|Topics in Pediatric Kidney Disease
There are several choices in drug regimens today. According to NAPRTCS data, over 90% of children with transplants in the US and Canada are on prednisone and are on cyclosporine, either as Sandimmune or Neoral. (NAPRTCS is the North American Pediatric Renal Transplant Cooperative Study, which tracks 80% of the pediatric transplants done in the US and Canada.)
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 past the basic two. The mainstay drugs for preventing rejection are cyclosporine and tacrolimus--mainly cyclosporine. The other drugs are additional protection, but not helpful to the same extent. Cyclosporine revolutionized transplantation--improved the success of renal and heart transplantation completely and was an impetus to really going after liver transplantation and then after that lungs, small bowel, and multiple organ transplant.
Most kids are now on Neoral, rather than the older form of cyclosporine, Sandimmune. Novartis (Sandoz) says that they will eventually stop making Sandimmune, which is ok. There will be generic, but of course their hope is that most will convert to Neoral. It is a better drug, although all of us have a few patients on Sandimmune who are doing great and don't want to rock their boats. Neoral is a microemulsion of cyclosporine and is absorbed better and more evenly from intestines to blood, which means that with diarrhea the cyclosporine blood levels stay up better. One problem we have had in the past is that if a child gets diarrhea, then cyclosporine is poorly absorbed, blood levels go down, and rejection results. I have seen that scenario more times than I can count. It is mostly a pproblem in little kids who get diarrhea the most--and more severely. Neoral makes this problem better, but there still can be an absorption problem with Neoral in diarrhea.
Neoral is absorbed better than is Sandimmune, and so the dose is usually a little lower. Since the cost is the same, 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 for size to get a good blood level. Once in a while no matter what you did with Sandimmune you couldn't get an adequate 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 Neoral can be divided into the serious and the aggravating. The serious are:
Let me take them one at a time. Nephrotoxicity is our biggest bug-a-boo. It is universal with the drug. 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 on to fine a better way to monitor the drug. It looks as if one level drawn 6 hours after a dose in kids taking it every 12 hours will correlate well with the average blood level. We may end up converting to following that.
The reason that following drug levels is so important is that too high levels give nephrotoxicity and low levels can allow rejection. 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.
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 the dose is raised too high and the blood levels are 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,ie serum creatinine level goes up. Acute nephrotoxicity is completely reversible; lower the dose and therefore the blood level, and the kidney function will improve.
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 tubules carry urine from the glomeruli (the filters) to the collecting system, from which it goes down the ureter. The tubules are active parts of the kidneys, as the filters are fairly nonselective, and they put many substances into the initial urine that the body needs reclaimed into blood--the tubules are 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 cyclo (except nephrotics who are still nephrotic) need to take in copious amounts water and a fair amount of salt (sodium), since they all have some tubular dysfunction. The lower the dose and the blood levels, the less will be the nephrotoxicity. When cyclosporine doses are well regulated, the chronic nephrotoxicity will only very slowly damage the kidney, over many, many years, and I don't think that it is something that you should obsess over. Before cyclosporine, the good kidneys lasted ten years, and many for far fewer years. Cyclo is our friend--with enemy potential, but the enemy can be kept at bay with good followup. One day we will replace it with a better drug--and in the case of most kids transplanted 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.
Some of this recommendation is based on data that we gathered at Stanford when I was there, and which we are just now putting together and making public. 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.
Hypertention 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 post-transplant are still on anti-hypertensive drugs. It is tied up in the effect on the kidney of cyclo. All one can do is to treat it. 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 trade names 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--ie 4 grams of sodium in a big kid per day. 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 reduces glomerular blood flow and will result in more renin production and higher BP. In addition the decreased blood flow to the kidney from the decreased blood flow will aggravate the nephrotoxicity.
Regarding infection, cyclo suppresses IL-2 which is a protein that is instrumental in regulating the activity of T-lymphocytes, which are the type of white blood cell that attacks the kidney in rejection. These same cells are important in fighting infection, particularly certain types of infection, like CMV and EBV viruses and funguses. With current regulation of cyclosporine doses, and the fact that we use much less prednisone after transplant than we used to use, infection is becoming 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 transplant now, since the risks are so much lower that they will catch something than in the past--unless it is the middle of a particularly bad season of flu, RSV, or if the child hasn't had chickenpox, chickenpox.
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, are at a higher risk of 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 is somewhat more the stronger the immunosupression and the longer it is given.
But I want to make it clear, when I talk about increased susceptibility, I don't mean that it 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.
It all comes down to: the transplant recipient
must be particularly aware of his/her health and body functions--get regular check-ups and
Now, the aggravating side-effects: hair, hair, hair--dose-related--or rather blood level related--and also related to individual susceptibility. Cyclo encourages hair growth everywhere--head, face ,arms, legs, chest, back, 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 so much. In my experience the Hispanic kids who have dark hair have the worst time. It can be removed by any means--delapitories, shaving, wax, but it can be a pain. Cyclo creates lots of Brooke Shields look-a-likes. 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 hypertention. 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 and very shaky.
So, still in the US and Europe most centers use cyclosporine as their first choice mainstay antirejection 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 disadvantages, so there are multiple ways to do things.
Now a word to the parents of children with nephrotic syndrome who are on cyclo. The doses of cyclo 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.