Transplantation: A Primer for Patients and Families
Susan B. Conley, M.D., Chief, Section of Nephrology
This primer is a compendium of "talks" I wrote on-line to the parents of Nephkids, a email support group on the internet for parents of children with significant kidney disease.
Finally: I have been saying that I would discuss what is new in transplant for a long time, so here goes!
I have been very interested in transplantation since my fellowship back in the mid 70's. At that time only about 50% of the transplants that we did worked and most patients had rejection episodes. Transplantation remains a major area of research, both clinical research and basic research in the laboratory. At present, more than 90% of kidneys transplanted from living donors will be working well at one year post-transplant, and over 80% of those from cadaveric donors will be working well. The kidney that is doing well after a year has an excellent chance of working well for many, many years. How many? I can't tell you, since continuous progress means that we do not have long-term statistics that apply to the current technology. By Far, the most common reason for loss of the kidney after the first year is noncompliance with the medical regiment meaning: 1)missing doses of medication, which can happen without the patient even realizing it's happening, or 2) not monitoring one's health. I think that especially in the pediatric patient that frequent blood draws. arc the best way to keep a handle on what is happening.
Let me talk a little more about noncompliance before I go on. Anyone can be noncompliant-it has nothing to do with how good a kid or person one is, rather it has to do with being human. The only way to be sure that a dose of medication was taken is to have a system. I think that the best system is to lay it out ahead of time-then if it is gone from the container it was taken, and if it is there it needs to be taken. I personally have taken multiple medications for many years, and I have one of those week-at-a-time medicine boxes, because it is the only way that I can stay compliant. To make This problem more complex, even the best of
Kids can decide to be difficult when it comes to taking meds, and sometimes they do it in a passive aggressive manner and hide their noncompliance. Parents who have told me that their children are cooperative and always take their meds have later sheepishly told me that they've found pills under the mattress, once in the telephone book-all over the place, when the parents had thought that the child had swallowed the pills. Why do they do this? --They are kids; they need no other reason. This kind of behavior does not correlate with intelligence or with how obedient the child seems to be. Be alert to it! Then there are teenagers, who nor infrequently decide that the kidney was meant to be theirs, so stop the meds on purpose. It may seem to work for a while not to take their medications, but it eventually is trouble. It is difficult to deal with keeping track of whether a teen takes the meds. They have to be given some autonomy, and you can't watch their every move-so how do you monitor? My best suggestion is monthly blood draws with drug levels - cyclosporine or tacrolimus (Prograf, FK) levels, I mean, and prayers that if noncompliance occurs that you'll catch it soon enough. Of course, the other key is good communication with your teen and frequent discussion of the importance or taking care of the kidney.
This discussion may seem like a digression from the original topic, but noncompliance has become one of our biggest research challenges in transplantation, since it is the most frequent cause of loss of the long- term graft. About a year ago there was an entire weekend conference on noncompliance in the transplant patient which brought together patients, families and health professionals.
There are other ways to be noncompliant with one's prescribed care than just not taking medications. One young man whom I recently treated lost his kidney in significant part because he did not urinate frequently. He has a bladder that was damaged by the presence of posterior urethra valves, a common defect in boys with kidney failure, and as a result does not have normal bladder sensation. He cannot count on the sensation that his bladder is full to tell him that he needs to void, but has to void by the clock, otherwise his bladder fills and puts back pressure on the kidney by backing the urine up, resulting in damage to the kidney.
This beings up another area of active thought and investigation regarding the transplant patient - how to use the abnormal bladder for transplantation. The most common birth defect of the urinary tract in boys is posterior urethral valves, and an abnormal bladder usually results. Rehabilitating this abnormal bladder for use with a transplant kidney is an area where we are learning rapidly. There is also controversy on what is best still-and different approaches to these problems. This topic alone could be a book, so I won't say more here, but I want you to be aware that we are learning a lot about this are of using defective bladders for transplantation. In the past, some children with abnormal bladders have been felt not to be transplant candidates, but now something can be done for most all of such children.
Renal transplantation, as well as heart, liver, lung, small bowel, and bone marrow transplantation, has gotten to be quite successful. Kidney transplants were the first solid organ transplants and are the most successful without too much change in success over the past few years, but the change is enormous over the past 30 years. The first transplant done was done in the 1950's and was identical twin to identical twin-and it worked without immunosuppression. Identical twins are really clones of each other and so an identical twin is the ideal donor. Transplant using other donors was first done in the 1960's with initial success rates of <50% at one year post-transplant. Initially only Imuran (azathioprine) and prednisone were used as immunosuppression. The Medicare law was passed in 1972 and went into effect in 1973, legitimizing renal transplantation and making it more universally available by paying for the transplant for the majority of patients in the United States.
Cyclosporine was discovered in the 1970's and was first used in Europe, then began to be used in adults experimentally in this country in 1980, and we used it on the first child in the US in Houston in 1981. It was released on the market a couple of years later. Cyclosporine greatly improved success rates. The steps since then have been important but of much less magnitude. Cyclosporine is a tricky drug to use, and so it has taken a long time to learn how to use it, and we are still learning. Neoral, which is a microemulsion form of cyclosporine, has made it somewhat easier to use, since absorption fr6m intestine to blood is better and more predictable with Neoral. Sandoz, now called Novartis, who make cyclosporine in both forms, the old form which is trade name Sandimune and the microemulsion form, Neoral, has considered pulling Sandimmune off the market at some point, leaving only Neoral, which should be fine.
There are three types of potential renal donors - living related, living unrelated and cadaver. Success rates are best with living related, next best with living unrelated and least with cadaver donors. Why are living unrelated better than cadaveric donors? Because the kidney from a living donor is optimally handled-the donor is healthy and not dying, so blood pressure is good and stable until the kidney is removed, and the time from removal of the kidney to placement in the recipient is short. This makes for less damage to the transplant kidney from any time of low oxygen and nutrients to the kidney. This shorter ischemic time (ischemic means without blood flow) also is important in setting the kidney up to be rejected. Isehemia (lack of blood flow and oxygen and nutrients) damages kidney cells-and in doing so releases proteins that turn on the recipient's immune system to mount a stronger rejection response. As soon as the blood vessels to the donor kidney are clamped off by the surgeon, a cold towel is wrapped around the kidney to start cooling it down, and it is kept cool until blood flow to it is re-established in the recipient-so while it is being sewn into the recipient, an attempt is made to still keep it cool. This time without blood flow is critical as I explained above. There are two types of ischemia time- warm ischemia time, which means time without blood flow to the kidney that the kidney is not cool, and cold ischemia time. Warm ischemia time is what you want to be very short~ couple of minutes all together. Cold ischemia time is much, much better tolerated. Cold ischemia time of up to 12 hours is like nothing much happened to the kidney, of up to 24 hours is not bad, and it goes downhill from there, with occasional kidneys being transplanted with up to 72 hours of cold ischemia time. So living donor kidneys have the best chance. Kidneys from an identical twin have close to 100% success, with failure only coming from technical, surgical problems which are not very many these days unless the bladder is abnormal. Living related donor kidneys have a greater than 90% chance of success atone year and cadaver kidneys a >80% chance atone year. Down the line at 5 and 10 years the gap between living related and cadaver kidneys gets wider, with a 60+% chance of a living related kidney working at 10 years and <40% chance for a cadaver kidney. Statistics that I have just seen from UNOS (the United Network for Organ Sharing, in charge of distributing organs) show that the survival of a living unrelated kidney at 5 years is about 70%. If you take noncompliance out of the way-if patients were totally compliant with taking medications and getting check-ups, the statistics at 10 years would be much better, especially for the living donor grafts (kidneys). The success rates for living unrelated kidneys are close to those of living related kidneys.
With time and the development of better drugs to prevent rejection, matching, except in the case of an excellent match, seems to make less difference in success. There must be compatibility of the major blood group proteins, but matching of the tissue proteins (HLA antigens) becomes less important (less important but not altogether unimportant). Although major blood group compatibility is necessary, the Rh status does not matter for transplantation. Blood group 0 is the universal donor. Blood group AR is the universal recipient.
Let me explain blood group compatibility. You have the potential to get one blood group protein from each parent. The two proteins are A and B. From each parent you can get one or neither of the proteins, A and B. You are type 0 if you get neither, type A if you got A from both parents or get A from one and nothing from the other, type B if you got B from both parents, or B from one and nothing from the other, AIB if one gave you A and the other gave you B and 0 if neither one gave you anything. If you are type A then you have antibodies in your blood to type B and vice versa. If you are type 0, you have antibodies to type A and B both. The blood-type proteins A and B are also on the kidney cells if they are in your blood. So, if you put a kidney of type A into someone of type 0, the kidney gets attacked by the antibodies to type A. But you can put an 0 kidney into someone of type A because the kidney has no blood type proteins on its cells to be attacked. In that case, the antibodies to type B that the person with blood type A has (remember if you don't have that type protein, then you have that type antibodies) don't have any proteins on the kidney to attack.
The reason that matching of the tissue proteins, the ULA antigens, seems to make less difference in success is that we have better drugs now than every to calm the immune system and keep the kidney from being attacked. This attack of the new kidney by the recipient's immune system is called rejection.
As we get more and more successful in doing kidney transplantation, more people are candidates to receive a transplanted kidney. We used to consider small children and older people to be poor candidates for transplantation, but that is no longer the case. The waiting list for kidneys, and every organ, gets longer every year, and about 40,000 people are waiting for a kidney now in this country. In 1998, there were about 5800 people who died in the United States and donated organs. That means that there were potentially 11,600 kidneys, of which most but not all could be used; some were affected by disease or trauma. An adult generally waits for three or more years on the list before getting a kidney. Children get some priority, and don't have to wait as long as adults, as they automatically get credited with extra waiting time, as if they had been waiting longer, with the younger children getting the most priority, and the older teens being treated as adults. There are some special circumstances also which can give one a higher priority. The system is run by UNOS, the United Network for Organ Sharing, based in Richmond, Virginia. UNOS is supported by the government but is a private nonprofit agency, run by ordinary people and health care providers. Much effort is donated to the agency by interested volunteers to oversee its activities and make transplant organ
Distribution is as fair and safe as possible. I do personally believe that it is both. The big problem is that there just aren't enough organs. We in the kidney arena are lucky, because the kidney is a paired organ, living donation is possible, and because we have dialysis to sustain life until transplantation can be done. The number of cadaver donors is increasing 5-6% from year to year at present but the waiting lists for all the organs are increasing much faster. The best donor is one who dies an accidental death and becomes brain dead so that the organs can be removed while the heart is beating. Non-heart-beating donors are beginning to be used a little as a source of kidneys, but there is not as good a success rate because of a longer warm ischemia time. Though we are doing a better job of educating the public that donation is a good thing, education about accidents and safer cars and seatbelts, etc make for fewer people who die because of brain death. So we are going to need to do more living donor transplants if all who need kidneys are going to get them-which makes sense since they do better anyway. Too bad that the donor has to go through pain! My experience is that it is a rare parent who doesn't want to donate to a child. But some children don't have donors because parents aren't a blood group match (yes, it is possible for both parents to be blood group incompatible) or because parents aren't healthy enough to be a donor.
The donor must be 100% healthy for the surgery and must have a healthy kidney to keep and a healthy kidney to give away. The donor must not be at risk of developing kidney disease him or herself, meaning that he or she must not have anything like hypertension or diabetes which could affect the kidneys we don't want to risk the donor, left with only one kidney, getting kidney disease so that he/she finds him/herself in the position where it might have been better to have two kidneys. As long as the donor is healthy, and every center screens donors thoroughly, then the risk to the donor is very, very low. The risk of a major problem with anesthesia for a healthy person is less than I in 40,000. Life insurance companies do not change rates because one has only one kidney, as long as the one kidney is healthy. Their statistics show that life expectancy is the same if you have one or two kidneys. The donor can have children after donation. The question that comes up to me most often from parents if we find a health problem or find something wrong with one kidney for example a stone in one kidney-is, can't I choose to donate anyway and give my best kidney to my child? And the answer is no; we won't put a donor at risk. I remind parents that sick children need healthy parents who will always be there for them. And I ask if there are any other relatives who might want to donate - or godparents or very close friends. I personally think that living unrelated donation is quite reasonable-and is going to be the most tenable solution to the donor shortage In the programs where I have been Medical Director of Kidney Transplantation, we have considered living unrelated donors, who had a true strong tie to the child and were volunteering completely altruistically, as far as we could tell.
The donor surgery is usually 3-4 hours long if done traditionally with a flank (around the side just above the waist) incision. Now a few centers are starting to remove the kidney laparoscopically - there is still a little incision through which to pull the kidney out, and then a couple of more little incisions for the scope, but this method makes it all easier, with less incision to heal. The donor who has traditional surgery usually stays in the hospital 5-6 days. If the donor has a quietjob, return to work maybe feasible in 34 weeks, but ifthe donor is a hard laborer, then it may be necessary to stay out of work 2 or more months. There is pain, particularly in the first couple of days after surgery, but there are also good anti-pain meds and a machine called a patient-controlled analgesia pump. This little pump is hooked into the IV, and when the patient pushes the button for the machine (the button is on a string, and the patient can hold it continuously in his/her hand even) the patient gets a dose of pain med. This means that there is no waiting for the nurse to come and then go get it-the theory is that if you take a dose of pain meds as the pain staffs, then it can never build up and it is easier to control. The machine will only give you so much medicine in any given time period, so that you can't get too much and get into trouble. Most patients don't take as much medicine as they are allowed. These machines are pretty standard these days, so that you will be able to have one if you are a donor. The recipient can have one too, as long as he/she is old enough to use it.
The usual child or teen post transplant does almost all of the things that anyone else does. Perhaps telling you about a few people who have transplant kidneys will make the point best! We can invite some ofthem to speak to the group. I don't have an email address for all of them, but those for whom I do I will send a message and ask them to reply to the group. I am using their names because I know them well enough to feel that that presents no problem. Frank Germanero is a man whom I would guess is in his 40's and has had a cadaver transplant since he was an adolescent, I know for longer than 20 years, and I think for longer than 25 years. lie is very advice in the National Kidney Foundation and has been President of the Wisconsin affiliate and nationally has been on multiple committees including the national executive committee. Frank has 74 or S children and is an elementary school principal. He has had kidney disease since he was very young. Stephen Willis is a student at the University of California at Davis. He is determined to be a pediatric nephrologist, and I believe that he will succeed. He now has his second kidney. He received it in July, 1996. Peter Lundin, M.D. is about 50 years old. He developed kidney failure while in college from glomerulonephritis, went onto hemodialysis, and was on home hemodialysis for many years, through the rest of college, medical school, residency, fellowship and for years as a practicing adult nephrologist. After many years on dialysis he decided to be transplanted. Through his many years of kidney disease, he has continued to practice nephrology and is on the faculty of one of the New York City medical schools. William Litchfield is in his 50's and is an engineer. Bill was on home hemodialysis for many years and he set up his dialysis machine and dialyzed on the floor of the Senate to convince Congress to pass the Medicare law covering renal failure. He is an engineer and an executive, and has since had a transplant. A few years ago, he spent two years living in Singapore as a consultant. If you ran into any of these people on the street, you would have no idea that they had ever had any serious health problems. So, the message is that life can be good and worthwhile and goals can be accomplished in spite of the need for dialysis and transplant. Attitude plays a major role.
As parents, you need to be sure to have goals and aspirations for your child with kidney disease the same as you do for your other children. Yes, they need empathy, and sometimes even sympathy, but they also need to know that you know that they can handle it all. When they are feeling too badly to do schoolwork or go to school, you need to allow them to rest, but when they are better, you need to discuss a plan to catch up or at least resume. Your child with a transplant will always need to take medications, probably multiple pills a day, but the chances are that by six months or so post-transplant that those pills will be taken in two doses a day, which is quite manageable. Your child with a transplant will always need checkups and regular blood tests. The routine for my patients who are stable and out a year or more from transplant is to have blood drawn once a month and be seen every 1-2 months, depending on the situation. The blood can be drawn at a lab that is open on the weekend. Most children and adolescents are now In the hospital only 1-1 ˝ weeks post-transplant and are only out ofschool 1-2 months. Most ofthat 1-2 months schoolwork is possible, so that he/she doesn't need to fall behind in school. We use much less prednisone than we used to and the Cushingoid side effects (fat face and abdomen) are not that much of a problem for most kids. Cyclosporine does promote hair growth and "Brooke Shields" eyebrows, but there are ways to handle that if it is objectionable. Readmissions to the hospital are infrequent the great majority of children who receive a living related kidney never have a rejection episode. Rejection episodes, which are times when the immune system gets the upper hand and attacks the kidney, are more frequent in those who receive a cadaver donor kidney, but less than 50% of cadaver kidney recipients will have such an episode in the first year. Three new drugs that just came out in January, 1998 and are similar in their use and action, called Zenapax, Simulect and Thymoglobulin, have reduced the frequency of rejection episodes significantly. These drugs, which I will discuss later in this treatise, along with other advances in how we manage patients after transplantation, are reducing the amount of prednisone needed while at the same time improving results. So, puffing it all together, the child who needs or has a kidney transplant has a good future ahead, but that child will always need to pay attention to his/her health in order to stay healthy. He/she must Incorporate care of him/herself including the kidney into everyday life, but can lead a relatively normal life.
New drugs are coming down the pike almost every month in the transplant world now, which is wonderful because we are now able to individualize drug regimens to fit specific situations. We now routinely tailor regimens dependent on how strong immunosuppression ion we think is needed. Second transplant recipients who lost the first kidney to rejection need stronger anti-rejection drugs that those getting their first transplant. Those who are found to have more reactivity to the donor on pre-transplant treating need more immunosuppression than those who do not. The goal is to prevent rejection episodes. We now believe that acute rejection episodes tend to lead to chronic rejection; chronic rejection is slow but inexorable - can't be stopped, although we are learning ways to slow it down. Acute rejection episodes occurring in the first couple of months post transplant often can be reversed completely without squaelae, but not always. So immunosuppression is thought of in different phases. In the first days to weeks after transplant surgery, heavy duty drugs are used to prevent rejection. There are many ways to start out strongly to prevent the immune system from initially recognizing the kidney. Often at this stage intravenous (needle in the vein) drugs are used which are called induction agents, for example Zenapax, Simulect and Thymoglobulin, which are the newest, along with OKT3 and ATOAM (ATG), which have been used for years. These are all anti-lymphocyte antibody preparations-~-they contain antibodies against lymphocytes, which are the while blood cells that mediate the rejection response. Zenapax, Simulect, and Thymoglobulin have few side-effects, while OKT3 is also a good drug, but can cause violent illness, including fever, vomiting and diarrhea. ATOAM can also make kids sick in the same way OKT3 does, but usually not to the same degree. I think that over the next few years ATOAM and OKTS will go away and newer better similar drugs like Zenapax, Simulect and Thymoglobulin will come to the fore. They will get more and more specific such that they knock out the immune response against the kidney and leave the ability to fight infection intact.
There are many different protocols for suing antirejection medications during the week of the transplant and then as time goes on. Many of them involve the antilymphocyte drugs that I just discussed. Sometimes these are not used and IV cyclosporine is started right away and given until oral cyclosporine is taken and tolerated. Another option is to use FKSO6 (tacrolimus or Prograf) starting at the time of transplant. FK506 is easily absorbed by the intestines, so can be given orally soon after the surgery. Gradually as time goes on after transplantation, immunosuppression is switched over to a maintenance type of regimen. Many different regimens are used now. Some are stronger than others, they are tempered to the needs of the recipient. Current regimens include, but are not limited to:
-prednisone, Imuran (azathioprine) and Neoral
The approach now to the prevention of rejection on a chronic basis is to use two or more drugs which act each in a little different way, such that immunosuppression can be tailored to individual needs~ Also using multiple drugs means that lower doses can be used of each drug to minimize bad side effects There are a whole host of new maintenance drugs coming down the pike on top of the choices we already have now in drug regimens. According to NAPRTCS data, over 90% of children with transplants in the US and Canada are on prednisone and on cyclosporine, either as Sandimmune or Neoral. (?'4APRTCS is the North American Pediatric Renal Transplant Cooperative Study, which tracks >80% of the pediatric transplants done in the US and Canada, and has done so since January 1, ~987.) Most of these children are also on Cell Cept (mycophenolate mofetil, or MMF) or Imuran (azathioprine). Most of the children who are not on cyclosporine are on Prograf (tacrolimus or FK or FK506). Most children on Prograf are also on prednisone. Fewer children on Prograf than cyclosporine are on a third drug like Imuran or CellCept. The mainstay drugs for preventing rejection are cyclosporine and tacrolimus-and cyclosporine is more heavily used than tacrolimus. The other drugs are additional protection, but are not helpful to the same extent.
Cyclosporine revolutionized transplantation - improved the success of renal and heart transplantation tremendously and was an impetus to increasing the numbers of liver transplants done, and then after that the numbers of transplants of lung, small bowel, and multiple organ transplants. Most kids are now on Neoral, rather than the older form of cyclosporine, Sandimmune. Novartis (Sandoz) says that they are considering eventually stopping making Sandimmune, which would be ok. For most patients, Neoral is a better drug than is Sandimmune, although all of us have a few patients on Sandimmune who are doing great and don't want to rock their boats by changing them. Neoral is a microemulsion of cyclosporine and as such is absorbed better and more evenly from intestines into blood, which means that in the face of diarrhea blood levels of cyclosporine are better maintained. One problem we have had In the past is that if a child gets diarrhea, then cyclosporine is poorly absorbed from intestine into blood, blood levels go down, and rejection results. I have seen that scenario more times than I can count. It is most often a problem of little kids, who get diarrhea the most and more severely. Neoral makes this problem better, but there still can bean absorption problem with Neoral in the situation of diarrhea. Neoral is absorbed from intestine into blood better than is Sandimmune in most any situation. Dosing is based on blood level of the drug, so this means that the dose needed for Neoral is usually a little lower than for Sandimmune. Since the cost is the same for the two drugs, Neoral ends up being cheaper. This better absorption is especially important in the kids under 2 years old, who sometimes absorb either formulation less well than do older children and adults, and may need quite high doses relative to their size to get a good blood level. Once in a while no mater what you did with Sandimmune you couldn't get an adequate blood level for the first few weeks in a young child post transplant, and you ended up giving cyclosporine IV for a while; this happens far less with Neoral.
The side-effects of cyclosporine can be divided into the serious and the aggravating. The serious are: 1) nephrotoxoicity - i.e. toxicity to the kidney, 2) hypertension, S) susceptibility to infection, and 4) possible higher incidence of cancer. Let me explain them one at a time. Neplrr'otoxicity is our biggest bug-a-boo. It is universal with the drug, occurring in every transplant patient who takes it. Individual susceptibility plays a role, as do blood levels achieved-the more in the blood the more the kidney is affected. We follow "trough" blood levels, which are the levels in the blood right before a dose is given. These are helpful and give us a clue as to how much drug effect the patient is getting, but to really know, we need to do a kinetic profile, and look at the drug level every hour or two between doses and calculate an average blood level. Research is going onto fine a better way to monitor the drug. It looks as if level drawn just before and then one and six hours after a dose in kids taking it every 12 hours can be put into a formula to accurately estimate the average blood level throughout the 12 hour period. The reason that following drug levels is so important is that high levels that are too high cause significant nephrotoxicity while levels that dip too low can allow a rejection episode to start. Since absorption from intestines to blood is variable, one can't judge how much to give based solely on body size like we do with most drugs where we give so much per kilogram or pound of body weight.
Cyclosporine nephrotoxicity comes in two forms-acute and chronic. Acute is of fairly rapid onset and happens when absorption changes such that more is absorbed, or when the dose is raised too high. and the blood levels suddenly jump higher than the kidney likes. As time goes on in the first months after transplant, the intestines' absorption of the drug improves and so usually we keep lowering the dose over the first months to year. So, since absorption is improving in the months after transplant, blood levels periodically rise, resulting in acute nephrotoxicity. This means that kidney function acutely decreases. i.e. the serum creatinine level goes up. (We follow the level of the waste product creatinine in blood as ct marker of how well the kidney is filtering the blood.) Acute nephrotoxicity is completely reversible,' lower the dose and therefore the blood level, and the kidney function improves. Chronic nephrotoxicity occurs to some degree in almost everyone who takes the drug this is really scarring of the kidney and damage to the tubules of the kidney. The flibules are the part of the kidney that carry urine from the glomeruli (the filters) to the collecting system, from which the urine starts down the ureter. The tubules are the line tuning pain of the kidney. The filters are fairly nonselective in their filtration of the blood, letting many substances pass into the initial urine that the body needs reclaimed into blood~--the tubules al-c the reclaimers. The tubules reclaim the right amount of salt and water to keep salt and water balance. In advanced tubular disease urine output is high and lots of salt and water is lost in the urine. I personally think that most, but not all (speak with your nephrologist), patients on cyclosporine need to take in copious amounts of water and a fair amount of salt (sodium), since they all have some tubular dysfunction and lose extra salt and water in the urine.
The lower the dose of cyclosporine and the lower the resulting blood levels, the less will he [lie nephrotoxicity. When cyclosporine doses are well regulated, the chronic nephrotoxicity wiII on average sIightly damage the kidney, over many, many years, and I don't think that it is something that you should let cause too much worry. Before we had cyclosporine, the best transplant kidney's lasted ten year, and many for far fewer years. CycIo is our friend -with enemy potential, but the enemy can be kept at bay, with good folllow-up. One day we will replace it with a better drug---and in the case of most kids tratnsplanted in the cyclo era, it will be before cyclo has done too much dirty work. I think that the nephrotoxicity is more progressive in kids who are not well-hydrated, and that is why I think that kids on cyclo should take plenty of salt and fluid-by that I mean a normal amount of salt, not be restricted, and take a lot of fluid. Also, as the kidney is in the body longer, the lower the blood level of cyclosporine needed to keep rejection at bay. Much higher levels are needed initially post-transplant than are needed down the pike. By 6 months to a year post-transplant, the blood levels needed stabilize. Lowering the amount in blood lowers the severity of the chronic nephrotoxicity induced.
Hypertension is the second noxious side-effect that I listed. It occurs in 75-80% of patients on cyclo in the early post-transplant period, and at 6 months post-transplant 50-60% of pediatric patients taking cyclo are still on anti-hypertensive drugs. If properly treated, the hypertension should not have negative consequences. There is some evidence that the gingival hyperplasia (overgrowth of the gums) that cyclo can cause also is aggravated by one particular anti-hypertensive drug called nifedipine (Procardia or Adalat are the tradenames in the US) so I avoid that drug except for short-term use in patients on cyclo. In some patients with hypertension from cyclo some mild salt restriction may be indicated, but I think that it is not indicated in most-normal, not excessive salt intake is best - i.e. about 4 grams of sodium in a big kid per day. Too little salt intake in a patient taking cyclo can actually aggravate the hypertension. Cyclo cuts down the blood flow to the filters, the glomeruli, and it is there that renin is made, which is a hormone that regulates blood pressure. Salt restriction reduces blood volume which in turn reduces glomerular blood flow and so results in more renin production and higher BP. In addition to potentially aggravating the hypertension, the decreased blood flow to the kidney from the cyclo will aggravate the nephrotoxicity.
Regarding susceptibility to infection, cyclo works by suppressing IL-2 production. IL-2 is a protein that is instrumental in regulating the activity ofT-lymphocytes, the white blood cells that attack the kidney in rejection. These same cells are important in fighting infection, particularly certain types of infection, like infection caused by CMV and EBV viruses and by funguses. As we get better and better at regulation of cyclosporine dosing. coupled with the fact that we use much less prednisone after transplant than we used to use, infection becomes less and less of a problem. The risk of infection is greatest in the first weeks and months post-transplant. Personally, I only keep kids out of school for 4-6 weeks after transplantation now, since the risks are so much lower that they will come down with a serious infection than in the past. Unless it is the middle of a particularly bad season of flu or of RSV infection (a respiratory virus that can cause severe problems in young children), or if the child hasn't had chickenpox, if chickenpox is rampant, then I suggest that kids go back to school 4-5 weeks post-transplantation.
Regarding the long term risk of cancer - we don't know enough here yet, but certainly kids on long-term cyclo (years), depending on dose, have a higher risk of getting cancer. Having rejection episodes and having the amount of immunosuppression raised periodically increases the risk. This risk is not just from cyclo but from the overall amount of immunosuppression given-so amount and time are probably the crucial factors-plus a big input of individual susceptibility. The reasons that immunosupression increase cancer risk are not completely understood. We think that all of us periodically have a wild cell start to multiply rapidly and form a cancer and that our immune Systems sense those early cancer cells as foreign and destroy them. It therefore makes sense that the person on immunosuppression is more susceptible to cancer. The susceptibility to cancer correlates with the strength of the immunosupression and the length of time it is given. But I want to make it clear, when I talk about increased susceptibility, I don't mean that cancer is inevitable-I mean that the incidence is higher than in the general population, so patients and doctors need to be aware-patients need to bring new symptoms to the attention of their doctors, and the doctors need to consider their significance carefully. Most transplant recipients do not get cancer. A precancerous condition called lymphoproliferative disease occurs once in a while: diagnosed early enough and treated, it will respond to treatment in most cases. It is caused by the EBV virus.
Overall, given these potential problems from these necessary drugs, it all comes down to: the transplant recipient must be particularly aware of his/her health and body functions and report changes to the transplant team, in addition to getting regular check-ups and blood draws. I am cautious; I recommend that even my most stable patients have blood drawn every 4-6 weeks and be seer by their nephrologist every I - 3 months, depending on the patient.
Now, the aggravating side-effects of cyclosporine: hair, hair, hair, dose-related, rather blood level related-and also related to individual susceptibility. Cyclo encourages hair growth everywhere-head, face arms, legs, chest, back, and pubes. The kids with darker skin and hair grow more extra hair than the fairer kids-and the hair is blonder in the fair kids so doesn't show much, In my experience the Hispanic kids who have dark hair have the worst time. It can be removed by any means - depilatories, shaving, wax, but it can be a pain. Cyclo creates lots of Brooke Shields eyebrows. The other cosmetic side-effect, which most parents don't pick up themselves is that when cyclo is given to young children in the first few years of life it gives them a typical facial bone structure with prominent brows and cheekbones-not necessarily a problem, just predictable.
Tacrolimus (FK506, Prograf) is not much different from cyclo when it comes to nephrotoxicity and hypertension It is worse for causing lymphoproliferative disease and may be worse regarding other infections and cancer - unclear. It is sometimes better for kids with rejection that cyclo won't stop - we often use it preferentially in kids who are high-risk for rejection-who have strong immune systems and have already lost a kidney rapidly to rejection post-transplant. Prograf causes diabetes in 10-20% of those taking it-this one is bad news! --once in a while cyclo causes diabetes, but not nearly as often. We are getting better at using tacrolimus, with time some of its bad side-effects-lymphoproliferative disease and diabetes - are at least partially dose-related, and we are learning to use lower doses than were used when it first came out. One big attraction of tacrolimus over cyclo has been the lack of the extra hair growth, Some kids do have a very difficult time with this; it can't be minimized, but I have a hard time with instances where this seems to be the only reason a patient will want to switch from cyclo to Prograf There are usually ways to deal with the hair - and one has to keep in mind that in the case of teenagers every little blemish can be seen as a major problem and self-esteem can be heavily linked to perception of physical beauty. So, still in the US and Europe most centers use cyclosporine as their first choice mainstay anti-rejection drug, but tacrolimus has a place in some patients-initially or later on after transplant. A few centers use it in everyone, and that is ok-now with all of the drugs that we have, one will find more and more variation in drug protocols between centers and between patients in the same center. All of these drugs are fairly difficult to use-lots of individual variation between patients and different effects and side- effects to balance, so that one thing that is important is the experience of the individual center or doctor with the drug being used. It is impossible to have extensive experience with all of the drugs available. Each one has advantages and disadvantages5 so there are multiple ways to do things. ~ow a word to the parents of children with nephrotic syndrome who are on cyclo. The doses ofcyclo that we use in most children with nephrotic syndrome are lower than the doses we use in children with transplant kidneys - so the side- effects are less. Also, children with nephrotic syndrome are generally on it for up to a few years-not for a lifetime!! So, don't get too bent out of shape by the potential side-effects.
The world of transplant is very exciting and moving ahead rapidly!! There are multiple new drugs, and it is getting so that we can individualize drug regimens much more than ever before based on immune system function, match of the kidney, the recipient's original disease, past transplant history, etc, etc. Very exciting are the new anti-lymphocyte antibody preparations which act against IL-2 which is an immune protein active in the lymphocyte in the rejection process. As noted earlier, they are: Xenapax (daclizumab), Simulect basiliximab), and Thymoglobulin. They are mainly be used prophylactically to prevent rejection and antigen recognition early-first dose immediately pretransplant and then at intervals for varying durations of time. Preventing antigen recognition means keeping the recipient's immune system from recognizing the key proteins of the donor kidney as foreign-perhaps longAerm, notjust while the drug is in the body. They also allow us to use lower doses of other immunosuppressant drugs, such as prednisone, cyclosporine and tacrolimus, which cuts down the side-effects experienced by the patient in the first few months. Then there is rapamycin (nickname rapa), also now called sirolimus, and a related drug, currently known of as RAD, which will be used in conjunction with cyclosporine or tacrolimus, and will work synergistically-i.e. the two drugs together do better than one would expect if their good effects were just additive. Rapa (sirolimus) and RAD are currently being used experiementally in children and look very good. We will continue to develop new drugs and find better ways of combining them.
The bottom line is that I see for the future:
likely to happen and be one way to solve the donor shortage
To realize the best for your child, you need to be sure that the transplant is done in a center experienced in pediatric renal transplantation and where the transplant team is involved with the use of these new drugs and keeps up with all of this new stuff. In experienced hands, the chances are greater than 9OQt that receiving a kidney transplant will make the lives of the recipient and therefore his/her family better!'. Be careful also about listening to experiences of even as recently as 5 years ago and think that your experience will be the same -it won't- things are rapidly changing for the better. Remember, most patients arc out ofthe hospital within a week and a half, and they go back to school at 5-6 weeks after transplant without much in the way of restrictions, participating in physical education and all but the 'dangerous sports" like varsity football. They are on unrestricted diets. They take pills, probably quite a few, twice a day, once in a while three times a day. They need to weigh themselves, take their temperature and blood pressure once or twice a day. They are mildly Cushingoid (round steroid face) for a month or two, but the dose of prednisone is down to 2-3 mg (baby), 5 mg (5-lU year old), 7.5 rng girl. IC mg ( teen boy) a day by 3 months post-surgery' and these doses don't cause much side-effects. The kids have more energy and feel better than they did on dialysis or with advancing renal failure. Even those kids who thought that they felt fine prior to transplantation find that they feel better after it is done. For most recipients, it is truly a miracle!!