The standard terminology for this combined transplant is Simultaneous Kidney

8/7/2019 The standard terminology for this combined transplant is Simultaneous Kidney

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The standard terminology for this combined transplant is SimultaneousKidney-Pancreas Transplant; I have reversed the two organ names inorder to shift the emphasis slightly. When I received a pancreas-kidney transplant, word of the successful procedure began to circulateamong 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 onewith diabetes and its many complications. Everyone seemed to knowabout kidney transplants, but almost no one, even a few in thediabetes community, had heard of pancreas transplants.

The site examines the history of transplantation, the immunology,tissue typing, and immunosuppressant drugs that maketransplantation 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 journalarticles, informational links, and opportunities to contact the authorcomplete it.

I hope to inform more people of the option of transplantation, of itsadvantages and its drawbacks, and to provide a firsthand account ofthe preparations, the procedure, the recovery, and the care needed toprotect the new organs.

Background

Although they could not be called "successful" in the modern meaningof "successful transplant," individuals carried out experiments in


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transplantation as early as the late 18th century. John Hunter(England) experimented with transplanting organs from a male into afemale chicken. Samuel Bigger (Ireland) successfully transplanted afull 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 allograftssurvived for as long a seven weeks, although there was no evidencethat any neural activity occurred in the grafts.(1) Dr. Edward Zimpioneered human corneal transplants in 1906; the non-vascularizedcornea avoids most of the rejection problems associated with organsthat are directly connected to the blood or lymphatic systems. Variousbone, joint, and vascular transplants followed, again with widelyvarying outcomes.

Dr. Joseph E. Murray of Brigham &Women's Hospital in Boston performedthe first successful kidney transplant(from a living identical twin) in 1954.Drs. Richard Lillehei and William Kellyperformed the first simultaneouskidney-pancreas transplant (SKPT) in1966 at the University of Minnesota,Minneapolis, MN. The 1966 proceduresurvived for two months before beingrejected by the body's immunesystem. 1967 brought the first

successful liver transplant by Dr.Thomas Starzl at U. Colorado inDenver. The first pancreas-onlytransplant, again by Lillehei inMinneapolis, occurred during 1968, aswell as the first successful heart transplant, performed by Dr. NormanShumway at Stanford University.(2)

Between 1954 and 1970, the major immunosuppressant drugs used tocontrol rejection were 6-mercaptopurine, a related drug azathioprine,and corticosteroids; all of these drugs suffered from a lack ofspecificity in suppression, leaving the organ recipient very, verysusceptible to infections, while not entirely controlling rejection.

In 1970, the discovery of a new anti-rejection agent namedcyclosporine, isolated from a Norwegian soil fungus (Beauveria nivea),accelerated transplant activity. With the advent of a more effectiveanti-rejection drug and improved surgical techniques, the number and


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variety of transplant procedures increased, and graft survival rates andlength of graft survival times increased dramatically.

1981 brought the advent of the heart-lung transplant by Dr. BruceReitz at Stanford. In 1983, Dr. Joel Cooper in Toronto performed the

first single-lung transplant, followed by the first double lung transplantin 1986.(2)

Living, related donor liver transplants (segmented), and living, relateddonor single-lung transplants followed, as well as living, related donortransplant of a segmented pancreas.

Advances in the immunosuppressant drugs, as well as technicalimprovements in surgery and postoperative monitoring maketransplants initially more successful and the longevity of the graftsmuch greater.

Even procedures that in the past were strictly forbidden, such astransplanting recipients with HIV or Hepatitis C virus are beingexplored. As of January 31, 2000, the University of California SanFrancisco began a kidney and liver transplant program for HIV infectedindividuals.

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 hassufficient vitality to survive for seven weeks the operation oftransplantation without wholly losing its identity as brain substance -suggests an interesting field for further research, and I have no doubtthat 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 individualsspend their entire working lives trying to better understand its intricateactions and reactions. It is outside the scope of this document to givemore than a brief summary of information about immunity; however,some knowledge of the immune system and the way that it functionsis crucial to understanding organ transplantation and the suppression


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of organ rejection. (For sources of more thorough discussions ofimmune function, see Links.)

Self and Non-self

The immune system can distinguish between material that the bodyconsiders "self," and material that it considers "non-self," for examplebacteria, 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 immunesystem can produce specific cells to chemically "fit" receptors on theinvading element, like a key in a lock. By attaching an immune cell toan invaderand only to an invaderthe system can martial other cellsto attack and destroy the non-self matter. Another example of thecomplexity of the immune system is the fact that it can sense whenthe foreign elements have been eradicated, and turn off the productionof the attacking cells; it is self-limiting.

A section of a specific chromosome known as the MajorHistocompatibility Complex (MHC) mediates much of the immuneresponse. Because the genes of the MHC vary tremendously fromperson to person, transplanted tissue is recognized as "non-self" (anexception would be tissues from identical twins, whose entire geneticcode is derived from a single, split zygote). The MHC also allows thedifferent types of immune cells (B-cells, T-cells, macrophages, and

others) to chemically communicate with each other. These cells canalert 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 newtype), and signal when the danger has passed and production of theattackers is no longer needed.

There are two classes of MHC antigens, Class I and Class II. Class Iantigens alert killer T-cells (T-8 or CD-8 protein) to the presence ofbody cells that have been invaded by bacteria or viruses, or changedby cancer or disease. Class II antigens, located on B-cells and otherimmune cells, can capture and break down antigens, making themmore visible to the helper T-cells (T-4 or CD-4 protein). These twoclasses of antigens become more important to us in our considerationof transplants when we discuss tissue typing and donor/recipientmatching.

Structures and Cells of the Immune System


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classes of immunoglobulinsIgA, IgD, IgE, IgG, and IgM. Twoprincipal types are IgG and IgA. IgG circulates in the blood andthrough the tissues, coating infectious organisms and making themeasier targets for the immune cells. IgA is concentrated more in thetears, saliva, and secretions of the respiratory and GI tract. IgA is

plentiful in the tissues that surround the portals to the body, in otherwords, points where organisms can enter without a cut or a break inthe 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. Theyalert other immune cells to the presence of an invading organism. Thehelper T-cells usually carry the T-3 or T-4 marker (more about thesemarkers later). Killer T-cells (cytotoxic T-cells) can directly attack anddestroy infected or damaged cells. The killer T-cells usually carry theT-8 marker. Unlike the B-cell, however, the helper T-cell cannotrecognize antigens in their native state; the antigen must be brokendown by B-cells or macrophages and presented to the helper T-cellreceptors that fit the chemical fragments of the antigen. The T-4 cellsrespond to antigen that is bound to a Class II MHC molecule, while T-8cells search for antigen that is bound to Class I MHC molecules.

When a T-cell is activated by contact with its specific antigenafragment of a virus, a protein from a bacterium, or a protein present ina transplanted organit secretes chemicals known as cytokines orlymphokines. 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 thisactivity toward areas where the antigen is located.

The T- and B-cell activation and intercommunication are two of themore important actions of the immune system which must besuppressedor at least confusedin order to prevent rejection oftransplanted organs.

Some of the more important cytokines involved in organ rejection arecalled interleukins because they are messengers between theleukocytes (white blood cells). There are numerous interleukins, butthe two of greatest interest to transplantation are Il-1 and Il-2. Il-1,principally derived from B-cells, activates T-cells and other attackingcells. Il-2, produced when an antigen activates a T-cell, encouragesthe T-cell to replicate and then encourages the new T-cells rapidly todevelop. Again, it is often the interruption of this cycle of action that


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allows transplanted tissue to avoid detection, or at least avoiddestruction.

Mentioned earlier, phagocytes and macrophages are in placethroughout 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 defensecells. Macrophages also can scavenge dead or worn out cells andremove them from the tissues. Macrophages can be targeted foractivation by a lymphokine, which acts upon a receptor on themacrophage, and directs it to seek out a single type of microbe ortumor cell.

The immune response involves numerous other cell types, amongthem 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 isnear the surface of the skin (although the same reaction goes onanywhere infection is present, even deep in the body.) Thisinflammatory response is a part of the "complement cascade", acomplex chain of events that occur in a precise sequence during animmune response. Chemicals released by the immune cells can dilateblood vessels to increase blood flow, and thus the number of immune

cells that can reach the infected location. Swelling arises from theincreased flow of lymph and associated immune substances to thearea where they are most needed. In addition to the extra fluidpresent in the area, swelling is aggravated by products of thebasophils, mast cells, and other "cell destroyers" that can chemicallyirritate the surrounding tissue.

Corticosteroids reduce this inflammatory response, which in turnreduces the number of immune cells reaching the source of theantigen, and can slow or stop the complement cascade from triggeringother immune responses.

Transplants and immunity

The discussion above indicates the versatility and adaptability of theimmune system. These otherwise valuable properties make theimmune system the enemy of organ transplants. For a transplantedorgan to "take up residence" in a recipient's body, the immune


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response must be eliminated, or at least minimized. A great deal ofthis immune suppression is accomplished by a combination of drugs(see Immunosuppressant Drugs later in this discussion). The othermajor factor influencing donor organ/recipient matching is thehistocompatibility of the two different tissues' genetic makeup.

Recalling our discussion of self/non-self identification, tissue typing iswhere you want as many "self" markers as possible to match, and asfew "non-self" markers as possible to show up. Next, we will examineHLA, 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 mustascertain that the blood groups are compatible. The following chartshows which particular blood groups can donate to, or receive from,the other blood groups. (Rh factor does not enter into tissue typingdecisions.*)

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, notnecessarily the practical application of blood group matching. Forreasons of fairness, organs are allocated primarily to their own bloodgroup. 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 onparticular blood group lists. (3)

Finally, [blood group matching] does not seem to make much of adifference in the case of liver transplants; the reason for this isunclear. [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
http://www.transplantbuddies.org/library/immunbasic.htmlhttp://www.transplantbuddies.org/library/immunbasic.html


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blood-group identical livers. [The choice]still [is the] use [of] bloodgroup identical livers when at all possible, because the success rate ishigher overall. The allocation schemes for organs takes theseprinciples into account. (3)

Certain blood group combinations carry strict prohibitions, but thechoice of compatible blood group matches is less rigid.

HLA and PRA: Transplant Tissue Typing

Earlier, we discussed the Major Histocompatibility Complex and theClass I and Class II antigens. The potential match between therecipient's tissues and the donor's tissues uses a method call HumanLeukocyte Antigen testing, or HLA.

HLA testing either includes or excludes a particular recipient and aparticular donor as a transplant match. HLA looks at six markers,antigens that are carried on the surface of the body's leukocytes. TheClass I antigen markers are designated HLA-A, HLA-B, and HLA-C; theClass 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 thehelper T-4 cells, macrophages, and B-cells. Since these six HLAantigens are carried on the surface of the cells, they are highlyreactive with the B- and T-cells, and therefore, the closest possiblematch 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 24specificities encoded by HLA-A, 52 byHLA-B, and 11 by HLA-C [and]thereare at least 20 specificities encoded forHLA-DR, nine for HLA-DQ, and six forHLA-DP. (4) Estimates of the totalnumber of possible HLA combinationsvary between 10,000 and 13,700.

To perform the HLA test, samples ofknown HLA antigens are incubatedwith samples of serum (containing thesubject's antibodies); a positivereaction indicates the presence of thatspecific antigen on the subject's cells.A close match between recipient and

Antigen/Peptide Complexof MHC


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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 PercentReactive Antibody, since the result is expressed as a percentage), or

PRA, also tests histocompatibility. This test combines the subject'sserum with samples of cells (which contain antigens) taken from up to60 different individuals. The combination again shows if the subjecthas acquired antibodies (for example, from a blood transfusion) to aspectrum of antigens. Possible antibody/antigen mismatches arepreliminarily screened out. By counting the number of reacted cells ina given sample, the PRA test also shows how strongly the antibodiesreact with the antigen. If 50 or 100 cells react, then that sample is50% reactive. The results of this test, then, show which antigens reactwith a subject's antibodies, and how severely they react. Obviously, intransplantation better matches are indicated by fewer reactivesamples, and less severely reactive samples.

After the HLA test identifies a potential donor/recipient match, and thePRA testing eliminates a broad cross-section of antibody/antigenmismatches, a crossmatch is performed. The crossmatch combines thedonor's cells with the recipient's serum and vice-versa, to verify thatantigens 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 whatantigens and antibodies should be avoided in a potential match. Sincethe HLA markers are inherited from one's parents, the markers remainconstant; the lab must perform this test only once. However, sinceantibodies can arise or subside, the PRA test should be repeated atleast 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 sixmarkers present on a child's leukocytes, a group of three derives fromthe father, the other group of three derives from the mother. Since thechild inherits each halfeach haplotypefrom a parent, a child-parentmatch is almost always a one-haplotype match (i.e., 3 of 6 HLAmatch). (A theoretical possibility would be that both parentscoincidentally share an identical haplotype; this could make the childan identical match to one parent, and a one-haplotype match to the


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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 andsix paternal antigens (although not necessarily the same three

antigens from each parent), they can offer a match ranging from azero of six antigen match, up to a six of six antigen match. Theselection of antigens is an individual occurrence with each child, sowhile one can calculate the statistical odds of a perfect match, there isno guarantee that it will occur, no matter how many siblings one mayhave. 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 donorsprovide the largest source for kidneys, the only source for hearttransplants, and very close matches are quite common. A six-of-sixHLA match with no PRA reactivity is the best possible match. Five-of-six matches, and four-of-six matches are more common and areconsidered quite good matches. Depending upon the rarity of theblood group and the specific HLA antigens, matches that aretheoretically less perfect are frequently made, and with modernimmunosuppressant drug therapy, are very often long-term successes.

Living related donor transplants still have an edge in terms of thelongevity of graft survival. This fact is generally thought to have as

much to do with the physical and biochemical condition of the organ atthe time of transplant as with the exactitude of the HLA match:

A wide variety of powerful vascular mediators are released in thepresence of severe brain injury. As a consequence of this'catecholamine storm,' hearts and lungs from cadaver donors maymanifest such severe deterioration in function that they become toodamaged to transplant. All cadaver organs sustain this type of injury,some to a greater degree than others. For example, hearts damagedin this way manifest lesions, such as contraction band necrosis, andkidneys manifest acute tubular necrosis. In fact, in kidneys, this effectis stronger than the effect of HLA matching as evidenced by the datathat shows that the outcomes from kidneys from spousal donors aresuperior to outcomes from cadaver donors with the same degree ofHLA matching. (5)

Still, with improving drug therapy, cadaveric donors are gainingground relative to living-donor graft longevity.


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Tissue typing is a complex process, and the foregoing is just an outlineof the major steps in recipient/donor matching. A large portion of thismatching must be done accurately and rapidly in the last hours beforetransplantation (speed being essential in the case of cadavericdonors). 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 Rhfactor affects only erythrocytes, or red cells, whereas HLA typing isdependent upon leukocytes, or white cells, and their properties.

Immunosuppressant Drugs

As mentioned earlier, the first transplants were performed usingcorticosteroids, azathioprine (6-mercaptopurine). While somewhateffective in suppressing immune response, they suffered from a lack ofspecificity, suppressing the total immune system, and yet not entirelystopping rejection.

The corticosteroids (Prednisone and others) are among the oldest anti-rejection drugs; as noted earlier, these drugs work principally byreducing the inflammatory response, and slowing the complementcascade. These drugs also affect virtually every other aspect ofimmune 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 centersare removing corticosteroids entirelyat least for some patients.

In 1970, a new immunosuppressant was discovered in a soil fungus inNorway (Beauveria nivea) and called Cyclospoine-A (brand namesSandimmune, and later, Neoral). Approved for wide use by the US FDAin 1983, cyclosporine, while it seems to have severalimmunosuppressant effects, principally interferes with the action ofhelper T-lymphocytes.

New immunosuppressant agents continue to be developed. In 1984, asubstance was isolated from a soil bacterium (Streptomycestsukubaensis) found near a mountain outside Tokyo. The refined drugwas named tacrolimus (Prograf) and was approved by the US FDA in1994. Tacrolimus seems to work by interfering with the ability ofinterleukin-2 to communicate with the T-cell receptors, suppressingthe activation and replication of the T-cells.


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Cyclosporine and tacrolimus are both the same broad class of drug:calcineurin inhibitors. Calcineurin is a cellular protein that assistsenzyme functions and the complex processes of IL-2 in signalingbetween 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 theFDA for manufacture and distribution by Wyeth-Ayerst. This drug, likethe others, must be used in combination with other drugs to suppressseveral actions of the immune system. However, sirolimus is acompletely different class of drug from the calcineurin inhibitors; it is aTOR (target or rapamycin) inhibitor. This drug also interrupts IL-2synthesis and signaling, but at a different point in the chain of eventsthan the calcineurin inhibitors. It seems to be far less toxic to tissuesthan the other drugs.

Azathioprine, mentioned earlier, is still in wide use (brand nameImuran). Azathioprine and a newer drug, Mycophenolate Mofetil(CellCept), have a similar end result, though the two have differentways of achieving it. The outcome in both cases is the suppression ofwhite blood cell proliferation (B-cells, T-cells, and macrophages). Onedrawback to Imuran is that, while it does suppress the white cellsnormally activated in an immune response, it also can suppress redcell and platelet production, which can be an unwanted side-effect. In1995, CellCept was approved by the US FDA for use in kidneytransplants, and in subsequent years has been approved for use in

other organ transplants. CellCept works by limiting the division anddevelopment of white blood cells, but seems to have little effect onother bone-marrow products. The major side effects aregastrointestinal discomfort, and the possibility of a lowered whitecount, usually reversible with reduced dosage. An uncommon, but veryserious, side-effect of these two, particularly of CellCept is thepotential for post-transplant lymphoproliferative disorder, essentially atype of white blood cell cancer. When the white blood cells begin toreproduce out of control, then the drug usually must be stopped tosave the patients life. The transplanted organ is inserious jeopardy if this should happen.

A relatively new development inimmunosuppression is the use of monoclonalantibodies to fight tissue rejection. OKT3, ATGAM,Simulect, and Zenapax all function by binding toreceptor sites on the T-cells, thus preventing theiractivation by the transplanted tissue antigens;

Computer Model ofZenapax


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they do not suppress the entire immune system. While the body canmanufacture antibodies against the OKT3, Zenapax is less "visible" tothe human immune system, and is much less likely to provoke anotherimmune 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 rejectionepisode; another medication very similar to ATGAM that is used inacute 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 rejectionepisodes.These drugs are quite powerful and are not suited tomaintenance immunosuppression; they are used almost exclusively totreat patients in the first few weeks after transplant, or to stop acuterejection episodes.

New drugs are always in development, and the list above is far fromcomplete, but it does cover some of the most widely used anti-rejection drugs. A new drug, ISAtx247 manufactured by Isotechnika ofEdmonton, Alberta, Canada entered Phase-1 clinical trials August 28,2000. The drug is reportedly 3 time more potent than Cyclosporineand at the same time 5 times less toxic. Clinical trials continue. Othernew or investigational drugs include variations on older formulations,as wells as entirely new classes of immunosuppressants. Included areGusperimus (15-deoxyspergualin), brand name Spanidin, anintravenous immunosuppressant that suppresses production of

cytotoxic T cells, neutrophils and macrophages; Medi-500 (formerlyT10B9), an intravenous monoclonal antibody targeted against thehuman T cells; FTY 720, an oral myriocin derivative rthat alterslymphocyte infiltration into grafted organs; Medi-507, an intravenoushumanized antibody directed against the CD2 T cell; HLA-B2702peptide, an intravenous human peptide that blocks the action of NKcells and T-cell- mediated toxicities. Of those drugs mentioned, FTY720 is perhaps the closest to completetion of clinical trials.

Other Drugs

Many other medications that are not immunosuppressants are used tocomplement the anti-rejection drugs.

Bactrim (trimethoprim/sulfamethoxazole or TMP/SMZ) treats bacterialinfections, particularly Pneumocystis carinii pneumonia. Bactrim isusually taken long-term by transplant patients. Levaquin (levafloxacin)or one of the erythromycins can be used to prevent infection following


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dental work. A wide variety of antibioticsvancomycin, clindamycin,tobramycin, many cephalosporins and quinolonesare available foruse; the drug chosen is based on the location of the infection and thespecific organism causing it.

Cytovene (gancyclovir), or Valcyte (valgancyclovir), can be used totreat cytomegalovirus. Cytomegalovirus can affect numerous part ofthe anatomy, causing retinitis, gastroenteritis, and pneumonia. Otherantiviralscan be used in some cases, but viruses are particularlydifficult to handle under immunosuppression.

A number of anti-fungal drugs can be used to treat yeast or fungusinfections. Among these are Mycostatin (nystatin), Mycelex(clotrimazole), Diflucan (fluconazole), and Nizoral (ketoconazole).

Other minerals and supplements may be needed to maintain theelectrolyte balance, and to replace numerous elements lost through abladder-drained exocrine duct of a pancreas transplant.

Since several of the required immunosuppressants may causehypertension, blood pressure medication may be required, althoughcalcium-channel blockers like Cardizem and Procardia can propitiatethe bioavalability of some immunosuppressants, requiring a smallerdose to acheive the same blood level. Also, since someimmunosuppressants can elevate cholesterol and other blood lipids, amedication 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 tounderstand that this drug plan has been tailored for you and for youalone. Never change anything about your medication, the dosage, thetime that you take it, whether you take it with or without food,anything at all, without consulting your transplant team! A change inone drug may require concomitant changes in several other drugs.Adjustments will be made by the transplant team in response to thelevels indicated by your periodic labwork. Never add over-the-counterproducts or herbal remedies without consulting your transplant team.Many so-called "safe and natural" products can have disastrous effectswhen combined with your immunosuppressant drugs.

The interrelationships between all these very powerful drugs aremultifaceted and quite complex, and any unplanned changes can haveserious consequences. Compliance with your drug regime, long-term,


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is perhaps the single most important facet in maintaining the health ofthe transplants.

Procedures

As previously noted, the original 1966 pancreas transplant wassimultaneous with a kidney transplant; this is the most commontransplant procedure involving a pancreas today. SimultaneousKidney/Pancreas transplant (SKP) is followed in number performed byPancreas After Kidney (PAK) transplants and finally, by PancreasTransplant Alone (PTA). Statistics from the International PancreasTransplant Registry (IPTR) show the distribution among theprocedures:

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%)

325were Pancreas and another organ or type unknown

(2%)

One reason that the first pancreas transplants were done inconjunction with kidney transplants, and the reason that most are stillSKP, is that for any transplant, immunosuppression is required.Immunosuppression is never without risk; each drug has its ownsyndrome of side effects. Among these side effects are: Increasedsusceptibility to infections, bone and joint weakness (sometime leadingto hip or knee replacement), accelerated cataract formation, additionalfunctional loads on kidney and pancreas, elevated cholesterol, gastricproblems including ulcers, elevated blood pressure, and increasedcancer risk. In addition, there are numerous less severe side effects

like insomnia, hirsutism, night sweats, nightmares, and mood swings.


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While diabetes is treatable with insulininjections (or other medications) andfrequent blood glucose monitoring,many diabetics eventually developcomplications from the disease, among

them, retinal damage, cardiovascularproblems including arteriosclerosis,kidney failure, neuropathy, andamputation of extremities due to poorcirculation.

Kidney failure is treatable with dialysis,but dialysis, too, has its problems.Fluid intake and diet must bemonitored closely. Anemia can besevere if not monitored and treated.Bone loss (osteopenia,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 oflife is compromised.

Since there are several compromises with insulin therapy, withdialysis, and with transplantation, it is a judgment call by physicianand patient which choice is the best choice. In very broad terms,kidney failure is the more immediately dangerous of the twoconditions. Transplantation is the treatment of choice for many renalpatients who may also have diabetes mellitus. The logical argument,then, is the following: If the renal patient must be onimmunosuppressant drugs for the kidney transplant, why nottransplant a pancreas at the same time and eliminate the diabetes(which, quite often, is the cause of the renal failure)? Many physiciansare reluctant to transplant a pancreas alone for diabetes without renalfailure, feeling that the side effects of the immunosuppressant drugsare more detrimental than the complications of diabetes. So, while PTAprocedures are far fewer in number than those accompanying kidneys,their number is growing.

Pancreas alone transplants are more easily justified in severalsituations. For example, in cases where hypoglycemic unawareness

Section through

normal kidney


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has developed, the sudden, unnoticed onset of very low blood sugarcould have disabling or even life-threatening effects. Very labile or"brittle" diabetes, in which blood sugar control is extremely difficult, isanother condition that makes a stronger case for use of a pancreastransplant and immunosuppression. Advanced neuropathy can also be

helped by pancreas transplantation. Unfortunately, early in the diseaseit is very difficult to predict which patients will develop complicationsand which patients will not. While tight glycemic control is always thegoal, and there are correlations between glycemic control and fewercomplications, there is no absolute correlation between tight glycemiccontrol and absence of complications, there is no absolute guaranteethat somewhat looser glycemic control will produce accelerateddevelopment of complications in all patients. Only after complicationsbegin to develop can a responsible decision about transplantation andimmunosuppression be made.

Several diabetic complications stabilize after transplant, and a few caneven be demonstrated to improve. Proliferative retinopathy tends tostabilize following a pancreas transplant, although extant damage tothe retina from neovascularization does not reverse. "Neuropathyimproves or stabilizes in most pancreas transplant recipients. Nerveconduction 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 inperipheral vascular function, evidenced by improved oxygenation ofthe tissues and decreased capillary leakage.

One other matter to consider in PTA is the handling of the pancreaticexocrine secretions. In SKP, with both organs from the same donor,kidney function can be monitored as a surrogate for direct monitoringof pancreas rejection. This enables enteric drainage for thetransplanted pancreas' exocrine secretions (the pancreatic duct drainsinto the duodenum), which is essentially the way the native pancreashandles this function. In the absence of an HLA-identical kidney, thebest way to monitor the transplanted pancreas is by draining theexocrine secretions into the bladder; urine can then be sampled forpancreatic enzymes, particularly amylase, and these levels are used toindicate potential rejection episodes. There are additional factors to beconsidered in either technique. In a bladder-drained transplant,numerous chemical elements (which would have been reabsorbed bythe intestine with an enteric-drained procedure) are lost through theexocrine 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


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must be given to bicarbonate replacement because without itmetabolic acidosis can result. The enzymes and the pH of the exocrinesecretions can aggravate noninfectious chemical cystitis and refluxpancreatitis. 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 notsimple: The procedure is major surgery, and is very stressful to thebody, as are the immunosuppressant drugs, which require a lifetimecommitment. And it is not necessarily permanent " Long-term insulinindependence is achieved in 80% of recipients of pancreas graftsplaced simultaneously with a kidney, in >70% of recipients of apancreas after a kidney, and in >60% of non uremic recipients of apancreas alone." (8) The required use of immunosuppressant drugscan lead to non-autoimmune diabetes mellitus, or even recurrence ofthe original autoimmune DM. (A few recent studies debate whetherinsulin resistance or beta-call damage is a more common cause ofpost-transplant diabetes. [Transplantation, 2001;71:1417-1423])

This procedure is possible because an individual can survive quite wellwith a single healthy kidney. While the human body provides a pair ofhighly adaptive kidneys, it gives us only a single pancreas to workwith. While a few transplants have been done by excision of a sectionof pancreatic tissue from a living related donor, these segmented-graft

survival rates have been disappointing. Almost all pancreas grafts aretaken from cadaveric donors. (A side-note here on cadaveric renaltransplants versus living donor transplants: The best graft survivalrates in kidney transplantation are grafts taken from a living, relateddonor, whose HLA typing is frequently closer to that of the recipientthan matches from cadaveric donors; ischemic time is minimized withliving donors.)

Again regarding the length of time on a waiting list, several sources inthe US have vastly divergent views on times for SPK transplants.

"In an interview with Reuters Health, Dr. Humar commented that themain stumbling block to broader use of pancreas transplantation forpotential cure of Type 1 diabetes is the supply of donor organs,because the waiting list for a combined kidney/pancreas transplant iscurrently between 2 and 3 years in the US." (9) Contrarily "thenumber of pancreas transplants being performed is less than thenumber of cadaver donors theoretically available." (7) My experience


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at Carolinas Medical Center, Charlotte, NC, is that for Type A bloodgroup, 6-9 months is an average wait, and anything over a year is rarefor SPK transplants. The list for pancreas-kidney transplants issignificantly shorter than the list for kidney alone, principally becauseof the more strident screening before acceptance in the SKP program.

SPK is a more stressful surgical procedure so fewer people are goodcandiates for it.

Recently, islet cell transplantation shows promise as an alternative toPTA or even to PAK transplants. Dr. A.M. James Shapiro and hiscolleagues at the University of Alberta in Edmonton harvested isletcells from cadaveric donors and inject the cells into the recipient'shepatic artery. The cells attach to the liver tissue. Althoughimmunosuppressants are required to prevent rejection, corticosteroidsgenerally are not, because the individual cells are not subject to thesame inflammatory response as is a solid organ.

Variations of the Edmonton protocol are spreading rapidly across theUS; still, large-scale, long-term studies of islet cell transplant functionare not easily available.

Another recent experimental project involves the University ofAlberta's Drs. Ray V. Rajotte and Gregory S. Korbutt, CarolinasMedical Center's Drs. Paul F. Gores and Craig Halberstadt, and Dr.Helena P. Selawry, formerly of the University of Tennessee MedicalCenter. This project will utilize modified Sertoli cells. The native Sertoli

cells provide privileged immunity to developing spermatozoa. Themodified Sertoli cells would provide a privileged immunity zone aroundislet cells, or even around solid organ allografts, thus reducing or eveneliminating the need for immunosuppressant drugs.

Transplantation is not a cure for either diabetes or renal failure; it isanother treatment option; with improved surgical techniques, newdrug therapies, and more specific techniques of manipulating geneticimmunology, it will become a more and more desirable choice.

References

1. ReNeuron, Ltd, "ReNeuron and brain stem cell transplantation,"September 21, 1999http://www.reneuron.com/reneuron/releases/pressreleases/1999-10-1/?version=1#history
http://www.reneuron.com/reneuron/releases/pressreleases/1999-10-1/?version=1#historyhttp://www.reneuron.com/reneuron/releases/pressreleases/1999-10-1/?version=1#historyhttp://www.reneuron.com/reneuron/releases/pressreleases/1999-10-1/?version=1#historyhttp://www.reneuron.com/reneuron/releases/pressreleases/1999-10-1/?version=1#history


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2. United Network for Organ Sharing, Donation andTransplantation: About Transplantatoin: Historyhttp://www.optn.org/about/transplantation/history.asp

3. Dr. Jeff Punch, University of Michigan, Organ TransplantationFAQ, 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 Outlineshttp://www.d.umn.edu/medweb/micro/outlines/IX_HistoAnt.txt.

5. "Nonimmune Mechanisms of Graft Injury and Inflammation andTheir 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 Categoryhttp://www.iptr.umn.edu/ar_2002/2002_page2.htm7. "Pancreas transplantation: an update," Sutherland D.E.,

Gruessner R.W., Gores P.F., Brayman K., Wahoff D., GruessnerA. Diabetes Metab Rev. 1995 Dec;11(4):337-63

8. "Current Status of Pancreas Transplantation for the Treatment ofType 1 Diabetes Mellitus," David E. R. Sutherland, MD, PhD, andRainer W. G. Gruessner, MD, PhD. Clinical Dabetes, V.15 N. 4July/August 1997http://journal.diabetes.org/clinicaldiabetes/v15n4J-A97/PG152.htm

9. "Decreased Surgical Risks of Pancreas Transplantation in theModern Era," Abhinav Humar, MD; Raja Kandaswamy, MD; DarlaGranger, MD; Rainer W. Gruessner, MD; Angelika C. Gruessner,PhD; David E. R. Sutherland, MD, PhD. Annals of Surgery2000;231:269-275

10. Sertoli TechnologiesIncorporatedhttp://www.sertoli.com/pages/568089/index.htm

11. Davidson, Ingemar J. A., "The Pancreas TransplantProcedure," (pp. 51-63), Kidney and Pancreas Transplantation-2nd edition, Landes Bioscience, Austin, TX, 1998

12. Davidson, Ingemar J. A., Arthur I. Sagalowsky, "TheKidney Transplant Procedure," (pp. 25-50), Kidney and PancreasTransplantation-2nd edition, Landes Bioscience, Austin, TX, 1998

13. University of Wisconsin-Madison, "UW Organ TransplantProgram: Organ Preservation"http://www.surgery.wisc.edu/transplant/patients/uwotp_research.shtml
http://www.optn.org/about/transplantation/history.asphttp://www.faqs.org/faqs/medicine/transplant-faq/part4/http://www.faqs.org/faqs/medicine/transplant-faq/part4/http://www.d.umn.edu/medweb/micro/outlines/IX_HistoAnt.txthttp://www.medscape.com/viewarticle/413137http://www.iptr.umn.edu/ar_2002/2002_page2.htmhttp://journal.diabetes.org/clinicaldiabetes/v15n4J-A97/PG152.htmhttp://journal.diabetes.org/clinicaldiabetes/v15n4J-A97/PG152.htmhttp://www.sertoli.com/pages/568089/index.htmhttp://www.surgery.wisc.edu/transplant/patients/uwotp_research.shtmlhttp://www.surgery.wisc.edu/transplant/patients/uwotp_research.shtmlhttp://www.optn.org/about/transplantation/history.asphttp://www.faqs.org/faqs/medicine/transplant-faq/part4/http://www.faqs.org/faqs/medicine/transplant-faq/part4/http://www.d.umn.edu/medweb/micro/outlines/IX_HistoAnt.txthttp://www.medscape.com/viewarticle/413137http://www.iptr.umn.edu/ar_2002/2002_page2.htmhttp://journal.diabetes.org/clinicaldiabetes/v15n4J-A97/PG152.htmhttp://journal.diabetes.org/clinicaldiabetes/v15n4J-A97/PG152.htmhttp://www.sertoli.com/pages/568089/index.htmhttp://www.surgery.wisc.edu/transplant/patients/uwotp_research.shtmlhttp://www.surgery.wisc.edu/transplant/patients/uwotp_research.shtml


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Images

[Homepage] Leonardo daVinci, A Study of Proportions, afterVitruvius's De Architecturahttp://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 Medicine33(8):31-33, 37-38, 40-42, 45, 1997. 1997 QuadrantHealthCom, 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 aminoacids from the mouse antibody (shown in dark blue), with about90% of a human antibody (shown in gray). Protein Design Labhttp://www.pdl.com/page_img/antibodies_zen3d.gif

[Procedures]Normal kidney section. http://www.med.utah.edu/
http://www.webcolombia.com/leonardo/Leonardo_Da_Vinci_Study_of_proportions_1.jpghttp://www.webcolombia.com/leonardo/Leonardo_Da_Vinci_Study_of_proportions_1.jpghttp://www.visi.com/~reuteler/vinci/female.jpghttp://www.rcsb.org/pdb/images/1A1Mx250c.jpghttp://www.pdl.com/page_img/antibodies_zen3d.gifhttp://www.med.utah.edu/http://www.webcolombia.com/leonardo/Leonardo_Da_Vinci_Study_of_proportions_1.jpghttp://www.webcolombia.com/leonardo/Leonardo_Da_Vinci_Study_of_proportions_1.jpghttp://www.visi.com/~reuteler/vinci/female.jpghttp://www.rcsb.org/pdb/images/1A1Mx250c.jpghttp://www.pdl.com/page_img/antibodies_zen3d.gifhttp://www.med.utah.edu/

The standard terminology for this combined transplant is Simultaneous Kidney

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