What Is the Main Idea?

There is a risk of patients who undergo kidney transplant operations developing antibody-mediated rejection after they receive their new kidneys. In the open-access research article “Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients”, published in the journal Transfusion Medicine and Hemotherapy, the authors analyze whether the Eurotransplant “acceptable mismatch” program heightens the chance of patients at increased risk of antibody-mediated rejection having better outcomes over the long term.

What Else Can You Learn?

In this blog post, chronic kidney disease (CKD) and kidney failure in general are discussed. Issues relating to the potential rejection of transplanted kidneys, particularly antibody-mediated rejection, are also described.

 Take-Home Message

Thorough assessment of patients who receive kidney transplants and of donated kidneys can reduce the risk of the recipient developing antibody-mediated rejection, and increase the long-term success of kidney transplants in patients at higher risk of developing it.

What Is End-Stage Renal Failure (ESRD)?

The kidneys do several important jobs in the body, including helping to control your blood pressure, making red blood cells, and removing waste products and extra water from your body to make urine (wee). If the kidneys become damaged and no longer work as well as they should, their ability to remove waste products from your blood is reduced and too much fluid and waste remains in the body. This is called CKD, an umbrella term that generally means that the kidneys have been permanently damaged by a variety of conditions and that kidney function (how well the kidneys do their job) is reduced.

Factors that can increase your risk of developing CKD include having diabetes, high blood pressure, and heart disease. People over 60 years of age are also more likely to develop CKD. Although CKD can initially be a mild condition, with no or few symptoms, some patients progress to ESRD (also known as end-stage renal failure and kidney failure) where kidney function drops to below 15% of its normal level. When this happens, it means that the kidneys have lost their ability to look after the body’s needs by themselves.

How Is ESRD Treated?

When the kidneys stop working, kidney replacement therapy in the form of dialysis or kidney transplant is needed so that the person can survive. Some people undergo dialysis, a procedure by which the blood is regularly “cleaned” by a machine that filters the blood to remove the excess water and waste products, for the rest of their lives. Other patients choose to receive dialysis until they can get a kidney transplant. This is a type of surgery that places a healthy kidney from another person (the “donor”) into the patient’s body (the “recipient”) to filter their blood, if they are fit enough. Data show that kidney transplantation is the best treatment option for patients with ESRD in the long term. However, there are a number of factors that can affect its success and patients can wait several years for a suitable kidney to become available.

 What Affects the Success of a Kidney Transplant?

When kidney transplants are successful, they offer the benefits of the person who receives the transplant having fewer restrictions on what they can eat and drink, and better quality of life. Patients with ESRD who receive a kidney transplant also tend to live longer than those who do not, although this is not guaranteed.

Nonetheless, a kidney transplant operation is a major procedure with risks of complications and infections. There are also risks that something might go wrong with the transplanted kidney. Furthermore, patients need to take immunosuppressant medicines (usually for the rest of their lives) that reduce the activity of the immune system so that it does not attack the new kidney as “foreign”, which can cause the new kidney to be rejected. There is also a risk of antibody-mediated rejection developing months or even years after the person receives their new kidney, which can cause the transplant to fail.

What Is Antibody-Mediated Rejection?

Antibodies are specialized proteins that are made by the immune system and recognize markers that are considered foreign to the body (these are called “antigens”), like on bacteria and viruses. Different antibodies specifically recognize and neutralize different antigens. When they have recognized and responded to a particular antigen once, antibodies against that antigen continue to circulate in the blood to provide protection against it if it is encountered again (this is how we become immune to some diseases).

As well as existing on the surfaces of bacteria and viruses, antigens are also present on the cells of our own bodies. The immune system uses specific antigens called human leukocyte antigens (HLAs) to recognize which cells belong in our bodies and which do not. When a kidney is transplanted, HLA mismatches between the donor and the recipient can be detected as “foreign” by the recipient’s immune system and trigger it to make donor-specific antibodies. This significantly increases the chance of the transplanted kidney being rejected or failing sometime after the operation.

Can the Risk of Antibody-Mediated Rejection Be Reduced?

The most effective way to reduce the risk of antibody-mediated rejection is for both the donor and recipient to be “HLA typed”. Each person has many HLA markers, and research has shown that at least six HLA markers of a donor must match those of the recipient for a transplant to have a chance of being successful, although much closer matches are usually required. Some HLA types are less common than others, so some patients may face a longer wait for a suitable donor to be found as a result. In addition, there is evidence that not all HLA mismatches are equal in terms of how they contribute to the risk of antibody-mediated rejection.

What Did This Study Investigate?

Eurotransplant is an international non-profit organization that facilitates cross-border exchange of donor organs between eight countries in Europe. By mediating between donor hospitals and transplant centers in its member countries, Eurotransplant aims to increase the likelihood that a person waiting for a transplant will find a suitably matched kidney and decrease the length of time that they will have to wait.

Some patients are classed as higher urgency by Eurotransplant, and these include patients for whom there is a risk that they have antibodies that will react to blood or tissue from another person (termed “immunized” patients). Because this means that the risk of organ rejection is also increased, immunized patients are eligible to join a dedicated program called the “acceptable mismatch” program. This identifies HLA mismatches that are unlikely to cause severe antibody-mediated reactions (in other words, they are “acceptable” to the potential recipient’s immune system).

In the short term, immunized patients who have received kidneys through the acceptable mismatch program have been shown to have similar rates of transplant survival over the short term as patients who are not immunized. However, data showing success rates over longer periods of time have been lacking. The authors of this study compared the long-term outcomes of immunized patients who received kidneys through the acceptable mismatch program with patients who received kidney transplants and were either not sensitized to HLA mismatches or were sensitized to a small extent (all patients were allocated kidneys by Eurotransplant). They also looked at whether HLA compatibility and the type of induction therapy received (this is a type of treatment that is given at the time of the transplant operation to reduce the risk of the new kidney being rejected) affected the chance of success.

What Were the Findings of the Study?

The authors of the study report that overall graft survival rates 10 years after transplant are similar between patients who are not sensitized and those who are allocated a kidney via the acceptable mismatch program. In contrast, overall graft survival after 10 years in patients who are slightly sensitized but are not eligible for the acceptable mismatch program is significantly lower than in patients who are not sensitized. Additionally, broad mismatches were identified by the study that can predict increased risk of antibody formation that can cause antibody-mediated rejection.

In conclusion, the authors state that patients on the acceptable mismatch program benefit from improved long-term outcomes, and that the risk of them developing antibodies that could cause rejection of their new kidneys is decreased. They also note that patients who are partly sensitized have better outcomes with a particular type of induction therapy compared with other types. Overall, the acceptable mismatch program delivers better outcomes for immunized patients with ESRD over the long term.

Note: One of the authors of this paper makes a declaration about grants, research support, consulting fees, lecture fees, etc. received from pharmaceutical companies. It is normal for authors to declare this in case it might be perceived as a conflict of interest. For more detail, see the Conflict of Interest Statement at the end of the paper.

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