The standard terminology for this combined transplant is Simultaneous

Kidney-Pancreas Transplant; I have reversed the two organ names in

order to shift the emphasis slightly. When I received a pancreas-
kidney transplant, word of the successful procedure began to circulate
among my friends and friends of the family. I was surprised to learn
the number of people who were unaware of pancreas transplantation,
or who had considered it as an option for themselves or a loved one
with diabetes and its many complications. Everyone seemed to know
about kidney transplants, but almost no one, even a few in the
diabetes community, had heard of pancreas transplants.

The site examines the history of transplantation, the immunology,

tissue typing, and immunosuppressant drugs that make
transplantation possible, and looks to the current practice in pancreas-
kidney transplantation. An ongoing personal account of my pancreas-
kidney transplant makes up the center of the site; selected journal
articles, informational links, and opportunities to contact the author
complete it.

I hope to inform more people of the option of transplantation, of its

advantages and its drawbacks, and to provide a firsthand account of
the preparations, the procedure, the recovery, and the care needed to
protect the new organs.

Background

Although they could not be called "successful" in the modern meaning

of "successful transplant," individuals carried out experiments in
transplantation as early as the late 18th century. John Hunter
(England) experimented with transplanting organs from a male into a
female chicken. Samuel Bigger (Ireland) successfully transplanted a
full cornea into the blind eye of a pet gazelle. Thompson, in 1890,
experimented with the excision of canine and feline frontal lobes from
the brain, replacing these with allografts; some animals and allografts
survived for as long a seven weeks, although there was no evidence
that any neural activity occurred in the grafts.(1) Dr. Edward Zim
pioneered human corneal transplants in 1906; the non-vascularized
cornea avoids most of the rejection problems associated with organs
that are directly connected to the blood or lymphatic systems. Various
bone, joint, and vascular transplants followed, again with widely
varying outcomes.

Dr. Joseph E. Murray of Brigham &

Women's Hospital in Boston performed
the first successful kidney transplant
(from a living identical twin) in 1954.
Drs. Richard Lillehei and William Kelly
performed the first simultaneous
kidney-pancreas transplant (SKPT) in
1966 at the University of Minnesota,
Minneapolis, MN. The 1966 procedure
survived for two months before being
rejected by the body's immune
system. 1967 brought the first
successful liver transplant by Dr.
Thomas Starzl at U. Colorado in
Denver. The first pancreas-only
transplant, again by Lillehei in
Minneapolis, occurred during 1968, as
well as the first successful heart transplant, performed by Dr. Norman
Shumway at Stanford University.(2)

Between 1954 and 1970, the major immunosuppressant drugs used to

control rejection were 6-mercaptopurine, a related drug azathioprine,
and corticosteroids; all of these drugs suffered from a lack of
specificity in suppression, leaving the organ recipient very, very
susceptible to infections, while not entirely controlling rejection.

In 1970, the discovery of a new anti-rejection agent named

cyclosporine, isolated from a Norwegian soil fungus (Beauveria nivea),
accelerated transplant activity. With the advent of a more effective
anti-rejection drug and improved surgical techniques, the number and
variety of transplant procedures increased, and graft survival rates and
length of graft survival times increased dramatically.

1981 brought the advent of the heart-lung transplant by Dr. Bruce

Reitz at Stanford. In 1983, Dr. Joel Cooper in Toronto performed the
first single-lung transplant, followed by the first double lung transplant
in 1986.(2)

Living, related donor liver transplants (segmented), and living, related

donor single-lung transplants followed, as well as living, related donor
transplant of a segmented pancreas.

Advances in the immunosuppressant drugs, as well as technical

improvements in surgery and postoperative monitoring make
transplants initially more successful and the longevity of the grafts
much greater.

Even procedures that in the past were strictly forbidden, such as

transplanting recipients with HIV or Hepatitis C virus are being
explored. As of January 31, 2000, the University of California San
Francisco began a kidney and liver transplant program for HIV infected
individuals.

In what seems to us today a classic piece of understatement,

Thompson said:

‘I think the main fact of this experiment - namely, that brain tissue has
sufficient vitality to survive for seven weeks the operation of
transplantation without wholly losing its identity as brain substance -
suggests an interesting field for further research, and I have no doubt
that other experimenters will be rewarded by investigating it.’
(Thompson WG, Successful brain grafting. NY Med J. 1890; 51: 701-
702).(1)

Immunology Basics

The human immune system is a vast and complex collection of

structures, cells, chemicals, and other elements; many individuals
spend their entire working lives trying to better understand its intricate
actions and reactions. It is outside the scope of this document to give
more than a brief summary of information about immunity; however,
some knowledge of the immune system and the way that it functions
is crucial to understanding organ transplantation and the suppression
of organ rejection. (For sources of more thorough discussions of
immune function, see Links.)

Self and Non-self

The immune system can distinguish between material that the body
considers "self," and material that it considers "non-self," for example
bacteria, viruses, or foreign organs. Further, in regard to the self/non-
self properties, the immune system can learn to recognize new "non-
self" elements, and to remember those that it encountered in the past.
When presented with a "non-self" molecule or structure, the immune
system can produce specific cells to chemically "fit" receptors on the
invading element, like a key in a lock. By attaching an immune cell to
an invader—and only to an invader—the system can martial other cells
to attack and destroy the non-self matter. Another example of the
complexity of the immune system is the fact that it can sense when
the foreign elements have been eradicated, and turn off the production
of the attacking cells; it is self-limiting.

A section of a specific chromosome known as the Major

Histocompatibility Complex (MHC) mediates much of the immune
response. Because the genes of the MHC vary tremendously from
person to person, transplanted tissue is recognized as "non-self" (an
exception would be tissues from identical twins, whose entire genetic
code is derived from a single, split zygote). The MHC also allows the
different types of immune cells (B-cells, T-cells, macrophages, and
others) to chemically communicate with each other. These cells can
alert each other to an invader, specify its location, identify its nature
(if it has been seen before) or specify its characteristics (if it is a new
type), and signal when the danger has passed and production of the
attackers is no longer needed.

There are two classes of MHC antigens, Class I and Class II. Class I
antigens alert killer T-cells (T-8 or CD-8 protein) to the presence of
body cells that have been invaded by bacteria or viruses, or changed
by cancer or disease. Class II antigens, located on B-cells and other
immune cells, can capture and break down antigens, making them
more visible to the helper T-cells (T-4 or CD-4 protein). These two
classes of antigens become more important to us in our consideration
of transplants when we discuss tissue typing and donor/recipient
matching.

Structures and Cells of the Immune System

The lymphatic system is populated by lymphocytes, the class of cells
that are the principal operating units of the immune system. Produced
in the bone marrow, the lymphocytes develop into several types: the
B-cells, the T-cells—so named because they mature in either the Bone
marrow, or in the Thymus gland—and the phagocytes (the root phage-
meaning "eat") and the phagocyte subcategories: macrophages,
microphages, erythrophages, and others. The macrophages are the
large white blood cells that can engulf and destroy a foreign cell or a
particle of debris in the body. The lymphocytes circulate constantly
throughout the body, by way of both the circulatory system and the
lymphatic system.

Lymphoid organs are the operating organs of the immune system,

located throughout the body, and connected by the lymphatic system,
which very roughly parallels the circulatory system. (Your physician
probably begins a search for signs of infection by checking for swelling
in the lymph "glands", small nodes concentrated in the neck, armpits,
abdomen, and groin. Such swelling indicates that the lymphocytes are
replicating and attacking a foreign organism; an immune response to
an infection is underway.)

Over the course of a lifetime, hundreds of thousands, millions, of

invading organisms, confront the immune system. In order to have
enough physical space for all the cells that "remember" the previous
infections, the immune system conserves a minimal number of each
cell type. When the body is again threatened by the same organism,
these few cells rapidly replicate, to create a large number of cellular
copies capable of fighting the infection. As mentioned, once the danger
has passed, the number of the attacking cells declines to await another
invader.

B-cells, T-cells, and their action

B-cells produce antibodies, chemical substances

that can destroy a virus or bacterium. Each B-
cell codes for a specific foreign organism, a
specific antigen—the rhinovirus of the common
cold, for example. If presented with its
matching antigen, the B-cell then "clones" itself
into more B-cells and produces large plasma
cells, which manufacture quantities of the
T4 cell,
antibody that the particular B-cell codes for.
with virus particles
Antibodies belong to a family of chemicals
attached to receptors.
known as immunoglobulins. There are different
classes of immunoglobulins—IgA, IgD, IgE, IgG, and IgM. Two
principal types are IgG and IgA. IgG circulates in the blood and
through the tissues, coating infectious organisms and making them
easier targets for the immune cells. IgA is concentrated more in the
tears, saliva, and secretions of the respiratory and GI tract. IgA is
plentiful in the tissues that surround the portals to the body, in other
words, points where organisms can enter without a cut or a break in
the skin.

T-cells fall into two basic types: helper T-cells, and killer T-cells.
Helper T-cells assist B-cells in the manufacture of antibodies. They
alert other immune cells to the presence of an invading organism. The
helper T-cells usually carry the T-3 or T-4 marker (more about these
markers later). Killer T-cells (cytotoxic T-cells) can directly attack and
destroy infected or damaged cells. The killer T-cells usually carry the
T-8 marker. Unlike the B-cell, however, the helper T-cell cannot
recognize antigens in their native state; the antigen must be broken
down by B-cells or macrophages and presented to the helper T-cell
receptors that fit the chemical fragments of the antigen. The T-4 cells
respond to antigen that is bound to a Class II MHC molecule, while T-8
cells search for antigen that is bound to Class I MHC molecules.

When a T-cell is activated by contact with its specific antigen—a

fragment of a virus, a protein from a bacterium, or a protein present in
a transplanted organ—it secretes chemicals known as cytokines or
lymphokines. These chemicals attach to locations on the antigen, then
call other elements into play. Lymphokines can activate T- and B-cells,
macrophages, cause the release of antibodies, and direct all this
activity toward areas where the antigen is located.

The T- and B-cell activation and intercommunication are two of the

more important actions of the immune system which must be
suppressed—or at least confused—in order to prevent rejection of
transplanted organs.

Some of the more important cytokines involved in organ rejection are

called interleukins because they are messengers between the
leukocytes (white blood cells). There are numerous interleukins, but
the two of greatest interest to transplantation are Il-1 and Il-2. Il-1,
principally derived from B-cells, activates T-cells and other attacking
cells. Il-2, produced when an antigen activates a T-cell, encourages
the T-cell to replicate and then encourages the new T-cells rapidly to
develop. Again, it is often the interruption of this cycle of action that
allows transplanted tissue to avoid detection, or at least avoid
destruction.

Mentioned earlier, phagocytes and macrophages are in place

throughout the body. Some macrophages develop special
characteristics depending upon where in the body they reside: lungs,
liver, kidneys, brain and other organs host these specialized defense
cells. Macrophages also can scavenge dead or worn out cells and
remove them from the tissues. Macrophages can be targeted for
activation by a lymphokine, which acts upon a receptor on the
macrophage, and directs it to seek out a single type of microbe or
tumor cell.

The immune response involves numerous other cell types, among

them basophils, neutrophils, eosinophils, mast cells, and platelets.

Inflammatory response

An indication that an immune response is underway is the warmth,

redness, and swelling that can easily be seen when the infection is
near the surface of the skin (although the same reaction goes on
anywhere infection is present, even deep in the body.) This
inflammatory response is a part of the "complement cascade", a
complex chain of events that occur in a precise sequence during an
immune response. Chemicals released by the immune cells can dilate
blood vessels to increase blood flow, and thus the number of immune
cells that can reach the infected location. Swelling arises from the
increased flow of lymph and associated immune substances to the
area where they are most needed. In addition to the extra fluid
present in the area, swelling is aggravated by products of the
basophils, mast cells, and other "cell destroyers" that can chemically
irritate the surrounding tissue.

Corticosteroids reduce this inflammatory response, which in turn

reduces the number of immune cells reaching the source of the
antigen, and can slow or stop the complement cascade from triggering
other immune responses.

Transplants and immunity

The discussion above indicates the versatility and adaptability of the

immune system. These otherwise valuable properties make the
immune system the enemy of organ transplants. For a transplanted
organ to "take up residence" in a recipient's body, the immune
response must be eliminated, or at least minimized. A great deal of
this immune suppression is accomplished by a combination of drugs
(see Immunosuppressant Drugs later in this discussion). The other
major factor influencing donor organ/recipient matching is the
histocompatibility of the two different tissues' genetic makeup.
Recalling our discussion of self/non-self identification, tissue typing is
where you want as many "self" markers as possible to match, and as
few "non-self" markers as possible to show up. Next, we will examine
HLA, PRA, and tissue typing.

For a much more thorough discussion of immunnology, see Dr.

Douglas Fix's General Immunology.

HLA and PRA Testing

Blood Group Matching

In order to match a potential recipient to a donor organ one first must

ascertain that the blood groups are compatible. The following chart
shows which particular blood groups can donate to, or receive from,
the other blood groups. (Rh factor does not enter into tissue typing
decisions.*)

Blood Type: Can Receive from Type: Can Donate to Type:

O O O, A, B, AB

A A, O A, AB

B B, O B, AB

AB O, A, B, AB AB

The chart shows the possible combinations of tissue compatibility, not

necessarily the practical application of blood group matching. “For
reasons of fairness, organs are allocated primarily to their own blood
group. Otherwise, the O patients would only have access to a fraction
of the organs, while AB patients would have access to all organs.
Nevertheless, there are some inequities in the waiting times on
particular blood group lists.” (3)

Finally, …[blood group matching] does not seem to make much of a

difference in the case of liver transplants; the reason for this is
unclear. [It]…is known that one can use `blood group incompatible'
livers (an A liver in a B patient) with success rates almost as good as
blood-group identical livers. [The choice]…still [is the] use [of] blood
group identical livers when at all possible, because the success rate is
higher overall. The allocation schemes for organs takes these
principles into account. (3)

Certain blood group combinations carry strict prohibitions, but the

choice of compatible blood group matches is less rigid.

HLA and PRA: Transplant Tissue Typing

Earlier, we discussed the Major Histocompatibility Complex and the

Class I and Class II antigens. The potential match between the
recipient's tissues and the donor's tissues uses a method call Human
Leukocyte Antigen testing, or HLA.

HLA testing either includes or excludes a particular recipient and a

particular donor as a transplant match. HLA looks at six markers,
antigens that are carried on the surface of the body's leukocytes. The
Class I antigen markers are designated HLA-A, HLA-B, and HLA-C; the
Class II antigen markers are designated HLA-DP, HLA-DQ, and HLA-
DR. The Class I antigens directly activate the T-8, or killer T-cells
(cytotoxic T-cells), while the Class II antigens principally activate the
helper T-4 cells, macrophages, and B-cells. Since these six HLA
antigens are carried on the surface of the cells, they are highly
reactive with the B- and T-cells, and therefore, the closest possible
match is required for the best results in transplantation.

The number of specific proteins encoded by these 6 antigens (actually,

the two sets of three antigens) is quite large. One source gives “24
specificities encoded by HLA-A, 52 by
HLA-B, and 11 by HLA-C [and]…there
are at least 20 specificities encoded for
HLA-DR, nine for HLA-DQ, and six for
HLA-DP.” (4) Estimates of the total
number of possible HLA combinations
vary between 10,000 and 13,700.

To perform the HLA test, samples of

known HLA antigens are incubated
with samples of serum (containing the
subject's antibodies); a positive
reaction indicates the presence of that
specific antigen on the subject's cells.
Antigen/Peptide Complex
A close match between recipient and
of MHC
donor means that these markers of "self" are similar or identical,
making the immune system less apt to attack the transplant.

The Panel Reactive Antibody test (sometimes referred to as Percent

Reactive Antibody, since the result is expressed as a percentage), or
PRA, also tests histocompatibility. This test combines the subject's
serum with samples of cells (which contain antigens) taken from up to
60 different individuals. The combination again shows if the subject
has acquired antibodies (for example, from a blood transfusion) to a
spectrum of antigens. Possible antibody/antigen mismatches are
preliminarily screened out. By counting the number of reacted cells in
a given sample, the PRA test also shows how strongly the antibodies
react with the antigen. If 50 or 100 cells react, then that sample is
50% reactive. The results of this test, then, show which antigens react
with a subject's antibodies, and how severely they react. Obviously, in
transplantation better matches are indicated by fewer reactive
samples, and less severely reactive samples.

After the HLA test identifies a potential donor/recipient match, and the
PRA testing eliminates a broad cross-section of antibody/antigen
mismatches, a crossmatch is performed. The crossmatch combines the
donor's cells with the recipient's serum and vice-versa, to verify that
antigens and antibodies from both donor and recipient are non-
reactive, or at least minimally reactive.

These three tests, then, show us what the donor's tissues and the
recipient's body consider “self” and “non-self”, and they show us what
antigens and antibodies should be avoided in a potential match. Since
the HLA markers are inherited from one's parents, the markers remain
constant; the lab must perform this test only once. However, since
antibodies can arise or subside, the PRA test should be repeated at
least monthly; if the potential recipient receives a blood transfusion,
the test should be repeated in no more than 10-14 days.

Living Donors, Cadaveric Donors, and HLA

Parents provide one's specific combination of HLA markers. Of the six

markers present on a child's leukocytes, a group of three derives from
the father, the other group of three derives from the mother. Since the
child inherits each half—each haplotype—from a parent, a child-parent
match is almost always a one-haplotype match (i.e., 3 of 6 HLA
match). (A theoretical possibility would be that both parents
coincidentally share an identical haplotype; this could make the child
an identical match to one parent, and a one-haplotype match to the
other. However, the vast number of different HLA antigens considered,
the chance of this happening seems quite rare.)

Since one's siblings also combine some of the same six maternal and
six paternal antigens (although not necessarily the same three
antigens from each parent), they can offer a match ranging from a
zero of six antigen match, up to a six of six antigen match. The
selection of antigens is an individual occurrence with each child, so
while one can calculate the statistical odds of a perfect match, there is
no guarantee that it will occur, no matter how many siblings one may
have. Aunts, uncles, and other relatives can make possible matches,
as can totally unrelated individuals.

Cadaveric donors draw from a more random gene pool, at least,

compared to that of a recipient and family. Still cadaveric donors
provide the largest source for kidneys, the only source for heart
transplants, and very close matches are quite common. A six-of-six
HLA match with no PRA reactivity is the best possible match. Five-of-
six matches, and four-of-six matches are more common and are
considered quite good matches. Depending upon the rarity of the
blood group and the specific HLA antigens, matches that are
theoretically “less perfect” are frequently made, and with modern
immunosuppressant drug therapy, are very often long-term successes.

Living related donor transplants still have an edge in terms of the

longevity of graft survival. This fact is generally thought to have as
much to do with the physical and biochemical condition of the organ at
the time of transplant as with the exactitude of the HLA match:

A wide variety of powerful vascular mediators are released in the

presence of severe brain injury. As a consequence of this
'catecholamine storm,' hearts and lungs from cadaver donors may
manifest such severe deterioration in function that they become too
damaged to transplant. All cadaver organs sustain this type of injury,
some to a greater degree than others. For example, hearts damaged
in this way manifest lesions, such as contraction band necrosis, and
kidneys manifest acute tubular necrosis. In fact, in kidneys, this effect
is stronger than the effect of HLA matching as evidenced by the data
that shows that the outcomes from kidneys from spousal donors are
superior to outcomes from cadaver donors with the same degree of
HLA matching. (5)

Still, with improving drug therapy, cadaveric donors are gaining

ground relative to living-donor graft longevity.
Tissue typing is a complex process, and the foregoing is just an outline
of the major steps in recipient/donor matching. A large portion of this
matching must be done accurately and rapidly in the last hours before
transplantation (speed being essential in the case of cadaveric
donors). Fortunately the technology exists to make possible quick,
precise tissue typing for optimal transplant results.

*The reason that Rh factor does not affect tissue typing is that Rh
factor affects only erythrocytes, or red cells, whereas HLA typing is
dependent upon leukocytes, or white cells, and their properties.

Immunosuppressant Drugs

As mentioned earlier, the first transplants were performed using

corticosteroids, azathioprine (6-mercaptopurine). While somewhat
effective in suppressing immune response, they suffered from a lack of
specificity, suppressing the total immune system, and yet not entirely
stopping rejection.

The corticosteroids (Prednisone and others) are among the oldest anti-
rejection drugs; as noted earlier, these drugs work principally by
reducing the inflammatory response, and slowing the complement
cascade. These drugs also affect virtually every other aspect of
immune response, including leukocyte and lymphocyte proliferation,
monocyte and basophil counts, and cellular communication.
Unfortunately, corticosteroids also have some of the more severe side-
effects. While they are still widely used, their use at lower dosages,
and lowering doses much sooner, is the current trend; a few centers
are removing corticosteroids entirely—at least for some patients.

In 1970, a new immunosuppressant was discovered in a soil fungus in

Norway (Beauveria nivea) and called Cyclospoine-A (brand names
Sandimmune, and later, Neoral). Approved for wide use by the US FDA
in 1983, cyclosporine, while it seems to have several
immunosuppressant effects, principally interferes with the action of
helper T-lymphocytes.

New immunosuppressant agents continue to be developed. In 1984, a

substance was isolated from a soil bacterium (Streptomyces
tsukubaensis) found near a mountain outside Tokyo. The refined drug
was named tacrolimus (Prograf) and was approved by the US FDA in
1994. Tacrolimus seems to work by interfering with the ability of
interleukin-2 to communicate with the T-cell receptors, suppressing
the activation and replication of the T-cells.
Cyclosporine and tacrolimus are both the same broad class of drug:
“calcineurin inhibitors”. Calcineurin is a cellular protein that assists
enzyme functions and the complex processes of IL-2 in signaling
between immune cells. They are quite effective at immunosuppression,
but they are also toxic to nerves, kidneys, and can cause diabetes.

Another drug, Rapamune (sirolimus), was approved 09/15/99 by the

FDA for manufacture and distribution by Wyeth-Ayerst. This drug, like
the others, must be used in combination with other drugs to suppress
several actions of the immune system. However, sirolimus is a
completely different class of drug from the calcineurin inhibitors; it is a
‘TOR’ (target or rapamycin) inhibitor. This drug also interrupts IL-2
synthesis and signaling, but at a different point in the chain of events
than the calcineurin inhibitors. It seems to be far less toxic to tissues
than the other drugs.

Azathioprine, mentioned earlier, is still in wide use (brand name

Imuran). Azathioprine and a newer drug, Mycophenolate Mofetil
(CellCept), have a similar end result, though the two have different
ways of achieving it. The outcome in both cases is the suppression of
white blood cell proliferation (B-cells, T-cells, and macrophages). One
drawback to Imuran is that, while it does suppress the white cells
normally activated in an immune response, it also can suppress red
cell and platelet production, which can be an unwanted side-effect. In
1995, CellCept was approved by the US FDA for use in kidney
transplants, and in subsequent years has been approved for use in
other organ transplants. CellCept works by limiting the division and
development of white blood cells, but seems to have little effect on
other bone-marrow products. The major side effects are
gastrointestinal discomfort, and the possibility of a lowered white
count, usually reversible with reduced dosage. An uncommon, but very
serious, side-effect of these two, particularly of CellCept is the
potential for post-transplant lymphoproliferative disorder, essentially a
type of white blood cell ‘cancer’. When the white blood cells begin to
reproduce out of control, then the drug usually must be stopped to
save the patient’s life. The transplanted organ is in
serious jeopardy if this should happen.

A relatively new development in

immunosuppression is the use of monoclonal
antibodies to fight tissue rejection. OKT3, ATGAM,
Simulect, and Zenapax all function by binding to
receptor sites on the T-cells, thus preventing their
activation by the transplanted tissue antigens;
Computer Model of
Zenapax
they do not suppress the entire immune system. While the body can
manufacture antibodies against the OKT3, Zenapax is less "visible" to
the human immune system, and is much less likely to provoke another
immune response. The fact that these drugs operate on the T-3 and T-
4 receptors gives them perhaps the highest specificity of all
immunosuppressants, with a very small occurrence of side effects.
OKT3 and ATGAM are used primarily to counter an acute rejection
episode; another medication very similar to ATGAM that is used in
acute rejection episodes is Thymoglobulin— anti-thymocyte globulin.
Zenapax, on the other hand, is used from the time of transplantation,
continuing for about ten weeks in order to prevent early rejection
episodes.These drugs are quite powerful and are not suited to
maintenance immunosuppression; they are used almost exclusively to
treat patients in the first few weeks after transplant, or to stop acute
rejection episodes.

New drugs are always in development, and the list above is far from
complete, but it does cover some of the most widely used anti-
rejection drugs. A new drug, ISAtx247 manufactured by Isotechnika of
Edmonton, Alberta, Canada entered Phase-1 clinical trials August 28,
2000. The drug is reportedly 3 time more potent than Cyclosporine
and at the same time 5 times less toxic. Clinical trials continue. Other
new or investigational drugs include variations on older formulations,
as wells as entirely new classes of immunosuppressants. Included are
Gusperimus (15-deoxyspergualin), brand name Spanidin, an
intravenous immunosuppressant that suppresses production of
cytotoxic T cells, neutrophils and macrophages; Medi-500 (formerly
T10B9), an intravenous monoclonal antibody targeted against the
human T cells; FTY 720, an oral myriocin derivative rthat alters
lymphocyte infiltration into grafted organs; Medi-507, an intravenous
humanized antibody directed against the CD2 T cell; HLA-B2702
peptide, an intravenous human peptide that blocks the action of NK
cells and T-cell- mediated toxicities. Of those drugs mentioned, FTY
720 is perhaps the closest to completetion of clinical trials.

Other Drugs

Many other medications that are not immunosuppressants are used to

complement the anti-rejection drugs.

Bactrim (trimethoprim/sulfamethoxazole or TMP/SMZ) treats bacterial

infections, particularly Pneumocystis carinii pneumonia. Bactrim is
usually taken long-term by transplant patients. Levaquin (levafloxacin)
or one of the erythromycins can be used to prevent infection following
dental work. A wide variety of antibiotics—vancomycin, clindamycin,
tobramycin, many cephalosporins and quinolones—are available for
use; the drug chosen is based on the location of the infection and the
specific organism causing it.

Cytovene (gancyclovir), or Valcyte (valgancyclovir), can be used to

treat cytomegalovirus. Cytomegalovirus can affect numerous part of
the anatomy, causing retinitis, gastroenteritis, and pneumonia. Other
antiviralscan be used in some cases, but viruses are particularly
difficult to handle under immunosuppression.

A number of anti-fungal drugs can be used to treat yeast or fungus

infections. Among these are Mycostatin (nystatin), Mycelex
(clotrimazole), Diflucan (fluconazole), and Nizoral (ketoconazole).

Other minerals and supplements may be needed to maintain the

electrolyte balance, and to replace numerous elements lost through a
bladder-drained exocrine duct of a pancreas transplant.

Since several of the required immunosuppressants may cause

hypertension, blood pressure medication may be required, although
calcium-channel blockers like Cardizem and Procardia can propitiate
the bioavalability of some immunosuppressants, requiring a smaller
dose to acheive the same blood level. Also, since some
immunosuppressants can elevate cholesterol and other blood lipids, a
medication to lower cholesterol may be added to your regime. Lasix or
other diuretics may be required if the patient is retaining fluid.

No matter what combination of drugs is prescribed, it is important to

understand that this drug plan has been tailored for you and for you
alone. Never change anything about your medication, the dosage, the
time that you take it, whether you take it with or without food,
anything at all, without consulting your transplant team! A change in
one drug may require concomitant changes in several other drugs.
Adjustments will be made by the transplant team in response to the
levels indicated by your periodic labwork. Never add over-the-counter
products or herbal remedies without consulting your transplant team.
Many so-called "safe and natural" products can have disastrous effects
when combined with your immunosuppressant drugs.

The interrelationships between all these very powerful drugs are

multifaceted and quite complex, and any unplanned changes can have
serious consequences. Compliance with your drug regime, long-term,
is perhaps the single most important facet in maintaining the health of
the transplants.

Procedures

As previously noted, the original 1966 pancreas transplant was

simultaneous with a kidney transplant; this is the most common
transplant procedure involving a pancreas today. Simultaneous
Kidney/Pancreas transplant (SKP) is followed in number performed by
Pancreas After Kidney (PAK) transplants and finally, by Pancreas
Transplant Alone (PTA). Statistics from the International Pancreas
Transplant Registry (IPTR) show the distribution among the
procedures:

IPTR (6) reports that of:

13,330 total pancreas transplants

777 were Pancreas Transplants Alone (6%)

1,816 were Pancreas After Kidney Transplants (14%)

10,412 were Simultaneous Kidney/Pancreas Transplants 78%)

were Pancreas and another organ or type unknown

325
(2%)

One reason that the first pancreas transplants were done in

conjunction with kidney transplants, and the reason that most are still
SKP, is that for any transplant, immunosuppression is required.
Immunosuppression is never without risk; each drug has its own
syndrome of side effects. Among these side effects are: Increased
susceptibility to infections, bone and joint weakness (sometime leading
to hip or knee replacement), accelerated cataract formation, additional
functional loads on kidney and pancreas, elevated cholesterol, gastric
problems including ulcers, elevated blood pressure, and increased
cancer risk. In addition, there are numerous less severe side effects
like insomnia, hirsutism, night sweats, nightmares, and mood swings.
While diabetes is treatable with insulin
injections (or other medications) and
frequent blood glucose monitoring,
many diabetics eventually develop
complications from the disease, among
them, retinal damage, cardiovascular
problems including arteriosclerosis,
kidney failure, neuropathy, and
amputation of extremities due to poor
circulation.

Kidney failure is treatable with dialysis,

but dialysis, too, has its problems.
Fluid intake and diet must be
monitored closely. Anemia can be
severe if not monitored and treated. Section through
Bone loss (osteopenia, normal kidney
osteodystrophy, osteomalacia) can occur with hyperparathyroidism,
often requiring surgery to remove the parathyroid gland.
Arteriovenous access (graft or fistula) can clot and require surgery;
access via catheter can lead to infection in the bloodstream.

In both conditions, diabetes and renal failure, life span is shortened,

compared to individuals affected by neither condition, and quality of
life is compromised.

Since there are several compromises with insulin therapy, with

dialysis, and with transplantation, it is a judgment call by physician
and patient which choice is the best choice. In very broad terms,
kidney failure is the more immediately dangerous of the two
conditions. Transplantation is the treatment of choice for many renal
patients who may also have diabetes mellitus. The logical argument,
then, is the following: If the renal patient must be on
immunosuppressant drugs for the kidney transplant, why not
transplant a pancreas at the same time and eliminate the diabetes
(which, quite often, is the cause of the renal failure)? Many physicians
are reluctant to transplant a pancreas alone for diabetes without renal
failure, feeling that the side effects of the immunosuppressant drugs
are more detrimental than the complications of diabetes. So, while PTA
procedures are far fewer in number than those accompanying kidneys,
their number is growing.

Pancreas alone transplants are more easily justified in several

situations. For example, in cases where hypoglycemic unawareness
has developed, the sudden, unnoticed onset of very low blood sugar
could have disabling or even life-threatening effects. Very labile or
"brittle" diabetes, in which blood sugar control is extremely difficult, is
another condition that makes a stronger case for use of a pancreas
transplant and immunosuppression. Advanced neuropathy can also be
helped by pancreas transplantation. Unfortunately, early in the disease
it is very difficult to predict which patients will develop complications
and which patients will not. While tight glycemic control is always the
goal, and there are correlations between glycemic control and fewer
complications, there is no absolute correlation between tight glycemic
control and absence of complications, there is no absolute guarantee
that somewhat looser glycemic control will produce accelerated
development of complications in all patients. Only after complications
begin to develop can a responsible decision about transplantation and
immunosuppression be made.

Several diabetic complications stabilize after transplant, and a few can

even be demonstrated to improve. Proliferative retinopathy tends to
stabilize following a pancreas transplant, although extant damage to
the retina from neovascularization does not reverse. "Neuropathy
improves or stabilizes in most pancreas transplant recipients. Nerve
conduction velocities and evoked muscle action potentials increase."
(7) Effects on cardiovascular complications of diabetes are less clear,
although there is some evidence that there is some improvement in
peripheral vascular function, evidenced by improved oxygenation of
the tissues and decreased capillary leakage.

One other matter to consider in PTA is the handling of the pancreatic

exocrine secretions. In SKP, with both organs from the same donor,
kidney function can be monitored as a surrogate for direct monitoring
of pancreas rejection. This enables enteric drainage for the
transplanted pancreas' exocrine secretions (the pancreatic duct drains
into the duodenum), which is essentially the way the native pancreas
handles this function. In the absence of an HLA-identical kidney, the
best way to monitor the transplanted pancreas is by draining the
exocrine secretions into the bladder; urine can then be sampled for
pancreatic enzymes, particularly amylase, and these levels are used to
indicate potential rejection episodes. There are additional factors to be
considered in either technique. In a bladder-drained transplant,
numerous chemical elements (which would have been reabsorbed by
the intestine with an enteric-drained procedure) are lost through the
exocrine secretions/urine mix and must be replaced with supplements.
Significant fluid is lost through exocrine secretions/urine with bladder-
drained transplant, and dehydration must be avoided. Particular care
must be given to bicarbonate replacement because without it
metabolic acidosis can result. The enzymes and the pH of the exocrine
secretions can aggravate noninfectious chemical cystitis and reflux
pancreatitis. While these complications are generally manageable,
their potential should be taken into consideration.

While at first glance it may seem that a pancreas transplant is a quick,

simple and permanent way to "cure" diabetes. It is not. It is not quick:
The evaluation and waiting list time can vary from 1-3 years. It is not
simple: The procedure is major surgery, and is very stressful to the
body, as are the immunosuppressant drugs, which require a lifetime
commitment. And it is not necessarily permanent " Long-term insulin
independence is achieved in 80% of recipients of pancreas grafts
placed simultaneously with a kidney, in >70% of recipients of a
pancreas after a kidney, and in >60% of non uremic recipients of a
pancreas alone." (8) The required use of immunosuppressant drugs
can lead to non-autoimmune diabetes mellitus, or even recurrence of
the original autoimmune DM. (A few recent studies debate whether
insulin resistance or beta-call damage is a more common cause of
post-transplant diabetes. [Transplantation, 2001;71:1417-1423])

This procedure is possible because an individual can survive quite well

with a single healthy kidney. While the human body provides a pair of
highly adaptive kidneys, it gives us only a single pancreas to work
with. While a few transplants have been done by excision of a section
of pancreatic tissue from a living related donor, these segmented-graft
survival rates have been disappointing. Almost all pancreas grafts are
taken from cadaveric donors. (A side-note here on cadaveric renal
transplants versus living donor transplants: The best graft survival
rates in kidney transplantation are grafts taken from a living, related
donor, whose HLA typing is frequently closer to that of the recipient
than matches from cadaveric donors; ischemic time is minimized with
living donors.)

Again regarding the length of time on a waiting list, several sources in

the US have vastly divergent views on times for SPK transplants.

"In an interview with Reuters Health, Dr. Humar commented that the
main stumbling block to broader use of pancreas transplantation for
potential cure of Type 1 diabetes is the supply of donor organs,
because the waiting list for a combined kidney/pancreas transplant is
currently between 2 and 3 years in the US." (9) Contrarily "…the
number of pancreas transplants being performed is less than the
number of cadaver donors theoretically available." (7) My experience
at Carolinas Medical Center, Charlotte, NC, is that for Type A blood
group, 6-9 months is an average wait, and anything over a year is rare
for SPK transplants. The list for pancreas-kidney transplants is
significantly shorter than the list for kidney alone, principally because
of the more strident screening before acceptance in the SKP program.
SPK is a more stressful surgical procedure so fewer people are good
candiates for it.

Recently, islet cell transplantation shows promise as an alternative to

PTA or even to PAK transplants. Dr. A.M. James Shapiro and his
colleagues at the University of Alberta in Edmonton harvested islet
cells from cadaveric donors and inject the cells into the recipient's
hepatic artery. The cells attach to the liver tissue. Although
immunosuppressants are required to prevent rejection, corticosteroids
generally are not, because the individual cells are not subject to the
same inflammatory response as is a solid organ.

Variations of the Edmonton protocol are spreading rapidly across the

US; still, large-scale, long-term studies of islet cell transplant function
are not easily available.

Another recent experimental project involves the University of

Alberta's Drs. Ray V. Rajotte and Gregory S. Korbutt, Carolinas
Medical Center's Drs. Paul F. Gores and Craig Halberstadt, and Dr.
Helena P. Selawry, formerly of the University of Tennessee Medical
Center. This project will utilize modified Sertoli cells. The native Sertoli
cells provide privileged immunity to developing spermatozoa. The
modified Sertoli cells would provide a privileged immunity zone around
islet cells, or even around solid organ allografts, thus reducing or even
eliminating the need for immunosuppressant drugs.

Transplantation is not a cure for either diabetes or renal failure; it is

another treatment option; with improved surgical techniques, new
drug therapies, and more specific techniques of manipulating genetic
immunology, it will become a more and more desirable choice.

References

1. ReNeuron, Ltd, "ReNeuron and brain stem cell transplantation,"

September 21, 1999
http://www.reneuron.com/reneuron/releases/pressreleases/199
9-10-1/?version=1#history
2. United Network for Organ Sharing, Donation and
Transplantation: About Transplantatoin: History
http://www.optn.org/about/transplantation/history.asp
3. Dr. Jeff Punch, University of Michigan, Organ Transplantation
FAQ, III, Part 4, "A More Technical Explanation of ABO Organ
Matching," http://www.faqs.org/faqs/medicine/transplant-
faq/part4/
4. O. A. Lukasewycz, Ph.D., Med 5454, "Human Immunology:
Histocompatibility Antigens", University of Minnesota Duluth,
Medweb Outlines
http://www.d.umn.edu/medweb/micro/outlines/IX_HistoAnt.txt.
5. "Nonimmune Mechanisms of Graft Injury and Inflammation and
Their Effects on Transplant Outcomes," Philip Halloran, MD,
©2000 Medscape http://www.medscape.com/viewarticle/413137
6. International Pancreas Transplant Registry, 2002 Anual Data
Report, Pancreas Transplants By Category
http://www.iptr.umn.edu/ar_2002/2002_page2.htm
7. "Pancreas transplantation: an update," Sutherland D.E.,
Gruessner R.W., Gores P.F., Brayman K., Wahoff D., Gruessner
A. Diabetes Metab Rev. 1995 Dec;11(4):337-63
8. "Current Status of Pancreas Transplantation for the Treatment of
Type 1 Diabetes Mellitus," David E. R. Sutherland, MD, PhD, and
Rainer W. G. Gruessner, MD, PhD. Clinical Dabetes, V.15 N. 4
July/August 1997
http://journal.diabetes.org/clinicaldiabetes/v15n4J-
A97/PG152.htm
9. "Decreased Surgical Risks of Pancreas Transplantation in the
Modern Era," Abhinav Humar, MD; Raja Kandaswamy, MD; Darla
Granger, MD; Rainer W. Gruessner, MD; Angelika C. Gruessner,
PhD; David E. R. Sutherland, MD, PhD. Annals of Surgery
2000;231:269-275
10. Sertoli Technologies
Incorporatedhttp://www.sertoli.com/pages/568089/index.htm
11. Davidson, Ingemar J. A., "The Pancreas Transplant
Procedure," (pp. 51-63), Kidney and Pancreas Transplantation-
2nd edition, Landes Bioscience, Austin, TX, 1998
12. Davidson, Ingemar J. A., Arthur I. Sagalowsky, "The
Kidney Transplant Procedure," (pp. 25-50), Kidney and Pancreas
Transplantation-2nd edition, Landes Bioscience, Austin, TX, 1998
13. University of Wisconsin-Madison, "UW Organ Transplant
Program: Organ Preservation"
http://www.surgery.wisc.edu/transplant/patients/uwotp_researc
h.shtml
Images

• [Homepage] Leonardo daVinci, A Study of Proportions, after

Vitruvius's De Architectura
http://www.webcolombia.com/leonardo/Leonardo_Da_Vinci_Stu
dy_of_proportions_1.jpg
• [Background]Leonardo daVinci, Anatomical Study of a Female
http://www.visi.com/~reuteler/vinci/female.jpg
• [Immunology Basics]T4 cell (in green) showing retroviral
particles (in red) attached to receptors. From: Hospital Medicine
33(8):31-33, 37-38, 40-42, 45, 1997. © 1997 Quadrant
HealthCom, Inc.
• [HLA and PRA Testing]Antigen/Peptide Complex of MHC,
Smith, K. J., Reid, S. W., Harlos, K., McMichael, A. J., Stuart, D.
I., Bell, J. I., Jones, E. Y. Immunity 4 pp. 215 (1996)
http://www.rcsb.org/pdb/images/1A1Mx250c.jpg
• [Immunosuppressant Drugs]Computer model of Zenapax®,
Humanized antibody, combing about 10% of a mouse antibody
(shown in red), that binds to its target, a few additional amino
acids from the mouse antibody (shown in dark blue), with about
90% of a human antibody (shown in gray). Protein Design Lab
http://www.pdl.com/page_img/antibodies_zen3d.gif
• [Procedures]Normal kidney section. http://www.med.utah.edu/