The crisis has caused many to call for more sensitive screening tests, which
could pick up antibodies sooner. Currently, the screens cannot pick up on the small number of antibodies
produced in HIV infections within the last 90 days or Hepatitis C infections within the last 1821 days
before a donation is made.
NAT(nucleic acid testing) is now being done by many organ procurement organizations and is able to
detect HIV and Hepatitis C directly within seven to ten days of exposure to the virus.

Transplant laws

Both developing and developed countries have forged various policies to try to increase the safety and
availability of organ transplants to their citizens.Austria,Brazil,France,Italy,PolandandSpainhave
ruled all adults potential donors with the "opting out" policy, unless they attain cards specifying not to
be. However, whilst potential recipients in developing countries may mirror their more developed
counterparts in desperation, potential donors in developing countries do not. TheIndian government
has had difficulty tracking the flourishing organ black market in their country, but in recent times it has
amended its organ transplant law to make punishment more stringent for commercial dealings in
organs. It has also included new clauses in the law to support deceased organ donation, such as making
it mandatory to request for organ donation in case of brain death. Other countries victimized by illegal
organ trade have also implemented legislative reactions. Moldova has made international
adoption illegalin fear of organ traffickers. China has made selling of organs illegal as of July 2006 and
claims that all prisoner organ donors have filed consent. However, doctors in other countries, such as
the United Kingdom, have accused China of abusing itshigh capital punishment rate. Despite these
efforts, illegal organ trafficking continues to thrive and can be attributed to corruption in healthcare
systems, which has been traced as high up as the doctors themselves in China and Ukraine, and the
blind eye economically strained governments and health care programs must sometimes turn to organ
trafficking. Some organs are also shipped to Uganda and the Netherlands. This was a main product in
thetriangular tradein 1934.
Starting on 1 May 2007, doctors involved in commercial trade of organs will face fines and suspensions
in China. Only a few certified hospitals will be allowed to perform organ transplants in order to curb
illegal transplants. Harvesting organs without donor's consent was also deemed a crime.
On 27 June 2008, Indonesian,Sulaiman Damanik, 26, pleaded guilty inSingaporecourt for sale of his
kidney toCK Tang's executive chair,Tang Wee Sung, 55, for 150millionrupiah(S$22,200). The
Transplant Ethics Committee must approve living donor kidney transplants. Organ trading is banned in
Singapore and in many other countries to prevent the exploitation of "poor and socially disadvantaged
donors who are unable to make informed choices and suffer potential medical risks." Toni, 27, the other
accused, donated a kidney to an Indonesian patient in March, alleging he was the patient's adopted
son, and was paid 186 million rupiah (20,200USD). Upon sentence, both would suffer each, 12 months
in jail or 10,000Singapore dollars(7,600USD) fine.

In an article appearing in the April 2004 issue ofEcon Journal Watch,economistAlex

Tabarrokexamined the impact of direct consent laws on transplant organ availability. Tabarrok
found that social pressures resisting the use of transplant organs decreased over time as the
opportunity of individual decisions increased. Tabarrok concluded his study suggesting that
gradual elimination of organ donation restrictions and move to a free market in organ sales will
increase supply of organs and encourage broader social acceptance of organ donation as a
practice.

Ethical concerns

The existence and distribution of organ transplantation procedures indeveloping countries, while
almost always beneficial to those receiving them, raise manyethicalconcerns. Both the source
and method of obtaining the organ to transplant are major ethical issues to consider, as well as
the notion ofdistributive justice. TheWorld Health Organizationargues that transplantations
promote health, but the notion of "transplantation tourism" has the potential to violatehuman
rightsor exploit the poor, to have unintended health consequences, and to provide unequal
access to services, all of which ultimately may cause harm. Regardless of the "gift of life", in the
context of developing countries, this might be coercive. The practice of coercion could be
considered exploitative of the poor population, violating basic human rights according to Articles
3 and 4 of theUniversal Declaration of Human Rights. There is also a powerful opposing view,
that trade in organs, if properly and effectively regulated to ensure that the seller is fully informed
of all the consequences of donation, is a mutually beneficial transaction between two consenting
adults, and that prohibiting it would itself be a violation of Articles 3 and 29 of theUniversal
Declaration of Human Rights.
Even within developed countries there is concern that enthusiasm for increasing the supply of
organs may trample on respect for the right to life. The question is made even more complicated
by the fact that the "irreversibility" criterion forlegal deathcannot beadequately definedand can
easily change with changing technology.

Artificial organ transplantation

Surgeons in Sweden performed the first implantation of a synthetic trachea in July 2011, for a 36year-old patient who was suffering from cancer. Stem cells taken from the patient's hip were
treated with growth factors and incubated on a plastic replica of his natural trachea.