1. Having children after a transplant: What information is available?
2. How does blood type matching work?
3. What is CMV?
4. What is a virus?
5. Why does a virus make us sick?
6. Why are viruses such a problem for transplant patients?
7. What organs are infected by CMV?
8. How is CMV diagnosed?
9. Is CMV serious?
10. How do I know if I have had CMV or not?
11. Can I get CMV again?
12. If it is known that CMV positive organs give CMV disease to CMV negative people, why is this type of transplant performed?
13.How is CMV treated?
14.What makes CMV disease more likely?
15. Is CMV associated with other problems besides the viral disease?
16. What is Tissue Typing (HLA Typing)?
17. Why Can't Prednisone Be Discontinued Suddenly?
18.What is chronic rejection? What is being done about it?


1. Having children after a transplant: What information is available?
For the past several years, Sandoz has sponsored a National Transplantation Pregnancy Registry through the Thomas Jefferson University Hospital in Philadelphia. The person in charge of the registry is Dr. Vincent T. Armenti, MD, PhD, and he has published several papers on the subject.

Reports by Armenti and his co-workers (1992) indicated that, although the incidence of prematurity (58%) and low birth weight infants (38%) among female transplant recipients is significantly higher than that in the general population, the anticipated survival rate of these infants is greater than 90 %. They further report that among wives of male kidney recipients, the incidence of prematurity and low birth weight is 9% and 4% respectively. The investigators also note that in children fathered by male kidney recipients, the pattern of pregnancy outcomes resembles that of the general population.

The registry currently contains data on over 500 pregnancies; the majority of the pregnancies were in patients or wives of patients with kidney transplants (91%); the rest were in heart (6%) and liver (3%) recipients or their wives. In the 195 pregnancies fathered by transplant recipients, there have been 10 miscarriages, 1 elective abortion, and one stillbirth. Of the live births, only 17 were premature, and only 11 were of low birthweight. In cases in which the mother was the transplant recipient, a significant number of the first 264 pregnancies (resulting in 222 live births) concluded at a low gestational age, and resulted in an infant of low birth weight (Table 1); however, this did not seem specific for cyclosporine, but was seen in transplant recipients regardless of the immunosuppressive regimen which was used (Table 2). The prematurity and low birth weight thus seemed to be related to transplantation itself, rather than to the medications used to facilitate the survival of the graft.

A number of women, reported both in this registry and spontaneously, developed complications during the antenatal period: hypertension, pyelonephritis or uterine dystonia have been noted. In addition, disorders such as diabetes mellitus, epilepsy, encephalopathy, and secondary hyperparathyroidism have been reported.

Immediate neonatal problems included physiological jaundice, thrombocytopenia, leukopenia, or hypoglycemia in combination with mild disseminated intravascular coagulation which resolved spontaneously, and asphyxia in combination with intracerebral bleeding in a pre-term baby. One neonate developed convulsions on the third day postpartum and subsequently died; a complete absence of the corpus callosum was noted on autopsy. A further neonate required intermittent oxygen during the first two days, and was later treated for bilateral cataracts. Finally, a mild hypoparathyroidism was seen in a neonate who additionally suffered from stomatitis and neonatal ophthalmia. (sorry about the gritty details; these things *do* happen)

The early post-natal development of the babies appears to be unremarkable, except for respiratory distress in those infants who are either premature or of low birthweight. A 6% incidence of congenital abnormalities has been noted in these children, which does not differ statistically from the general population. There was no consistent pattern of congenital abnormalities observed. With the exception of one child with slight growth retardation, and another with delayed speech development, all children of transplant recipients have apparently shown normal physical and psychic development.

It has been shown that hypertension, preeclampsia, impaired renal function, infections, fetal growth retardation and premature labor occur at a higher incidence in pregnant patients receiving conventional immunosuppressive therapy after organ transplantation than in normal pregnant women (Penn, et al; Rudolph, et al; McDowell, et al). Babies born to organ transplant recipients often suffer from asphyxia, physiological jaundice, disseminated intravascular coagulation, thrombocytopenia, intracerebral hemorrhage, hypoglycemia and necrotizing enterocolitis, all of which are well-known complications of pre-term delivery (Glasgow, L.A. and Overall, J.C.). Despite the large amount of data which has been amassed, the information on pregnancy in patients treated with cyclosporine for autoimmune disease is too limited to allow the derivation of valid conclusions which may be applied universally.

It is likely that the congenital malformations reported were coincidental events, and not related to cyclosporine therapy, as the majority of babies who were exposed to cyclosporine throughout pregnancy did not show any birth defects and the malformations did not reveal a common pattern. Facial changes have recently been associated with the use of cyclosporine in prepubertal children with renal transplants (Reznik, et al). However, these findings have not been confirmed by other centers and it appears that the changes may have reflected the natural development of facial growth. For children exposed in utero to cyclosporine such an effect has not been described.

Conventional immunosuppressive agents used in transplantation such as azathioprine or steroids can induce birth defects in animals (Oethens, et al). In man, however, there is no established evidence that malformations occur in patients with these two drugs (Rudolph, et al; Rifle G. and Traeger, J.; Henderson, et al). According to animal studies cyclosporine has no teratogenic potential (Ryffel, B.). The results of this survey show that this drug does not induce birth defects. Although the drug crosses the placental barrier there is no evidence of a direct hazard to the fetus. However there is an increased incidence of complications in mothers and babies which apparently results from organ transplantation. Therefore, female transplant recipients wishing to conceive should be informed of these risks.

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2. How does blood type matching work?
A More Technical Explanation of ABO Organ Matching
In the case of liver, heart and lung transplants no 'matching' is done except for blood group (O,A,B,AB) and organ size. An O organ can be used in an O, A, B, or AB patient, whereas, an O patient can only receive an O organ. The reason it works this way is because cells have proteins for the blood group on their surface such that:

AB patients have both A and B proteins
A patients have A but not B protein
B patients have B but not A
O patients have neither protein.
If a patient lacks particular proteins, they develop antibodies to the ones they are lacking (the reason for this is unclear):

AB patients develop no antibodies
A patients develop antibodies against B
B patients develop antibodies against A
O patients develop antibodies against A and B proteins.
Now in practice, if a patient has a transplant with an organ that has proteins on it (say an A organ that has A proteins on it) and that patient already has antibodies against that protein (say a B patient that naturally has antibodies against A proteins) the organ will fail very quickly (within minutes). So if the B patient gets transplanted with an A kidney, it will not function and be promptly rejected (by antibodies against B protein). This makes O a universal donor and AB a universal recipient.

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.

Finally, what I have just explained does not seem to make much of a difference in the case of liver transplants; the reason for this is unclear. In other words 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. We still use 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.

Our blood type is determined by the genes we inherit from our parents. See ABO genetics for a technical explanation of how this works.

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3. What is CMV?
CMV is short for Cyto-Megalo-Virus. It is a member of the herpes virus family. This family of viruses also includes:

• herpes simplex (causes cold sores on the mouth and venereal disease)
• varicella-zoster (cause of chicken pox and shingles)
• Epstein-Barr (cause of mononucleosis and lymphoproliferative disease)

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4. What is a virus?
A virus is a type of organism that can only live and reproduce by infecting cells of a host. This is different from a bacterium or fungus that can live and reproduce in a broth of nutrients. The virus infects cells by binding to their surface causing the virus to be taken inside the cell. The virus then comes out of its shell and takes over the metabolism of the cell causing the cell to make more viruses rather than doing whatever the cell is supposed to do.

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5. Why does a virus make us sick?
There are several reasons why a virus can make us sick.

• The infected cell may die as a result of producing so many virus particles instead of doing whatever function it was supposed to do. This causes the cell to burst open and allows the newly generated virus particles to infect other cells. When the cells burst open, chemicals are released that make us feel sick.
• When the virus takes over the cell it causes the cell to make new (viral) proteins, some of which are taken to the cell surface. Immune cells constantly inspect the body for the presence of these viral proteins, and if they are found the cell is killed and again it bursts open releasing chemicals that make us sick. The more infected cells there are, the sicker we become.
• Finally, when the immune system determines that a large number of infected cells exist, many immune cells are called to the infected organ. Theses cells release chemicals called "cytokines" that make us feel sick. For example, when one gets a fever due to a virus it is caused not by the virus, but by the immune cells responding to the virus.

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6. Why are viruses such a problem for transplant patients?
Viruses are common following organ transplants because modern immunosuppression impairs the ability to recognize and eliminate viruses. Organ transplants are very similar to a virally infected cell in that they are a normal human cell that has unusual proteins on the surface. These proteins are called major histo-compatibility (MHC) antigens in the case of an organ transplant and viral proteins in the case of a virally infected cell. Bacteria and fungi, on the other hand, are completely different and the body responds to these sorts of infections differently than it responds to viral infections. The body fights off viral infections in a way very similar to the way it "rejects" organ transplants. Therefore, since modern immunosuppression is aimed specifically at the immune responses against transplanted organs, the immune responses against viruses are impaired as well.

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7. What organs are infected by CMV?
CMV can infect almost any organ and cause almost any type of infection. Organs infected by CMV include:

• CMV nephritis (CMV kidney infection)
• CMV hepatitis (CMV liver infection)
• CMV myocarditis (CMV heart infection)
• CMV pneumonitis (CMV lung infection, also called CMV pneumonia)
• CMV retinitis (CMV eye infection)
• CMV gastritis (CMV stomach infection)
• CMV colitis (CMV colon infection)
• CMV encephalitis (CMV infection of the brain)

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8. What is CMV viremia?
CMV viremia is CMV circulating in the blood. CMV viremia is determined by special blood cultures for CMV virus.
What are the symptoms of CMV? Since CMV can infect almost any organ, it can cause almost any symptom. Characteristically it causes fever, low white blood cell counts (leukopenia), and malaise. The symptoms can vary from mild to severe. CMV hepatitis in a liver transplant recipient can cause elevations in liver enzyme levels that may be confused with rejection of a liver transplant. Similarly CMV nephritis in a kidney transplant recipient may cause elevated creatinine levels that may be confused with kidney transplant rejection. CMV pneumonitis may cause cough and shortness of breath. CMV gastritis and colitis may cause blood in the stools, nausea, vomiting, and diarrhea. CMV encephalitis may cause seizures, headaches, confusion, and coma.

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8. How is CMV diagnosed?
The diagnosis of CMV may be very, very difficult to make. Generally the history of the patient's transplant and illness must be considered together with all laboratory studies and tests. The real difficulty comes because a latent infection is not a problem, while an active infection (called CMV disease) is a problem. The symptoms are so broad and general that CMV can easily be mistaken for another problem. The tests for CMV are not very good because many times patients can have severe CMV infections yet the tests for CMV are not positive. Also, CMV virus grows very slowly in culture and often weeks are necessary before the test will indicate the presence of CMV in the culture. Probably the best evidence for CMV is evidence of CMV in the blood stream (CMV viremia), or on biopsy of an infected organ (inclusion bodies). However, even these tests are fallible. Because CMV is so difficult to diagnose, it is necessary to that physicians caring for transplant patients keep a keen eye out for symptoms that may represent CMV infection and to repeat tests as necessary to detect CMV when it is present.
Possible tests for CMV:

• CMV blood culture (called a "buffy coat" culture)
• CMV urine culture
• CMV sputum cultures
• CMV shell vial (a method of determining the presence of CMV antigens)
• CMV IgM antibody titers
• Biopsies of organs likely to be infected with CMV

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9. Is CMV serious?
CMV is variable. It can be deadly serious, or it may be very mild. It may cause a person to miserable for weeks, it may cause severe symptoms for only a few days, and it may cause very minimal symptoms at all.

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10. How do I know if I have had CMV or not?
A blood test called a CMV IgG titer indicates whether a person has ever been infected with CMV and developed an antibody to it. Once a person was infected with CMV, they will always be "CMV positive". If a person has never been infected with CMV they are called "CMV negative". CMV varies by region of the country; in some regions greater than 50% of adults are CMV positive adults. How did I get CMV?
CMV is transmitted by contact between mucous membranes (the mouth and the genitals) and live virus. Live virus is present in the secretions of infected CMV patients. Patients with normal immune systems experience a "flu-like" illness of fever, malaise, and cough.

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11. Can I get CMV again?
Absolutley. Once infected with CMV, the virus remains latent and therefore can cause infection again in the future. The mechanisms of getting CMV are:

• Primary infection: this occurs if a CMV negative patients receives a CMV positive organ or is transfused with CMV positive blood. Depending on the organ transplanted and the immunosuppression used, roughly 60-80% of CMV negative patients will get CMV disease if they receive a CMV positive organ and no other treatment.
• Reactivation: this occurs if a CMV positive patient receives a CMV negative organ, or a CMV positive organ. The latent CMV infection the person had before the transplant can become active again and cause disease.
• Superinfection: this occurs when a person that has had CMV infection in the past and receives a different serotype of CMV in the form of a CMV positive organ transplant or transfusion. The latent virus of donor type CMV can then activate and cause CMV disease in the recipient.
  

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12. If it is known that CMV positive organs give CMV disease to CMV negative people, why is this type of transplant performed?
CMV negative donors are usually the much fewer in number than CMV positive donors. For this reason, CMV negative persons might have to wait several times as long to get an organ. The decision to transplant positive organs into negaitve recipients is made by the transplant center in order to avoid inordinately long waits for organs among CMV negative recipients.

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13.How is CMV treated?
The most common treatment for CMV infection is ganciclovir, an anti-viral drug. Although clinical improvement generally occurs, ganciclovir is not able to kill virus in the same way that some antibiotics are able to kill bacteria. An alternative drug is called foscarnet. Acyclovir is an anti-viral drug that is most active against herpes simplex infections. It has some activity against CMV, but ganciclovir is usually considered to be a better choice. However, ganciclovir can only be give intravenously while acyclovir can be given orally.

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14.What makes CMV disease more likely?
As explained above, the most likely circumstance of getting CMV infection is a CMV negative patient that gets a CMV positive organ. Immunosuppression also may make CMV disease more likely, especially antibodies like OKT3 and ATGAM. CellCept may also have some tendancy towards reactivating CMV infection. Can CMV be prevented? Many efforts have been made to try and limit the number of patients that get CMV disease. Many transplant centers now use some sort of treatment at the time of transplant to prevent future CMV infection including ganciclovir, acyclovir, and passive immunity. Passive immunity is the administration of antibodies pooled from the blood of healthy patients. Some studies have shown that these treatments may make the chance of developing CMV lower in some circumstances. Differrent transplant centers have different protocols dealing with CMV because each center is faced with a different incidence of CMV, and they each use different amounts and types of immunosuppression. Also, the CMV problem is different for the different organs transplanted: lung, heart, kidney, pancreas, and liver. Therefore what works well for one center may not work well for another center. No strategies is yet able to prevent all CMV disease. Can CMV be prevented by a vaccine?

CMV vaccines have been studied extensively but have not yet been conclusively shown to be worthwhile.

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15. Is CMV associated with other problems besides the viral disease?
Yes, scientists have proposed that CMV may be involved with precipitating rejection and with causing coronary artery disease in heart transplant patients. CMV infection can also be immunosuppressive, therefore predisposing to other simultaneous infections.

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16. What is Tissue Typing (HLA Typing)?
Each of us has several genetic markers located on the surface of most of our white cells. One particular group of genetic markers is called HLA or Human Leukocyte Antigens (leukocyte refers to white cell, and antigen refers to genetic marker). Tissue Typing is the name given to the test which identifies an individual's HLA. This information is critical before a patient receives a donor organ.

Since everyone inherits these Human Leukocyte Antigens from their parents, it is possible to distinguish which set of HLA's were inherited from one's father and likewise from one's mother (if tissue typing is performed on both parents). For example, suppose your HLA is the following 1,8,10/2,7,11, (each number represents a separate inherited antigen). The antigens are inherited as a group, from each parent. Each set of antigens is called a haplotype. Keeping in mind that you must inherit one haplotype from each parent.

To learn more about HLA typing, please check HLA Matching, Antibodies, and You (at the Michigan Transplant site)

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17. Why Can't Prednisone Be Discontinued Suddenly?
Prednisone is a synthetic steroid hormone. It cannot be stopped abruptly because the adrenal gland, which makes natural steroid hormones for the body, is suppressed by long term prednisone administration. Since some steroids are necessary for life, abruptly stopping prednisone leaves one without any steroids at all, a condition known as Addisonian crisis. Given time, if the adrenal is stimulated to produce steroids by gradual reduction in the dosage of prednisone, it will eventually begin to wake up and produce natural steroids in most cases. It is thought that if one becomes ill, more steroids are needed since the natural response to stress (like trauma, an operation, an infection, etc) is for the adrenal gland to pour out steroids. Until one's adrenal gland is up to par though, this is not possible. So anyone on steroids or recently weaned off steroids needs to be aware of this. We give all our patients "Medic Alert" bracelets that state they are a transplant patient and have been on steroid supplements. I recommend all transplant patients have one.

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18.What is chronic rejection? What is being done about it?
There are three general forms of rejection: hyperacute, acute, and chronic. "Hyperacute" rejection occurs within minutes of transplantation due to antibodies in the organ recipients blood stream that react with the new organ and result in organ failure within the first hours after transplantation. The kidney and heart are most susceptible to this problem, the liver is relatively resistant. Hyperacute rejection has not been sufficiently studied in pancreas or lung transplantation. Cross matches are done between a particular kidney and a potential recipient of that kidney to decrease the likelihood that hyperacute rejection will occur. "Acute" rejection generally occurs in the first 6 to 12 months after transplantation. Lymphocytes from the thymus (t-cells) are blamed for causing acute rejection. For most organs, the only way to show unequivocally that rejection is occurring is by biopsy of that organ. For practical reason, however, biopsies are not always done when acute rejection is suspected. In some circumstances treatment for rejection is begun and a biopsy is performed at a later date if the organ doesn't seem to be improving. This strategy varies from organ to organ and transplant center to transplant center. The diagnosis and treatment of acute rejection can be extremely difficult at times.

Chronic rejection is less well defined than either hyperacute or acute rejection. It is probably caused by multiple factors: antibodies as well as lymphocytes. The definitive diagnosis of chronic rejection is again generally made by biopsy of the organ in question. The heart is an exception to this generalization: chronic rejection in heart grafts is felt to be manifest by accelerated graft atherosclerosis. In other words, the transplanted heart rapidly develops "hardening of the arteries". Kidneys with chronic rejection have fibrosis (scarring) and damage to the microscopic blood vessels in the substance of the kidney. Livers with chronic rejection have a decreased number of bile ducts on biopsy. This is referred to as the "vanishing bile duct syndrome". Transplanted lungs with chronic rejection are said to have "bronchiolitis obilterans" a scarring problem in the substance of the lung.

To date, most research has focused on graft survival for the first three years. It is not that we, the physicians involved with transplantation, don't care about long term results. The long term problem is simply tough to tackle. Animal models exist but they do not perfectly reflect what goes on in humans. Most studies on people that look at long term outcome are not well "controlled", so their conclusions are nebulous. To be "controlled" a study needs to have two groups of patients, one that received a particular treatment and one that didn't. The best kind of controlled study is prospective and randomized, meaning the decision as to which treatment the patient has is decided before the treatment begins in a random fashion. This eliminates many biases that otherwise appear. Theses studies take very long time periods, are extremely difficult and labor intensive and require large numbers of patients to look at long term results. More typically, studies use "historical controls" meaning that one group, say patients transplanted from 1987 to 1990 is compared to another group of patients transplanted at a different time point, like 1984 to 1986. The problem with such studies is that so many things changed between the two groups. Techniques change: better perfusion solutions for the organs, quicker, more accurate methods of measuring blood levels of cyclosporine ("Sandimmune"). New agents, like FK506 (tacrolimus or "Prograf") are introduced and other agents are removed from the market. Understanding of common infections in transplant patients improves; this improves overall results even though the improvement wasn't exactly related to what immunosuppression they received. The studies therefore get muddled over the years. To look at ten year results today we have to look at transplants that were done in 1985 when techniques were significantly different in many ways from the way we do things now. So the bottom line is that much of what we do today is not firmly based on actual evidence that it is the one best treatment. This explains why different transplant centers do different things: their particular experience has been biased by the particular patient population.