Renal Transplantation Rejection

What is Renal Transplantation Rejection?

Kidney transplantation is the best treatment for patients with severe kidney disease or those in the final stage of kidney failure. It improves the quality of life and offers better survival chances than just relying on dialysis. Matching the donor kidney with the recipient is really important, since our body sees a transplanted kidney as foreign or an “alloantigen”.

Essentially, our bodies produce a response to defend the body when tissue or cells from a different genetic makeup (like a donated kidney) are transplanted. This immune response can destroy the new kidney if not properly managed and is known as allograft rejection.

Allograft rejection is inflammation or changes in the transplanted kidney. It’s caused by the recipient’s immune system detecting the non-self (“foreign”) antigen in the new kidney, even when the kidney is functioning properly.

Both our innate and adaptive immune systems take part in the process of rejection. The T cells in our immune system are the main type which recognize the donated kidney. There are also other molecules and proteins, called cytokines, that play a key role in this process. Kidney transplant rejections can be broadly grouped under different categories, depending on their nature and timing:

1. Hyperacute rejection: This happens minutes after the transplant, typically due to the presence of antibodies incompatible with the donor’s blood type. Because of careful tests done before the transplant, this is rarely seen nowadays.

2. Acute rejection: Can happen anytime after the transplant, usually within days to weeks. This can be either:

   • Antibody-mediated rejection (ABMR): Usually shows signs of antibodies reacting against the donor’s kidney and causing injury to the kidney. Like inflammation of the tiny filtering units (glomerulitis) or small blood vessels (peritubular capillaritis).

   • Acute T-cell mediated rejection (TCMR): Characterized by the infiltration of T cells into the new kidney, causing inflammation.

3. Chronic rejection: Occurring more than three months after the transplant. This can either be chronic antibody-mediated rejection or chronic T cell-mediated rejection.

4. A mixture of acute and chronic rejection: This refers to an acute rejection happening on top of an existing chronic rejection.

What Causes Renal Transplantation Rejection?

There are certain elements that can increase the chance of a kidney being rejected after a transplant. These elements include:

* If the patient has been sensitized – this refers to having high levels of antibodies in the blood that react against the donated organ.
* The type of transplant: If the kidney comes from a donor who has died, there’s a higher chance of rejection compared to a living donor.
* The older the donor, the higher the chances of the kidney being rejected.
* The longer the kidney is left without blood flow (referred to as “cold” and “warm” ischemia time), the higher the risk of rejection.
* Higher mismatch in human leukocyte antigens (HLA), which are proteins found on most cells in your body, increases the chance of rejection.
* Positive B cell crossmatch, which means that the recipient’s blood has shown a reaction to the donor’s blood.
* Blood type incompatibility between the donor and recipient.
* Younger patients are more likely to reject the kidney than older ones.
* People of Black race are more likely to reject the kidney than people of White race.
* Delayed functioning of the new kidney.
* Not taking the prescribed medicines properly.
* Previous incidents of rejections.

Not having adequate suppression of immune response using medicines also increases the chance of rejection.

Risk Factors and Frequency for Renal Transplantation Rejection

With the help of modern and powerful drugs that suppress the immune system, we’ve been able to lower the rate at which acute allograft (transplant) rejections occur and increase the survival of these transplants. Nowadays, the chance of acute rejection in the first year is around 7.9%. It’s also been observed that kidney transplants from living donors have a lower rejection rate compared to those from deceased donors. This could be because of a better match and less time the organ spent without blood supply.

Signs and Symptoms of Renal Transplantation Rejection

Patients going through episodes of acute rejection, typically don’t show obvious symptoms. The dysfunction of an allograft, or transplanted organ or tissue, is often noticed through routine blood tests. If there is a sudden increase in serum creatinine in the blood, where it goes up by 25% or more from the normal level, healthcare providers may suspect that the patient’s body is rejecting the allograft. If creatinine levels are not decreasing as they normally should after a transplant, this can also be a sign of possible rejection. Other warning signs include newly developed or worsening protein in the urine, and newly developed or worsening high blood pressure.

Sometimes, a body rejecting an allograft may cause symptoms like fever, pain in the area of the transplant, blood in the urine, painful urination, high blood pressure, retaining fluid and decreased amount of urine.

• Sudden increase in creatinine by 25% or more
• Creatinine levels not decreasing after a transplant
• New or worsening protein in the urine
• New or worsening high blood pressure
• Fever
• Pain at the site of the transplant
• Blood in the urine
• Painful urination
• High blood pressure
• Fluid retention
• Decrease in the amount of urine

Testing for Renal Transplantation Rejection

When a person who had a kidney transplant experiences a rise in blood creatinine levels (a waste product that kidneys usually remove), doctors need to follow a similar approach as they would if they were inspecting an instance of acute kidney injury — sudden damage to kidneys that makes them unable to filter waste from your blood. They would also need to add some procedures to check for possible transplant rejection.

The steps to evaluate how well the kidney transplant (also called an “allograft”) is functioning include:

* Exclude pre-renal causes: Doctors assess your overall circulatory health by looking at things like blood pressure and fluid balance.
* Rule out post-renal causes: One key concern, particularly in older patients, is the bladder or urinary tract problems that block urine output. Doctors often use an ultrasound scan to check this.
* Complete blood count: A full blood test includes checking for anemia (low red blood cell count) and thrombocytopenia (low platelet count), which could help to rule out a potentially dangerous condition called thrombotic microangiopathy (TMA, a disorder that results in the formation of blood clots in small blood vessels).
* Look for abnormal levels of electrolytes (minerals) in your blood. Imbalances here could point towards complications related to chronic kidney disease (CKD, a long-term condition where the kidneys don’t work as well as they should) or acute kidney injury.
* Urinalysis (UA) and urine culture: It’s crucial to exclude infection as a reason for acute kidney injury. These tests can identify any harmful bacteria present in your urine.
* Check for protein in the urine: This can be achieved by either a urine protein to creatinine ratio (UPCR) test, or collecting your urine over a 24-hour period. High levels of proteins in your urine can indicate a problem with your kidney transplant.
* Look for specific viruses like BK polyomavirus and cytomegalovirus (CMV) in patients who appear to be at risk. This can be done through a technique known as polymerase chain reaction (PCR) which amplifies the DNA of the virus if it exists.

Apart from the above, doctors would run tests for donor-specific antibodies. If these are present in your body, it could be a sign that your body is rejecting the kidney transplant.

An ultrasound that includes a doppler (a special ultrasound technique that evaluates blood vessels and blood flow) would be used to study the blood flow in and around your transplant kidney.

Some transplant centers may use a test that looks for DNA from the donor. If your body is starting to reject the transplant kidney, donor DNA will show up in a blood test, often before there’s any visible increase in creatinine.

Treatment Options for Renal Transplantation Rejection

When determining a treatment plan for organ rejection, doctors consider many variables like the type and severity of the rejection, scores indicating the presence and severity of chronic disease, and any other health conditions the patient might have.

1. Hyperacute Rejection – Unfortunately, there is no effective treatment for this sudden and severe organ rejection. Therefore, prevention is very important, including:

* Ensuring blood type compatibility between the donor and recipient. Sometimes blood type mismatches can be managed carefully using pre-transplant measures like removing anti-ABO antibodies (proteins in the patient’s blood that will attack the transplant), using blood cleansing techniques called plasmapheresis, along with drug therapies.
* Performing a pre-transplant cross-match test between the donor’s and recipient’s blood. If the recipient has antibodies (proteins made by the immune system) that react with the donor’s HLA antigens (proteins on the transplant that the immune system may see as foreign), the transplant should not go forward unless these antibodies can be removed pre-transplant.

2. Antibody-Mediated Rejection (AMR) – This type of rejection is caused by antibodies that the recipient’s immune system makes to attack the transplanted organ. Treatment may include:

* Plasma exchange, which is a blood-cleansing process to reduce the amount of harmful antibodies.
* Intravenous immunoglobulin (IVIG), or proteins that help boost the immune system or reduce inflammation.
* Medications like rituximab or bortezomib, which target specific immune cells or proteins to prevent them from attacking the transplanted organ.
* In very rare cases, a splenectomy (removal of the spleen) has been reported to be successful in treating very resistant rejections.

3. T Cell-Mediated Rejection – This type of rejection is caused by a type of immune cell called a T cell that attacks the transplanted organ. Treatments might include high-dose intravenous steroids, rATG (a drug that targets T cells), and adjusting the doses of drugs that suppress the immune system to prevent them from attacking the transplant.

4. Chronic Rejection – This long-term, slow rejection is often caused by antibodies attacking the transplant. In cases where the patient has high levels of a waste product called creatinine in their blood, which indicates poor kidney function, and/or a lot of protein in their urine, treatments similar to those for AMR may be used. However, they are generally not effective in these situations.

What else can Renal Transplantation Rejection be?

In the event of problems with a kidney transplant (also known as renal allograft dysfunction), it’s crucial to consider causes that are not related to the body rejecting the transplant. These causes can differ depending on how much time has passed since the operation.

Here are the most common reasons for kidney transplant issues not related to rejection in the first week after a transplant:

• Injury due to blood flow restoration (postischemic acute tubular necrosis or ischemia-reperfusion injury)
• Lack of fluid in the body leading to kidney injury (volume depletion leading to pre-renal AKI)
• Complications from the surgery, such as fluid gatherings, blood clotting in the vessels, issues with multiple kidney arteries from the donor, and the presence of calcium oxalate crystals deposits in renal allograft

Other problems can occur between the first week and the third month after a transplant, or even later:

• Volume depletion
• Acute tubular necrosis
• A condition called Calcineurin inhibitor nephrotoxicity, caused by specific medication, which can lead to sudden kidney problems or progressive kidney disease
• Blockage in the urinary tract (urinary obstruction)
• Infections such as bacterial pyelonephritis and viral infections (BK polyomavirus and CMV)
• Acute and chronic interstitial nephritis
• Returns of prior kidney diseases, such as Focal segmental glomerulosclerosis (FSGS), Primary membranous nephropathy, Diabetic nephropathy, Ig A nephropathy, and C3 Glomerulonephritis (C3 GN)
• New onset kidney diseases (de novo glomerular disease)
• Issues with small blood vessels in the kidney (thrombotic microangiopathy) which can occur in patients with a history of thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), antiphospholipid antibody syndrome or can be due to Calcineurin inhibitor nephrotoxicity
• Narrowing of the main kidney artery (transplant renal artery stenosis)
• Cell growth disorder after a transplant (Post-transplant lymphoproliferative disease)

What to expect with Renal Transplantation Rejection

Acute rejection episodes can lead to long-term problems with the transplanted organ or graft. For example, acute rejection can eventually lead to chronic graft dysfunction, which means that the transplanted organ isn’t working as well as it should.

Rejections mediated by T cells, a type of white blood cell, tend to have better outcomes. This is particularly true if these rejections respond well to treatment and if blood tests (such as the serum creatinine test, which measures kidney function) show improvement close to the previous levels after treatment.

However, certain conditions are linked to worse outcomes for the transplanted organ. These include acute rejections that happen after three months, vascular rejections (which involve the blood vessels), and rejections that don’t respond well to treatment. In cases where treatment doesn’t lead to a significant improvement (specifically, if the serum creatinine level doesn’t reach at least 75% of the previous value), the prospects for the transplanted organ are not good.

The presence of a new type of antibodies, called de novo DSAs, any time after the transplant can also negatively impact the transplant outcome. The chances of a poor outcome for the graft increase by 5% per year when these antibodies are present, compared to recipients without these antibodies.

Because of these potential outcomes, each instance of acute rejection should be taken seriously. It’s necessary to respond with proper treatment and close monitoring. This often involves adjusting the ongoing drug regimen that’s used to suppress the immune system and prevent rejection.

Possible Complications When Diagnosed with Renal Transplantation Rejection

The main risk related to acute rejection is the failure of the organ transplant if it’s not correctly and promptly treated. Despite treatment, each occurrence of rejection can still negatively impact the survival of the transplanted organ.

The treatment for acute rejection can seriously weaken the immune system and increase the recipient’s risk of side effects from the drugs used, which are known as immunosuppressive agents. These drugs can cause several side effects, including:

• Increased risk for heart conditions
• Risk of developing post-transplant diabetes
• Problems with blood lipid levels (dyslipidemia)
• Risks of various types of cancer, including skin cancer (squamous cell carcinoma) and a disease causing abnormal growth of lymph nodes (post-transplant lymphoproliferative disease)
• Risks of various severe infections caused by bacteria, viruses, and other microscopic organisms (opportunistic infections)

CMV, a type of virus, can increase the risk of organ rejection as well. Doctors are faced with a delicate balance: it’s essential to manage the use of immunosuppressive drugs carefully to mitigate the risk of organ rejection while also taking into account their potential side effects.

Preventing Renal Transplantation Rejection

Not following the recommended treatment plan can be one of the main risks for transplant rejection, which happens when the body rejects the new organ. Therefore, it’s vital for patients to understand and be aware of their treatments to prevent this from happening. The better you understand your medications and treatment procedures, the less likely you are to experience transplant rejection.