What GP's need to know about the renal transplant patient

By Dr. Yvonne Ryan trainee North East training scheme  and Professor Peter Conlon Consultant Nephrologist, Department of Nephrology, Beaumont Hospital Dublin.

Since the first renal transplant in 1954 there have been huge advances made in organ transplantation both in terms of manipulation of immunological barriers to transplantation and the quality and specificity of the immunosuppressant medication used.

Often when presented with a renal transplant patient, non-nephrologists may have a fear of doing something or prescribing something that would interfere with their transplant medication or in some way harm their transplant. In some cases this fear is entirely justified and if in doubt you should speak to the nephrology team involved.

I hope GP’s will find this article helpful in diffusing any anxiety in the approach to managing common medical issues in a renal transplant patient. I have not included the first three months after transplant, during this period of very intense immunosupression the patients are entirely under the care of the Nephrologist and should they have any illness, no matter how trivial, they should consult with the transplant Nephrology team directly.

Transplant medication and drug interactions

The first issue I would like to discuss is the medications that a transplant patient takes.

The usual cocktail of immunosupression consists of three drugs:

• A calcineurin inhibitor (tacrolimus/Prograf or cyclosporine/Neoral)
• An anti-metabolite (mycophenolate mofetil/Cellcept or Imuran/azathioprine)
• And usually a small dose of life long steroid (prednisolone 5mg).

These three drugs are for life. Sometimes we may change them for example MMF to azathioprine if a woman is trying to get pregnant. But nearly all  renal transplant recipients are on a stable regimen of immunosupression and will be able to tell you the doses and indeed their most recent calcineurin level which you will find written into their transplant passport.

The caveats that come with this medication are that both the CNI inhibitor and MMF need to be taken at the same time twice a day eg 10am and 10pm. They should not miss a dose for any reason. If patients are unable to take their medication orally for whatever reason they should contact their nephrologists who will arrange their admission to receive an IV alternative.

There are many interactions with these medications but I will mention the most common/relevant to GP's

 Table 1

One of the most common interactions seen is if a transplant patient is prescribed clarithromycin. This results in a massive elevation in tacrolimus or cyclosporine levels as the clarithromycin inhibits the hepatic enzyme cytochrome P450 3A4 through which tacrolimus and cyclosporine are metabolised. This could potentially result in acute renal failure, tremor and neurological sequelae from calcineurin toxicity. Other inhibitors of CYP450 3A4 include some very commonly prescribed medication including erythromycin, fluconazole, ketoconazole and to a lesser extent calcium channel blockers such as nifedipine, verapamil and diltiazem. These drugs should not be prescribed for a renal transplant patient on calcineurin inhibitors.

Another common interaction is seen between those taking azathioprine who are inadvertently perscribed allopurinol. Very severe and even fatal marrow suppression can occur due to inhibition of azathioprine metabolism by allopurinol. If the patient is on azathioprine and has a severe episode of gout a short course of steroid (prednisolone 20mg for 5 days) or colchicine should be used. I suppose I had better say that under no circumstances should a renal transplant patient be prescribed an nsaid or a cox 2 inhibitor. The potential for damage with these drugs is myriad and it best to avoid them completely.

If a patient has persistent and very troublesome gout that cannot be managed with the strategies outlined above it is worth asking the Nephrologist if the patient would be suitable to change the anti-metabolite component of their immunosupression to an allopurinol friendly regimen eg MMF instead of azathioprine.

Nephrologists often get phone calls from GP’s asking about which vaccines are safe in a transplant patients. We advise all renal transplant recipients (and indeed dialysis patients) to receive the seasonal flu vaccine every year including the swine flu vaccine. We also advise transplant patients to receive the pneumococcal vaccine every 5 years. There are some vaccines that are NOT suitable for solid organ transplant recipients ie (post-transplantation) and those are any vaccine with live components or live attenuated components.  For example (and this is not an exhaustive list):  BCG, yellow fever, oral polio vaccine, varicella and rubella vaccines.

Generally we advise transplant recipients to avoid foreign travel in the first three months post transplant until transplant function is entirely stable. This is due to the high frequency of infection and complications at this time coupled with very frequent mandatory clinic visits (sometimes weekly).

After this period has elapsed and transplant function is stable the renal transplant patient can travel virtually anywhere in the world. However travel to under-developed countries is not without risk. For example we would advise the use of boiled or bottled water in any area where the standard of drinking water might be suspect. Disease like cryptosporidium can result in self-limiting diarrhoea in an immunocompetent host however in an immunosupressed transplant patient they can be life threatening. Also food preparation standards might not be acceptable and could place an immunocompromised patient at unnecessary risk. Another consideration is that the health services in some countries simply might not have the expertise to deal with a sick transplant patient.

Hypertension and cardiovascular risks

The most common cause of death in renal transplant recipients is now cardiovascular disease. The risks are much elevated compared to the general population and the prevalence of cardiovascular disease approaches 20 % post transplant. Managing risk factors such as hypertension, diabetes, dyslipidemia, and cigarette smoking is a major priority in the long term follow up of renal transplant patients.

The prevalence of arterial hypertension is high, up to 50% in renal transplant recipients. The British renal association recommends a blood pressure of <130/80mmhg. European Best Practice Guidelines recommend a Bp <130/85mmhg and <125/75mmhg if proteinuric. There is no particular evidence to support any one agent. We do use ACE inhibitors and angiotensin receptor blockers especially if the patient remains proteinuric but not in the early post transplant period when renal function is unstable. If a transplant patient has resistant hypertension consideration should be given to whether they have a transplant renal artery stenosis and auscultation the transplant might reveal a bruit.

We also measure fasting lipids at least annually to detect and treat hyperlipidaemia which has the same targets and treatment as the general population.

Particular attention is given to screening for Post-transplant diabetes which is very common given the steroid use and a known side effect of tacrolimus. A dipstick urine for glucose and a fasting glucose should be checked at every opportunity. Post-transplant diabetes should be managed in conjunction with a specialist in Diabetes but again treatment targets are similar to that for T2DM.

We encourage all transplant recipients to adopt a healthy lifestyle including smoking cessation, maintaining a healthy body weight and avoidance of excessive alcohol.

Malignancy

With greater transplant survival comes a lifetime risk of increase in skin and other malignancies. The following cancers occur much more frequently in the transplant population; vulval/anal carcinoma, post transplant lymphoproliferative disease, lip carcinoma, hepatocellular carcinoma and in situ cervical carcinoma.

Pre-cancerous and cancerous skin lesions are particularly common. To this end we recommend that transplant patients take maximum skin precautions post-transplant including sun block, hats and long sleeves if exposed to sun. Despite this many of our transplant patients will get numerous skin lesions including actinic keratoses, BCC’s, SCC’s and even melanoma. The renal transplant recipient should have their skin examined annually be a health care professional.  It is advisable to consider referring a transplant patient to a dermatologist for yearly expert review if they start to develop any suspicious lesions.

Screening for cervical, breast, colon and prostate cancer should be similar to that for the general population. Some guidelines recommend yearly cervical smear for all transplant recipients. Breast and testicular self-examination should be encouraged.

There is also a much higher incidence of renal cell carcinoma in both dialysis and renal transplant patients. It is unclear whether a screening ultrasound shoul be performed in these patients.

There is a particular entity which transplant patients are uniquely at risk of called post transplant lymphoproliferative disease. These are most commonly B-cell lymphomas. Patients who are EBV negative and seroconvert following transplant of an EBV positive organ are at the highest risk. All recipients receive some antiviral prophylaxis with valacyclovir in Ireland.  Symptoms may include fever, weight loss, anorexia, lymphadenopoathy and gastointestinal disturbance. The most commonly affected organs are the lymph nodes, liver, lung, and kidney. Treatment is with surgery where appropriate chemotherapy and modification of the patients immunosuppressive regimen.

And Finally…The sick patient

Any renal transplant patient has the potential to decompensate with infection or renal issues very quickly. Often due to immunosupression they will not mount an obvious or typical response for example fever, tachycardia or elevated leukocyte counts as one would expect. Sometimes even an acute abdomen does not present with typical peritonitic signs in an immunocompromised patient. In addition when these patients get sick, they may become hypoadrenal very swiftly due to long term use of steroid and may deteriorate rapidly if they do not receive stress steroid cover. They may not be able to take their transplant immunosupression orally and may need an iv alternative.

Any renal transplant patient who you suspect is seriously ill should be sent straight to hospital, preferably their Nephrology centre and the responsible nephrology team contacted to review the patient on arrival. If in any doubt phone the nephrology team directly.

References and Resources

Circulation 2003, 108:2154-2169 Kidney Disease as a Risk Factor for Development of Cardiovascular Disease A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention Mark J. Sarnak, MD, Cochair; Andrew S. Levey, MD, Cochair Anton C. Schoolwerth, MD, Cochair; Josef Coresh, MD, PhD; Bruce Culleton, MD L. Lee Hamm, MD; Peter A. McCullough, MD, MPH; Bertram L. Kasiske, MD; Ellie Kelepouris, MD Michael J. Klag, MD, MPH; Patrick Parfrey, MD; Marc Pfeffer, MD, PhD; Leopoldo Raij, MD David J. Spinosa, MD; Peter W. Wilson, MD

Clinical Microbiology Reviews, July 2003, p. 357-364, Vol. 16, No. 3 Vaccinations for Adult Solid-Organ Transplant Recipients: Current Recommendations and Protocols

British Renal Association Website http://www.renal.org/Clinical/GuidelinesSection/Post-operative-Care-Kidney-Transplant-Recipient.aspx

Nephrol. Dial. Transplant. (2002) 17(suppl 4) European Best Practice Guidelines for Renal Transplantation (Part 2) : 1-67.