PTLD - Post-Transplant Lymphoproliferative Disease

Now seems like a good time to say a little about PTLD, which stands for post-transplant lymphoproliferative disease. PTLD is caused by the EBV virus, and I think that it is useful to think of it as half way between mono (infectious mononucleosis) and cancer of the lymph nodes (lymphoma). Mono is a an infection of the lymph nodes and lymph system, which includes the spleen and thymus and lymphoreticular cells of the liver (the kidney also has some lymphoreticular cells), caused by the EBV virus (Epstein-Barr virus).. Viruses probably have something to do with quite a few cancers, especially those of the lymph system.

We all probably have little cancers and little virus infections start in our bodies frequently, and our immune system recognizes the cancer cells or virus as foreign, attacks and kills them off. So, when you are on medications that
blunt the activity of the immune system you are more susceptible to both, and as I said since cancer in some cases, all or in part, can be caused by a virus, then cancer/viral infection may be a simultaneous occurrence.

PTLD then occurs in patients who have decreased immune function, such as our children who receive transplants and are on prednisone, Imuran, cyclosporine (Neoral or Sandimmune), mycophenolate (Cell-Cept), tacrolimus (FK506 or Prograf), OKT3, ATG, MALG, Cytoxan, Zenapax or Simulect, and the like. The higher the doses of these drugs and the longer they are given, the greater the susceptibility to PTLD. This is one of the reasons that we are always in a dilemma about how much immunosuppressive medication to give--too much and you get infection or PTLD, and too little and you get rejection. But too little and you get rejection, and then you have to give even higher doses of immunosuppressive drugs than ever before and the risk of infection or PTLD increases.

The children who are at most risk of PTLD are those who get the most immunosuppression and those who get a transplant of an organ containing lots of lymph-type cells--so liver transplant recipients get it much more often
than do kidney transplant recipients, since there are many more lymph-type cells in the liver than the kidney. Those at least risk are those who get a first living related kidney, so get the least amount of immunosuppressive
therapy that we give, who never have a rejection episode, so never have the amount of immunosuppressive medication increased again after the initial tapering of doses post-transplant. Cadaver kidney recipients who never have a rejection episode are at relatively low risk, too.

Regarding the use of chronic immunosuppressive medications, those on FK506 (Prograf is the trade name, tacrolimus the generic name, FK506 the common name since it was called that when it was still experimental), are at more risk of PTLD than patients on cyclosporine (Neoral or Sandimmune). Of course, the lower the dose of FK506 given the lower the risk, and as we have gotten more experience with this drug we have learned to use lower doses, since it appears to be stronger than is cyclosporine. There are pros and cons to immunosuppressive bases regimens with cyclosporine and with FK506--neither one is clearly better. Experience in using the drugs is very important.

PTLD is most likely to occur soon after a time when high dose antirejection therapy is given--after a rejection episode is treated, and once in a while soon after transplantation is done, since we give the most antirejection therapy in the first few months post-transplant. History of receiving a lot of immunosuppressive therapy increases the risk. Children who developed their kidney failure from a disease requiring a lot of immunosuppressive therapy, like lupus or nephrotic syndrome/focal sclerosis, are at more risk than children who had no such prior therapy. Children who have had cancer treated in the past are at more risk. Children who have had multiple transplants or multiple rejection episodes are at more risk than those never having a rejection episode or those who receive a first kidney.

The kind of patient we most often see get it would be one who has had one or two prior transplants, was treated for rejection episodes with those transplants, and now is being treated again for rejection with a second or
third transplant. Treatment with OKT3, one of our most powerful immunosuppressive drugs, is predisposing to it, but it can also be a kidney-saver with bad rejection. So, what I am saying, is that for most of you it should be pretty low on your list of worries.

Heredity and personal genetic factors may also play a role--those who are more susceptible to cancer because of their genetic structure will also be more susceptible to PTLD. EBV virus can also be in the transplanted kidney in a "hibernating state", only to wake up when in the body of someone with depressed immunity.

So, it is very complex, and fortunately we do not see that much of it in the kidney transplant world. It is more common in the liver world.

It, of course, occurs in differing severities. It usually presents with enlarged lymph nodes or spleen or liver and/or decreased or increased white blood count (usually decreased) or decreased platelets, sometimes with an increase in severity of anemia (many renal transplant recipients are mildly anemic for a host of reasons that aren't anything serious). The earlier it is picked up the better--the easier it will be to treat.

We initially treat it by decreasing or sometimes even stopping immunosuppressive drugs. The PTLD itself is immunosuppressive, so while the PTLD is present, the immune system will be depressed by it and rejection will not occur. The tricky part is knowing when the activity of the PTLD is decreasing so that immunosuppressive drugs should be gradually restarted to prevent rejection from occurring. Of course, if you restart the immunosuppressive drugs too soon, then the PTLD will get worse, and if you don't start soon enough, then rejection will occur, causing you to use more immunosuppressive drugs, which can aggravate the PTLD again--you can see how you can get into a vicious circle, but sometimes this vicious circle cannot be avoided. The patient and family then feel like they are on an endless merry-go-round for a while, but with time they usually are able to get off of it.

Fortunately, as I said, we don't see that much of it in the kidney world and what we do see doesn't tend to be too severe, so that most of the time we don't get into this vicious circle too badly. Most of the time we can treat it and go on.

The tests that we do for it include lymph node biopsies, when we encounter a large lymph node, and CT scans of the abdomen, looking for an enlarged liver, spleen and lymph nodes along the aorta, where there are many of them.

Kidney transplantation presents the physician with many judgment challenges, for example, is this rejection likely to respond to increased immunosuppressive therapy with OKT3?--is the risk of PTLD higher than the chances of reversing the rejection and winning? Is the rejection episode such that chronic rejection will be left at the end of treatment, and even though the kidney will be temporarily "saved", will it be lost soon anyway? is it worth treating the rejection?, particularly since repeat transplantation is possible and sometimes the charm.

I hope that this treatise has helped to clear up a complex subject. Tina's advice and thoughts below are right-on, so I left then attached. My advice about the lymph node biopsy, is: if it were my child, they couldn't schedule it fast enough--most of the time it won't be PTLD, but you always want to pick up PTLD early as the earlier it is diagnosed, the easier it will be to treat.

Dr. Sue Conley