What Is Kidney Transplant? – Symptoms, Diagnosis, Treatment

What Is Kidney Transplant?/Kidney Transplant provides superior outcomes to dialysis as a treatment for end-stage kidney disease. Therefore, it is essential that kidney transplantation be part of an integrated treatment and management plan for chronic kidney disease (CKD). Developing an effective national program of transplantation is challenging because of the requirement for kidney donors and the need for a multidisciplinary team to provide expert care for both donors and recipients.

Kidney transplantation is the treatment of choice in patients with end-stage renal disease or severe chronic kidney disease as it improves the quality of life and has better survival advantages compared to dialysis. Various factors merit consideration to match the donor kidney with the recipient, as the donor kidney act as an alloantigen. In general, when transplanting tissue or cells from a genetically different donor to the graft recipient, the alloantigen of the donor induces an immune response in the recipient against the graft. This response can destroy the graft if not controlled. The whole process is called allograft rejection.[rx]

Allograft rejection is inflammation with specific pathologic changes in the allograft, due to the recipient’s immune system recognizing the non-self antigen in the allograft, with or without dysfunction of the allograft.

Types of Kidney Transplant

Both innate and adaptive immune systems play a significant role in rejection, But the T lymphocytes are the principal cells that recognize the allograft. There are other costimulatory molecules, and cytokines also play a major role in this reaction. Depending on the histopathology and immunological characteristics, the renal transplant rejections can be classified broadly under the following categories :

• Hyperacute rejection – Happens minutes after transplant, and it is related to the preformed antibody or ABO incompatibility; this is rarely seen now due to the very sensitive cross-match tests performed before the transplant.
• Acute rejection – This can happen any time after transplant, usually within days to weeks after transplant. It classifies into the following:
• Antibody-mediated rejection- ABMR – which usually demonstrates evidence of circulating donor-specific alloantibodies and immunological evidence of antibody-mediated injuries to the kidney. Like inflammation of glomeruli (Glomerulitis) or peritubular capillary (peritubular capillaritis).
• Acute T-cell mediated rejection- TCMR: which characterized by lymphocytic infiltration of the tubules, interstitium, and sometimes the arterial intima.
• Chronic rejection – It usually develops more than three months post-transplant. It can either be chronic antibody-mediated rejection or chronic T cells mediated rejection.

A mixture of acute rejection superimposed on chronic rejection.

Causes of Kidney Transplant

Certain factors correlate with an increased risk of rejection of the renal allograft after the transplantation. These factors are[rx][rx][rx]:

• Congenital, familial and metabolic disorders – These are conditions you are born with, inherit or that affect your metabolic system.
• Diabetes – This autoimmune disorder affects the kidneys, pancreas and other organs.
• Glomerular diseases – These are diseases that affect the glomeruli, which strain fluid in the kidneys.
• Hypertensive nephrosclerosis – This means there is damage to the kidneys caused by high blood pressure.
• Malignant hypertension – This is an extremely high blood pressure that damages the organs.
• Polycystic kidney disease – This disease causes numerous cysts or growths on the kidneys.
• Renovascular and other vascular diseases – These diseases cause blockages or narrowing in the renal arteries or veins.
• Tubular and interstitial diseases – These diseases affect the portions of the kidney outside the glomerulus, a cluster of blood vessels that filter waste products from the blood.
• Temporary lack of kidney function – Your new kidney may not start working immediately and you may need dialysis until it resumes normal kidney function.
• Organ rejection – Your body may reject the donor organ and you may need medication to help your body accept the new kidney.
• Kidney failure – Your new kidney may fail after a number of years and you may need to have a second transplant or go back on dialysis.
• Cancer – Immunosuppressant medication taken after transplant may leave you more vulnerable to disease.
• Diabetes – Medications taken after a transplant can cause diabetes.
• Heart attack or stroke – A transplant puts you at a higher risk than a healthy person who hasn’t had a transplant, especially if you have high blood pressure, high cholesterol or diabetes.

Potential side effects of a kidney transplant may include:

• Narrowing of the artery leading to the kidney—also called renal artery stenosis
• Blood clots
• Infection
• Bleeding
• Weight gain
• High blood pressure
• Prior sensitization – high panel reactive antibodies
• Type of transplant: Deceased donor has a higher rejection than a living transplant
• Advanced age of the donor
• Prolonged cold ischemia time
• HLA mismatch
• Positive B cell crossmatch
• ABO incompatibility
• Recipient’s age: Younger recipients have more rejection than older ones
• Recipient’s race: African American race greater than White race
• Delayed Graft function
• Therapy non-compliance
• Previous episodes of rejections
• Inadequate immunosuppression

Pathophysiology

Renal transplant rejection, as stated earlier, is an immunological response that leads to inflammation with specific pathological changes in the allograft, due to the recipient’s immune system recognizing the non-self (foreign) antigen in the allograft. There are different mechanisms postulated depending on the type of rejection, as follows:

• Hyperacute rejection – It is related to preexisting circulating antibodies in the recipient’s blood against the donor antigen (usually ABO blood group or HLA antigen), which is present at the time of transplantation. These antibodies attack and destroy the transplanted organ as soon as or within a few hours after allograft is revascularized.
• Acute T cell-mediated rejection – in which the recipient’s lymphocytes become activated by recognition of foreign [non-self] donor antigens in the transplanted organ by antigen-presenting cells (APC) through direct, semi-direct or indirect pathways, which leads to activation and infiltration of the T cells and damage to the allograft.
• ABMR – It is related to antibodies against foreign [non-selfx] donor antigens, mainly HLA antigen, which leads to damage to the allograft through activation of the complement-dependent pathway as well as independent mechanisms recruiting NK cells, polymorphonuclear cells, platelets and macrophages to attack the allograft. These antibodies can be either preexisting at a low level before the transplant or synthesized de novo post-transplant.
• Chronic rejection – it is related to both immune and nonimmune mediated factors. The primary risk factor for chronic rejection is non-compliance with immunosuppressive medication. It can be either chronic antibody-mediated rejection, which is mainly related to the presence of donor HLA-antigens donor Specific Antibody (DSA) or Chronic cellular rejection, which is uncommon.

Histopathology of Kidney Transplant

The standard way to detect rejection is a renal allograft biopsy, which serves to accurately grade the severity of rejection, differentiate between different types, and guide the treatment.

There are two major classifications for the histopathological diagnosis of renal allograft biopsy: the Banff classification system and the Cooperative Clinical Trials in Transplantation (CCTT). Later, both were incorporated into the Banff 97 classification, to standardize the histopathological diagnosis of renal allograft biopsy. Subsequently, Banff has had updates at regular intervals; the last one was in 2017.

When performing a kidney biopsy, it should have adequate tissue to give a definitive interpretation. Adequate core biopsy must contain ten glomeruli and two arteries and section thickness 3 to 4 microns (marginal if 7 to 10 glomeruli and one artery; unsatisfactory if less than seven glomeruli or no arteries).[rx]

The histological characteristics of each type of rejection are as follows:

• Hyperacute rejection – The transplanted kidney turns mottled, dusky, and black as soon as it revascularized. Severe endothelial injury, PMN infiltration, whispered thrombosis, ischemic tissue necrosis will appear on biopsy.
• ABMR – Histological features of ABMR include: arteriolar fibrinoid necrosis, fibrin thrombi in glomerular capillaries, glomerulitis, and peritubular Capillaritis, interstitial hemorrhage. Also, the presence of peritubular Capillary linear staining for C4d, which is a degradation product of the complement pathway that binds covalently to the endothelium, is highly suggestive of ABMR.
• Acute T Cell-Mediated Rejection – Characterized by diffuse lymphocytic infiltration in the tubule, interstitium of the kidney, and in severe cases, vessels of the allograft
• Chronic rejection lesions – like interstitial fibrosis, tubular atrophy, vascular fibrous intimal thickening, glomerular basement membrane double contouring (transplant glomerulopathy), arteriolar hyalinosis, hyaline arteriolar thickening

Banff system uses scores to assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies. It focuses mostly, but not exclusively, on the diagnostic features seen in rejection. According to the scoring of the various lesions described above, the staging is as below.

• Category 1 – Normal biopsy or nonspecific changes
• Category 2 – Antibody-mediated rejection – AMR: depending on the features of lesion further divided into acute AMR, chronic AMR active chronic AMR
• Category 3 – Suspicious (borderline) for acute T cell-mediated rejection – TCMR.
• Category 4 – TCMR. Depending on the score of chronic lesions, it further divides into acute TCMR, chronic TCMR, acute, chronic TCMR
• Category 5 – Interstitial fibrosis and tubular atrophy – IFTA
• Category 6 – Other changes not considered to be the result of acute or chronic rejection[rx]

Indications of Kidney Transplant

The indication for kidney transplantation is end-stage renal disease (ESRD), regardless of the primary cause.

• This is defined as a glomerular filtration rate below 15 ml/min/1.73 m². Common diseases leading to ESRD include renovascular disease, infection, diabetes mellitus, and autoimmune conditions such as chronic glomerulonephritis and lupus; genetic causes include polycystic kidney disease, and a number of inborn errors of metabolism. The commonest ’cause’ is idiopathic (ie unknown).
• Diabetes is the most common known cause of kidney transplantation, accounting for approximately 25% of those in the United States. The majority of renal transplant recipients are on dialysis (peritoneal dialysis or hemodialysis) at the time of transplantation.
• However, individuals with chronic kidney disease who have a living donor available may undergo pre-emptive transplantation before dialysis is needed. If a patient is put on the waiting list for a deceased donor transplant early enough, this may also occur pre-dialysis.

Advantages

• No longer need dialysis as long as kidney functions adequately
• Blood pressure is often easier to manage, but may still require medication
• Long-term follow-up care is less time-consuming than dialysis
• Fluid and dietary restrictions are usually no longer necessary
• May return to work
• Improved quality of life with expected increase in lifespan
• More cost-effective than dialysis
• Having a transplant means that you do not have to dialyse.
• You might find you have more energy, making you feel better able to cope with everyday life, including work or studies.
• Your sex life and fertility will probably improve (if it has been affected by CKD).
• If you have Type 1 diabetes and have a kidney and pancreas transplant you should no longer need to take insulin or tablets to control your blood sugar.
• You will not need to travel to the hospital for dialysis. However, you will need to come to the hospital for regular clinic appointments for up to six months after your transplant. After this time you will need to come to the clinic around three to four times a year depending on your needs.
• You will have a less restrictive diet than if you are on dialysis, although you will need to follow a low fat diet after a transplant.
• You do not need space at home to store equipment.
• You will be able to restart any sport or exercise after the transplant, although if you play contact sports please discuss this with your kidney doctor or nurse first. You must be a healthy weight for the operation so exercise is important while you are waiting for a transplant.

Contraindications of Kidney Transplant

Contraindications include both cardiac and pulmonary insufficiency, as well as hepatic disease and some cancers. Concurrent tobacco use and morbid obesity are also among the indicators putting a patient at a higher risk for surgical complications.

• Kidney transplant requirements vary from program to program and country to country. Many programs place limits on age (e.g. the person must be under a certain age to enter the waiting list) and require that one must be in good health (aside from the kidney disease).
• Significant cardiovascular disease, incurable terminal infectious diseases and cancer are often transplanted exclusion criteria. In addition, candidates are typically screened to determine if they will be compliant with their medications, which is essential for survival of the transplant. People with mental illness and/or significant on-going substance abuse issues may be excluded.
• HIV was at one point considered to be a complete contraindication to transplantation. There was fear that immunosuppressing someone with a depleted immune system would result in the progression of the disease. However, some research seems to suggest that immunosuppressive drugs and antiretrovirals may work synergistically to help both HIV viral loads/CD4 cell counts and prevent active rejection.

Disadvantages

• Risks involved from general anesthesia as with any major operation
• Addition of immunosuppressive medication (and possible side effects) to your current medicines
• Need for continued care by a kidney specialist. Your kidney function and response to the medications must be medically managed for a healthy, long-term outcome.
• Transplantation is a treatment not a cure for the underlying cause of your kidney failure.

Diagnosis of Kidney Transplant

Evaluation

The approach for elevated serum creatinine in a renal transplant recipient would be the same as evaluating for AKI with added workup for the rejection.

The specific workup for evaluating allograft dysfunction should include the following[rx]:

• Blood type testing – A test to determine what type of blood—O, A, B, or AB—you have, and whether your blood is compatible with the potential donor’s blood. Type O is the most common blood type and is considered a universal donor, meaning someone who has this type of blood can donate to any other blood type. Type AB is considered a universal recipient and can receive blood from people of any blood type. Between the different types of blood, there are some that can and cannot give and receive one another. This test will determine blood type compatibility with your donor.
• Serum crossmatching – A test involving the mixing of your blood with that of the kidney donor to determine whether your body’s cells will attack the donor’s cells. If this happens, it means you have antibodies against this donor’s cells, and the crossmatch is considered “positive,” an indication that your body would reject a kidney from this donor. If your body does not produce antibodies against the donor’s cells, the crossmatch is “negative,” meaning your body will likely accept the donor organ and cells. For a kidney transplant, you will need a negative crossmatch in order to proceed.
• HLA (human leukocyte antigen) testing – A blood test that determines which antigens you (and the potential donor) have inherited. Antigens are proteins found on the cells and they are what trigger the body to produce antibodies, which fight off bacteria, viruses, and anything perceived as foreign to the body. While there are many different types of antigens, there are six that have been identified as particularly important for successful kidney transplant. This test will help determine whether your HLA is likely to fight against (reject) your donor’s HLA.
• Mental health evaluation. Psychological and social issues involved in organ transplantation, such as stress, financial issues, and support by family and/or significant others are assessed. These issues can greatly affect the outcome of a transplant. The same kind of evaluation is done for a living donor.
• Blood tests. Blood tests are done to help find a good donor match, to check your priority on the donor list, and to help the chances that the donor organ will not be rejected.
• Diagnostic tests. Diagnostic tests may be done to check your kidneys as well as your overall health status. These tests may include X-rays, ultrasound, kidney biopsy, and dental exams. Women may get a Pap test, gynecology evaluation, and a mammogram.
• Rule out prerenal causes – Check orthostatic vital sign, blood pressure, and volume status
• Rule out post-renal – causes mainly obstructive uropathy in older adults by bladder scan, renal US
• CBC – Look for anemia and thrombocytopenia to rule out TMA
• Serum Creatinine – This blood test measures kidney function. It is checked each day while you are in hospital.
• Renal Scan – This test monitors blood flow to the kidney and kidney function.
• Renal Ultrasound – This test checks the kidney for any blockages or fluid collections around the kidney.
• Kidney Biopsy – This test is used to check for rejection.
• Electrolyte abnormality – related to CKD, AKI
• UA and urine culture – It is essential to rule out infection as a cause of AKI
• Check for proteinuria – Either UPCR or 24-hour urine collection as nephrotic range proteinuria correlates with the presence of extensive transplant glomerulopathy
• Check BK Virus, CMV PCR – in clinically indicated patients
• Testing for donor-specific antibodies
• Transplant renal ultrasound with doppler for renal arterial and venous indices
• Many transplant centers use testing for donor-derived free DNA testing. This test can be positive even before the actual rise in serum creatinine, suggesting possible rejection.

Differential Diagnosis

While dealing with renal allograft dysfunction, equal weight should be given to find out the possible etiologies other than the rejection.

The following are the most common reasons for allograft dysfunctions other than the allograft rejection.[rx]

A.  Immediate Post Transplant (less than one week):

• Postischemic acute tubular necrosis or Ischemia-reperfusion injury.
• Volume depletion leading to pre-renal AKI

3. Surgical complications:

• Fluid collection – urinoma, perinephric hematoma or lymphocele
• Vascular thrombosis – arterial and venous
• Multiple renal arteries from the donor’s kidney – infarction of the part of the allograft or necrosis of the ureter leading to urinary obstruction or urinary leak.
• Aeroembolism
• Calcium oxalate crystals deposits in renal allograft

B. Early (1 week to 3 months) and Late Post Transplant (over three months)

• Volume depletion
• Acute tubular necrosis
• Calcineurin inhibitor nephrotoxicity – manifesting as acute azotemia as well as chronic progressive renal disease.
• Urinary obstruction
• Infections  – Bacterial pyelonephritis andViral infections – BK ( polyomavirus) and CMV
• Acute and chronic interstitial nephritis

Recurrent primary glomerular diseases

• FSGS
• Primary membranous nephropathy
• Diabetic nephropathy
• Ig A nephropathy
• C3 GN
• De novo glomerular disease

Thrombotic microangiopathy

• In patients with a prior history of TTP, HUS, antiphospholipid antibody syndrome
• Associated with calcineurin inhibitor nephrotoxicity

Transplant renal artery stenosis

Post-transplant lymphoproliferative disease 

Preparation

You have to meet certain criteria to be approved for a kidney transplant. You cannot have an active infection, cancer or severe circulatory problems involving your heart, brain or major blood vessels. You must be willing to take medications for the rest of your life to prevent your body from rejecting the new kidney.

You will need a thorough medical evaluation. This includes:

• A physical examination
• A chest X-ray
• An electrocardiogram (EKG)
• Blood tests to check for:
• Anemia
• Viral illnesses such as HIV, hepatitis, herpes simplex virus and cytomegalovirus
• Blood samples to check:
• Your blood type and tissue type to determine if a donor is a good match.
• Possible additional tests:
• Cardiac tests
• Screenings for certain types of cancer

If you smoke or have problems with substance abuse, you must complete a treatment program before you receive your new kidney.

While you prepare for your kidney transplant, you will meet regularly with a transplant team at the medical center where you will have your surgery. These professionals can offer you a wide range of support services during the pre-transplant period.

The transplant team usually includes:

• A doctor who specializes in kidney problems (a nephrologist)
• A transplant surgeon
• Nurses
• A social worker

If your kidney transplant will come from a living donor, you usually will be able to schedule the time of your transplant surgery. In most cases, your pre-transplant waiting period will be only a few weeks. During this time, your donor will have medical tests. These will ensure that he or she is strong enough to undergo surgery. Additional tests will confirm that the donor’s kidneys are functioning normally.

If you do not have a living kidney donor, your name will be placed on a waitlist for a kidney from a dead donor. This donor must be a good match for you. The average waiting time for a kidney from a dead donor is two to three years. While you are on the waiting list, the transplant team will evaluate your health periodically. You must have medical insurance that will cover the cost of a transplant or be able to pay for it yourself.

What happens during a kidney transplant?

A kidney transplant requires a stay in a hospital. Procedures may vary depending on your condition and your healthcare provider’s practices.

Generally, a kidney transplant follows this process:

• You will remove your clothing and put on a hospital gown.
• An intravenous (IV) line will be started in your arm or hand. More catheters may be put in your neck and wrist to monitor the status of your heart and blood pressure, and to take blood samples. Other sites for catheters include under the collarbone area and the groin blood vessels.
• If there is too much hair at the surgical site, it may be shaved off.
• A urinary catheter will be inserted into your bladder.
• You will be positioned on the operating table, lying on your back.
• Kidney transplant surgery will be done while you are asleep under general anesthesia. A tube will be inserted through your mouth into your lungs. The tube will be attached to a ventilator that will breathe for you during the procedure.
• The anesthesiologist will closely watch your heart rate, blood pressure, breathing, and blood oxygen level during the surgery.
• The skin over the surgical site will be cleansed with an antiseptic solution.
• The surgeon will make a long incision into the lower abdomen on one side. The surgeon will visually inspect the donor kidney before implanting it.
• The donor kidney will be placed into the belly. A left donor kidney will be implanted on your right side; a right donor kidney will be implanted on your left side. This allows the ureter to be accessed easily for connection to your bladder.
• The renal artery and vein of the donor kidney will be sewn to the external iliac artery and vein.
• After the artery and vein are attached, the blood flow through these vessels will be checked for bleeding at the suture lines.
• The donor ureter (the tube that drains urine from the kidney) will be connected to your bladder.
• The incision will be closed with stitches or surgical staples.
• A drain may be placed in the incision site to reduce swelling.
• A sterile bandage or dressing will be applied.

Talk with your healthcare provider about what you will go through during your kidney transplant.

Treatment of Kidney Transplant

The treatment plan determination uses multiple factors, including the type of rejection, the severity of the histological lesion, the chronicity score, and the recipient comorbidity. So what will be discussed is a general guideline, but tailoring medical treatment of individual characteristics is needed.[rx][rx]

1. Hyperacute rejection

No effective therapy usually leads to early allograft nephrectomy, and so prevention is the key by assuring through the following

• i) ABO-compatibility between donor and recipient. Sometimes, it is advisable to address ABO incompatibility under specific criteria, and careful pre-transplant preparation of recipient with the removal of anti-ABO antibodies by plasmapheresis is an option, IVIG with or without rituximab
• ii) Pre-transplant cross-match [complement cell cytotoxicity test]: Recipient serum is added to donor lymphocytes. If the test is positive (which means the recipient has an antibody that reacts with the donor HLA antigens on lymphocyte), one should not proceed with transplant unless these antibodies are removable pre-transplant.

2. Antibody-Mediated Rejection

The treatment of acute antibody-mediated rejection also depends on the level of the antibody levels. Higher antibody levels need plasma exchange for the removal of the antibodies. The following are the different modalities used for AMR:

• i) Plasma Exchange: 3 to 5 sessions daily on every other day is used for antibody removal followed by IVIG and rituximab
• ii) IVIG: IV immunoglobulin (100 to 200 mg/kg) is used followed by the last session of plasma exchange when used in combination with plasmapheresis or higher dose 2g/kg after the final session of plasmapheresis.
• iii) Rituximab: Anti CD20 cell antibody rituximab (375 mg/m^2) is used in combination with IVIG followed by plasma exchange
• iv) Bortezomib: Plasma cell inhibitor bortezomib (1.3 mg/m^2) is also used in combination with plasma exchange and IVIG
• v) Splenectomy: Splenectomy is very rarely an option, but there are anecdotal reports of successful treatment of refractory rejections
• vi) Optimize the dose and the level of the maintenance immunosuppressive drugs.

3. T Cell-Mediated rejection

They receive treatment with the following agents based on the severity of the lesion.

• i) Methyl Prednisone IV (250 to 1000 mg daily) targeting T cells, B cells, and macrophages; given for 3 to 5 days
• ii) rATG – Rabit anti-thymocyte globulin IV (1 to 1.5 mg/kg) targeting T cell receptors. The duration varies among different transplant centers, but in general, it is for 7 to 14 doses based on the response and Cd3 level.
• iii) Optimize the dose and the level of the maintenance immunosuppressive drugs.

4.  Chronic rejection

Since the antibody-mediated rejection mechanism is a major cause of chronic rejection, the same therapy as ABMR has been used, but generally, these measures are ineffective when Scr is over 3 mg/dl and/or heavy proteinuria.

Anti-Rejection Medications

Anti-rejection medications, also known as immunosuppressive agents, help to prevent and treat rejection. They are necessary for the “lifetime” of the transplant. If these medications are stopped, rejection may occur and the kidney transplant will fail.

Below is a list of medications that might be used after a kidney transplant. A combination of these drugs will be prescribed dependent on the specific transplant needs.

Anti-inflammatory Medication

Prednisone is taken orally or intravenously. Most side effects of prednisone are related to drug dosage levels. Prednisone is used at low dosages to minimize side effects. The possible side effects of prednisone are:

• Changes in physical appearance such as puffiness of the face and weight gain.
• Irritation to the stomach lining.
• Increased risk of bruising and decreased rate of healing.
• Increased sugar level in the blood (steroid-induced diabetes).
• Unexplained mood changes. This may mean depression, irritability, or high spirits.
• General muscle weakness or pain in knees or joints.
• Formation of cataracts. A clouding of the lens of the eye occurs infrequently with long-term use of prednisone.

Anti-proliferative Medications

Azathioprine (Imuran®) is taken orally or intravenously. The most common side effects associated with azathioprine are:

• Thinning of hair
• Irritation of the liver
• Decreased white blood cell count

Mycophenolate mofetil – Although most centers still use treatments based on steroids and ciclosporin, tacrolimus and mycophenolate mofetil have emerged as effective and well-tolerated options for inducing and maintaining immunosuppression.^[rx]  Mycophenolate mofetil (CellCept) is taken orally. The most common side effects of mycophenolate mofetil are:

• Abdominal aches and/or diarrhea
• Decreased white blood cell count
• Decreased red blood cell count

Mycophenolate sodium – is taken orally. It provides the same active ingredient as mycophenolate mofetil and generally has the same side effect profile. It is enterically coated to potentially reduce abdominal aches and diarrhea.
Sirolimus (Rapamune) is taken orally. The most common side effects of sirolimus are:

• Decreased platelet count
• Decreased white blood cell count
• Decreased red blood cell count
• Elevated cholesterol and triglycerides

Cytokine Inhibitors

Cyclosporine (Neoral, Gengraf) is taken orally. The most common side effects of cyclosporine therapy are:

• Kidney dysfunction
• Tremors
• Irritation of the liver
• Excessive body hair growth
• High blood pressure
• Swollen/bleeding gums
• High potassium in the blood
• Increased sugar level in the blood (drug-induced diabetes)

Tacrolimus

(Prograf) is taken orally. The most common side effects of tacrolimus therapy are:

• Kidney dysfunction
• High blood pressure
• High potassium in the blood
• Increased sugar level in the blood (drug-induced diabetes)
• Tremors
• Headaches
• Insomnia

Antilymphocyte Medications

Antithymocyte globulin (Thymoglobulin®) is given intravenously. Thymoglobulin can cause:

• Decreased white blood cell and platelet counts
• Sweating
• Itching
• Rash
• Fever

Muromonab-CD3 (OKT3)

It is given intravenously and can cause

• Chills
• Fever
• Diarrhea
• Headache
• Shortness of breath

Anti-interleukin 2 receptor antibodies

Another major advance in the area of induction immunosuppression is the development of the anti-interleukin 2 receptor antibodies (basiliximab and daclizumab). These drugs have produced impressive reductions in the rates of early rejection in adult and paediatric transplants ^[rx] Once again, cost issues have restricted the use of these promising drugs.

Anti-interleukin-2 Receptor Antibody (Zenapax or Simulect) These two drugs are given intravenously. These medications rarely cause side effects but can include:

• Chills
• Headache
• Allergic reaction

Alemtuzumab (Campath)

• Fever
• Chills
• Rash
• Shortness of breath
• Decreased white blood cell counts

Sirolimus

Sirolimus is another immunosuppressant that has entered the clinical arena in the United States and, more recently, in Europe. Impressive reductions in the rates of early rejection and hypertension with sirolimus compared with alternative agents need to be balanced against adverse changes in lipid profiles and a lack of data on long term outcome.^[rx]

Ciclosporin

Almost 20 years after ciclosporin’s introduction, clinicians are still learning how to use this drug. Recent studies have shown that it is better to adjust the dose of ciclosporin according to blood levels two hours after treatment (C2 monitoring) than trough levels. Preliminary data show that this new technique produces reductions in rejection rates and side effects.^[rx] The advantage of this technique needs to be compared with the claims of alternative immunosuppressive agents.

CNI Minimization

• Minimization refers to lowering target blood trough levels of CNIs, with or without another immunosuppressive agent. A systematic review and meta-analysis showed that CNI minimization was associated with a relatively low risk of AR and overall improved allograft function.[rx] The timing of CNI minimization was also studied. CNI minimization during the first six months post-transplant reduced the incidence of rejection compared to reducing CNI doses in the second 6 months post-transplant. No head to head trials, however, were conducted to compare early and late minimization directly.
• Combining low dose CNI with mycophenolic acid (MPA) preparations also reduced the risk of AR with no difference in mortality. Pairing CNI minimization with a mammalian target of rapamycin (mTOR) inhibitor (such as sirolimus or everolimus) did not increase the risk of biopsy-proven AR. It led to an improvement in kidney function in some studies. It is worth noting. However, that full dose CNI plus mTOR inhibitor therapy increases the risk of nephrotoxicity.[27]

CNI Conversion

• Conversion refers to switching CNI to another maintenance drug. Converting from CNI to an mTOR inhibitor showed improvement in kidney function, which was more observed with the conversion from Cyclosporine compared to Tacrolimus.[rx] Conversion to an mTOR inhibitor was also associated with a lower risk of cytomegalovirus (CMV) infection.[rx]
• Conversion to Sirolimus showed better outcomes in patients with GFR exceeding 40 ml/min with less proteinuria, suggesting that conversion should occur before significant parenchymal damage.[rx] Grimbert et al. suggested that early conversion to mTOR inhibitors within one year was associated with increased production of dnDSA, which increased the risk of antibody-mediated rejection.

CNI Withdrawal

• Withdrawal refers to tapering CNIs until completely discontinued. CNI withdrawal with either MPA or mTOR inhibitor-based regimens was associated with an increased risk of rejection. Early withdrawal (<6 months post-transplant) was associated with an increased risk of graft loss, with insufficient evidence for both rejection and a decrease in renal function. Late withdrawal with the continuation of MPA preparations was associated with an overall greater risk of rejection.[rx] CNI withdrawal from Azathioprine based regimens was also associated with increased rejection.[rx]

CNI Avoidance

• Avoidance refers to CNI free regimens planned from the start. Initial trials to avoid CNIs while using Daclizumab or anti-thymocyte globulin were associated with an increased risk of AR, which required reintroduction of CNIs in some patients.[rx] Sirolimus based immunosuppression regimens were also compared to CNI based regimens. Comparing Sirolimus to Tacrolimus in MPA based regimens showed an increased risk of graft loss. Sirolimus, however, was associated with improved kidney function and reduced risk of CMV infection.[rx]

Belatacept

• A novel fusion protein that inhibits T cell activation, was also compared to CNI based regimens. Vincenti et al. randomized patients into three groups; a Cyclosporine, an intensive Belatacept, and a less intensive Belatacept based regimen. Patients were followed for seven years.
• Patients on Belatacept based regimens showed a 43% reduction in risk of graft loss and death, compared to cyclosporine. Kidney function improved in both belatacept based regimens, while it declined with cyclosporine.[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK549762/
• https://www.ncbi.nlm.nih.gov/books/NBK234415/
• https://www.ncbi.nlm.nih.gov/books/NBK553074/
• https://www.ncbi.nlm.nih.gov/books/NBK75298/
• https://www.ncbi.nlm.nih.gov/books/NBK174855/
• https://www.ncbi.nlm.nih.gov/books/NBK535435/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970386/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391826/
• https://pubmed.ncbi.nlm.nih.gov/15249346/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549004/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1122448/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798135/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216502/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354079/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031688/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524555/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106688/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530294/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881977/
• https://en.wikipedia.org/wiki/Kidney_transplantation
• https://medlineplus.gov/kidneytransplantation.html
• https://www.nhs.uk/conditions/kidney-transplant/risks/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/kidney-transplantation
• https://www.health.harvard.edu/diseases-and-conditions/kidney-transplant
• https://www.kidney.org/atoz/content/kidney-transplant
• https://www.mayoclinic.org/tests-procedures/kidney-transplant/about/pac-20384777
• https://www.niddk.nih.gov/health-information/kidney-disease/kidney-failure/kidney-transplant
• https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/kidney-transplant
• https://transplantsurgery.ucsf.edu/conditions–procedures/kidney-transplant.aspx
• https://www.urologyhealth.org/urologic-conditions/kidney-transplant
• https://nephcure.org/livingwithkidneydisease/kidney-failure/transplant/
• https://www.mykidney.org/TreatmentOptions/KidneyTransplant.aspx
• https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=92&contentid=P07708
• https://www.crozerkeystone.org/transplant
• https://columbiasurgery.org/conditions-and-treatments/living-donor-kidney-transplants
• https://www.emedicinehealth.com/kidney_transplant/article_em.htm
• https://www.bcm.edu/healthcare/specialties/transplant/abdominal-and-liver-transplant/kidney-transplant
• https://www.barnesjewish.org/Medical-Services/Transplant/Kidney-Transplant/Kidney-Failure
• https://stanfordhealthcare.org/medical-treatments/k/kidney-transplant-surgery/complications.html
• https://www.pinnaclehealth.org/our-services/transplant-program/kidney-transplant/
• https://myhealth.alberta.ca/Health/aftercareinformation/pages/conditions.aspx?hwid=ud1689
• https://www.mainlinehealth.org/specialties/kidney-transplant-program/surgery-and-organ-donation