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Organ Donation and Transplantation - What is transplant rejection?

 

Key Points

  • Rejection is damage to a transplant caused by the body’s natural defences
  • Natural defences are reduced by drugs, which all kidney transplant patients must take
  • A rejection crisis can be treated with extra drugs

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The normal function of the immune system (natural defence)

The usual job of the immune system is to fight invaders into the body. These might be germs or bugs, or foreign objects such as splinters. The body recognises these invaders and tries to eliminate them from the body. The blood not only carries oxygen and nutrients to all parts of the body, but also carries the natural defences to where they are needed in the body. The blood contains two main types of defence system. One is white blood cells which stick to germs and kill them. The other type of defence is antibodies which are smaller than the white blood cells and, by sticking onto germs, either make them burst apart or help the white blood cells to stick to them.

The immune system is very powerful, and is very good at recognising what is part of the body and what is not, and leaving alone those normal parts of the body which have a ‘friendly face’. Although blood transfusions can be given without rejection, this is an exception and organs such as kidneys, the liver, the heart and so on are recognised as invaders. Even though these organs may come from the same species (human), everyone (apart from identical twins) is slightly different, and the body can recognise these differences. The damage the immune system does to a kidney transplanted from one person to another is called rejection.

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The rejection process

‘Rejection’ means that someone’s body recognises that the transplanted kidney is not ‘its own’ and tries to ‘reject’ it from the body. Even when someone is ‘well matched’ with their transplant kidney (in terms of blood group and tissue type), some degree of rejection (approximate risk is 15 out of 100 transplants) is common. The severity of rejection varies from patient to patient. Rejection may be either acute (see below) or chronic (see later). Luckily, there are drugs – called immuno-suppressant drugs (click here for details of drug treatment) – that can help prevent and treat the rejection process.

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Acute rejection

‘Acute’ means short-term and of rapid onset, requiring immediate action. Acute rejection can occur in the first few months (particularly the first few weeks) after a transplant. It is common – about 15% of people experience acute rejection in the first three months after a transplant. If acute rejection has not occurred within one year of the operation, then it is unlikely to happen, so long as the anti-rejection drugs are taken regularly.

Acute rejection may sometimes cause pain and fever, but usually there are no symptoms. Doctors will suspect that someone has acute rejection if the blood creatinine is either not coming down after a transplant, or if it has started to fall and then remains stable or increases again. However, acute rejection is not the only reason why there may be problems with blood creatinine levels after a transplant and these other possibilities are usually looked for first.

Acute rejection can be caused by white blood cells attacking the kidney (‘cellular’ or ‘T cell mediated rejection’), or it may be caused by antibodies against the kidney. Antibody mediated rejection often requires stronger treatment. It is not common to loose a kidney from acute rejection it can be treated. If you do not take your anti-rejections medications your risk is 100% and this invariably leads to the loss of the transplant.

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Investigation of acute rejection

Tests that might be performed include an ultrasound scan (a sound-wave picture). This will show if the ureter (the tube that takes urine from the kidney to the bladder) is blocked and there is dilation of the kidney. Other tests use specialist scanning techniques called a radio-isotope scan and a Doppler scan. Either of these will show if there are any problems with the blood supply to the new kidney.

The only way to be sure whether a transplant kidney is being rejected is to do a test called a biopsy. For this test, a hollow needle called a biopsy needle is used to remove a very small piece of the new kidney. This piece of kidney is then looked at under a microscope for any signs of rejection. It is common to have two or more biopsies in the weeks after the operation.

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Treatment of acute rejection

f the biopsy shows signs of rejection, then a high-dose steroid drug called methylprednisolone will be given. This drug is usually given by intravenous injection, once a day for three days. These are called ‘pulses’ of methylprednisolone. Very often, this treatment will suppress the rejection process and the creatinine will start to decrease. Occasionally, someone may need two courses of this drug.

If pulse methylprednisolone does not work, the anti-rejection drugs will be changed to something stronger. The exact changes depend on the severity of rejection and the protocols in different transplant units. If cyclosporin is being used to prevent rejection, it may be changed to tacrolimus (‘Prograf’ / 'Adoport') and rejection may subside. If someone is already on tacrolimus, but is also taking azathioprine, the azathioprine may be switched to mycophenolate.

Sometimes a five-to-ten-day course of a stronger intravenous drug may be given, such as anti-thymocyte globulin (ATG). This powerful course of injections has a 90% success rate. There can be a reaction after the first dose with fever, diarrhoea, joint and muscle pain, wheeze, and shortness of breath due to fluid on the lungs (pulmonary oedema). There is a higher risk of infections for several months after a course.

 

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Chronic rejection

‘Chronic’ means long-term and it starts slowly. The immune system may attack and reject the transplant kidney, but in a different way than in acute rejection. Chronic rejection is often caused by antibodies in the blood against the transplanted kidney, and investigation of someone with chronic rejection should include a check of the blood for these antibodies.

Chronic rejection looks like a slow ageing of the new kidney. It is probably started by a very low level of rejection on the kidney, perhaps caused by antibodies against the kidney. However, the rejection itself is very mild, unlike acute rejection. What does seem to happen is that the kidney gradually gets scarred, and this is caused by factors such as high blood pressure just as much as by any rejection. For this reason, many transplant doctors do not use the term ‘chronic rejection’ any more, but talk of ‘chronic allograft nephropathy’.

If it happens, it will usually be more than a year after the transplant operation. Doctors may suspect chronic rejection if a patient’s blood creatinine starts to rise slowly after it has been stable for some time. As with acute rejection (see above), the only sure way to diagnose the condition is to do a biopsy.

There is no treatment for chronic rejection that can be guaranteed to be successful, but some patients get an improvement if the anti-rejection drugs are changed. One particular concern is that the anti-rejection drugs cyclosporin and tacrolimus are slightly toxic to the kidney. They are normally so good at preventing rejection that this does not matter, but in chronic rejection they may worsen kidney damage. Therefore, if someone is on one of these drugs and has chronic rejection, either the dose will be markedly reduced, or they will be stopped and an alternative anti-rejection drug started, such as mycophenolate or sirolimus. There may not be as ‘strong’ as cyclosporin or tacrolimus, but are not directly toxic to the kidney.

The level of blood pressure is also thought to be very important in chronic rejection, as high blood pressure can also worsen kidney damage. A blood pressure of 130/80 or below is the ideal target, and may require the use of several different blood pressure drugs.

The severity of chronic rejection varies. Mild chronic rejection may stabilise without causing any symptoms, just a rise in the blood creatinine level. However, more severe chronic rejection will eventually lead to failure of the kidney (and therefore to restarting dialysis or having another transplant). Chronic rejection may take years to happen, but it is much the most common cause of transplant failure after the first year.

Complications:               
There are risks associated with all major and minor operations, which can lead to serious complications or even death. The transplant operation and the days immediately after it carry the same risks.  These will have been explained to you by the transplant co-ordinators, kidney doctor (nephrologists) and surgeon during your pre-transplant assessments.  They will be explained to you again at the time of your transplant before you sign the consent form.    


The risks for patients undergoing kidney transplantation:
The kidney failing in the first year                      10 out of 100
Bleeding needing blood transfusion                    5 out of 100
Problem with the join between the kidney and the bladder        7 out of 100
Blockage of the blood vessels supplying the kidney            2 out of 100
Narrowing of the blood vessels supplying the kidney              5 out of 100
Wound infection                                5-10 out of 100
Collection of fluid around the kidney                    7-10 out of 100
Blood clots in the legs                            1-3 out of 100
Acute rejection of the new kidney                        15 out of 100
Delayed kidney functioning requiring the need for dialysis        40 out of 100
Risks of acquiring infections or transmissible cancers from the donor 1 out of 20000*
Risks of immunosuppression (see below)
Recurrent disease

*Approximately 1 in 2000 donors have a hidden cancer or 1:100 an infection  that we do not know about, we cannot predict which donors have these hidden cancers or infection, even though the assessments are quite robust  and viruses are checked for. Such diseases may be inadvertently transmitted to you from such high risk donors and thus the need for further treatment for life for example with antivirals.

*Approximately 2 in 100 donors have died from a cancer in the brain or other cancers treated in the past. We make every effort to get all the details of these cancers and treatments before deciding the organ is safe to use. Nevertheless there is a small chance this may be passed to you.

Your consultant may feel that it is in your best interest to receive a blood transfusion during or after the transplant. The reasons for a blood transfusion will be discussed with you before the operation. The risks of blood transfusion are low and you will receive a leaflet about this.

You may develop other conditions related to receiving a kidney transplant. However the risks are very small and the consultant will discuss these with you fully before the operation prior to you signing your consent form.
                                                     
These drugs are very powerful and common side effects include the following:

General side effects of taking immunosuppressive drugs
The drugs stop you rejecting the kidney by weakening your immune response.  A consequence of this is that you are more susceptible to some infections and cancers.  The infections tend to be viruses or other infectious agents that are already in your body at the time of the transplant.  They may also be in the transplanted kidney, rather than infections that you catch from other people.  The most common virus to cause problems is called cytomegalovirus.  Some patients are given a drug called valganciclovir to prevent infection.  

Transplant patients are more likely to get skin cancer and it is important to take precautions to avoid sunburn.  Two out of every 100 patients transplanted will get a cancer of the blood called lymphoma (see later section).

Potential side effects of specific drugs

Tacrolimus
Tremor of your hands
Hot flushes and tingling in the hands and feet
Increase in blood pressure
Increase in blood cholesterol
Diabetes in 10 of every 100 patients transplanted
Nightmares (first two weeks)
Constipation and wind pains (first two weeks)

Prednisolone
Weight gain due to increased appetite
Round (“moon”-shaped) face which can change how you look
Increase in blood pressure
Increase in blood cholesterol
Diabetes
Personality change - very rarely
Osteoporosis (thinning of the bones)

Mycophenolate mofetil
Abdominal cramps and/or diarrhoea
Abnormality of bone marrow function.  This may make you more susceptible to
 infection or bleeding.  It may result in you becoming anaemic.   

The side effects are related to the dose of the drugs, which are reduced gradually over the first three months.  They may be treatable, for example with blood pressure tablets.  Many are self-limiting and they will usually go within a few days or weeks of the transplant. These do not need to be treated.

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The National Kidney Federation cannot accept responsibility for information provided. The above is for guidance only. Patients are advised to seek further information from their own doctor.

NKF Controlled Document No. 259: What is transplant rejection? written: 01/05/2001 last reviewed: 23/09/2016