8.1.1 Organs for Transplantation

Organs from brain‐dead donors are the main source for renal transplantation. Although it would be desirable to have all patients with ESRD undergo transplantation, this is not possible because of the shortage of donor organs.

There are a number of ethical and regulatory guidelines and legislations surrounding organ donations. These are highly dependent on cultural and historical attitudes of each country. These vary from organ retrieval from patients who are brain dead without explicit consent to the need for formal written declaration of either the deceased or the next of kin. The number of organ donations varies amongst different countries depending on attitudes and legislation [2] (Table 8.2).

As the need for donor kidneys is much greater than actual donations, measures aimed at increasing the organ pool have been implemented, such as less stringent criteria regarding donor age and comorbidities. This has led to the use of kidneys from much older donors and of so‐called ‘marginal organs’. Experience has shown that reasonable results can still be obtained.

An alternative to the use of cadaver donor organs is life donation. Again, legislation differs amongst countries. Some allow it for unrelated and even unconnected persons (e.g. the US and the UK), whereas others restrict it to relatives and closely connected persons. Commercial life donation is illegal in European countries but allowed in some other countries (e.g. Iran). Some Asian countries have programs of using organs from donors who undergo the death penalty (e.g. Singapore and China). ‘Cross‐over’ live donor transplantation between couples with an incompatible ABO constellation is legal in only some countries (i.e. Netherlands, UK, US). The US and the UK also allow for so‐called ‘altruistic kidney donation’, which is a completely unrelated and anonymous live kidney donations [3].

8.1.2 Organ Allocation

The procurement, allocation, and transplantation of human organs is regulated by law and special authorities oversee this process. In the UK, this is the Human Tissue Authority (HTA). Organ allocation can be on a purely national basis (e.g. UK, Norway, Switzerland, and France), whereas other European countries (Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, Netherlands, and Slovenia) have formed a multinational institution, Eurotransplant, to increase the donor pool and improve matching.

Allocation is based on age, waiting time, blood group, human leucocyte antigen (HLA) matching, and in some countries (e.g. the UK), on body size of donor and recipient. Children are given priority. The waiting time varies between different programs. In the UK, on average it is three years and in Germany five. Patients with rare blood groups and rare HLA‐constellations have a longer wait time.

8.1.3 Waiting Lists and Preparation of the Recipient

Putting a patient on a waiting list for kidney transplantation requires the diagnosis of ESRD. The day on which chronic dialysis begins is counted as the beginning of the wait time. ‘Preemptive renal tranplantation’ before a patient has actually become dependent on dialysis is only possible with a live donation.

Contraindications against renal transplantation are conditions which endanger the success of the surgical procedure, risk severe complications of immunosuppression, or put doubt on the necessary compliance required for successful immunosuppressive treatment [3, 4]. A history of malignancy requires several years of recurrence‐free survival before immunosuppression can be considered safe (Table 8.3).

Investigations need to assess cardiovascular fitness for anaesthesia and surgery, to exclude common malignancies, to examine the state of the large pelvic vessels and the degree of renal anaemia, hypertension, and secondary hyperparathyroidism. Chronic or latent infections of the urinary tract should be treated. Bladder capacity and residual diuresis have to be assessed. In severe bladder disorders, preparations for urinary diversion with renal transplantation must be considered.

Pretransplant nephrectomy is indicated for nonfunctioning kidneys that are a source of repeated infections, bleeding, or the cause of medically refractory hypertension. In patients with polycystic kidneys, it is usually not necessary to remove a kidney to make room for a transplant. It is better to leave both native kidneys unless they cause problems because the residual water diuresis increases the quality of life (QoL) under dialysis considerably.

All potential recipients require blood group and HLA typing as well as the assessment of the presence of preformed antibodies. For a successful transplantation, the risk of rejection needs to be minimised. ABO blood group compatibility and as much HLA compatibility as possible is aimed for. Preformed antibodies may exist as a result of previous exposure to HLA‐antigens by blood transfusion, pregnancies, or may be have been induced by autoimmune diseases. A high level of preformed antibodies does not preclude successful transplantation, but immunosuppression needs to be more intensive.

8.1.4 Selecting Donors

Potential donors who are brain have to be screened for infections and cancer, so that these are not transmitted to the immunocompromised transplant recipient. Contraindications for organ donation in general are listed in Table 8.4.

Brain death implies that there is irreversible loss of brain stem function, and this is based on neurological examination, electroencephalogram (EEG), or cerebral angiography. Usually, these investigations have to be repeated to document irreversibility. Diagnostic criteria for brain death is strict and should be made by physicians not involved with organ procurement and transplantation (Table 8.5). It is the duty of the explanting surgeon to make sure that the appropriate criteria for the diagnosis of brain death have been used.

Concern for the feelings of bereaved relatives as well as the need to release scarce intensive care resources require that surgery for organ retrieval should be performed soon [5]. If consent from the next of kin is required, a trained transplant coordinator is likely to have the necessary skills to present organ donation as an opportunity for good amidst tragedy.

8.1.5 Kidneys from Living Donors

Organs from living donors could potentially make up for the shortage of cadaveric kidneys. There are several advantages of live‐donor renal transplantations: the donor and recipient operations can be planned and performed almost simultaneously so that ischaemia time is minimised. Secondly, persons selected for live kidney donation are healthy, and therefore, live donor kidneys are perfect kidneys in contrast to cadaver kidneys, which are often of comparatively poor quality.

In addition to the contraindications that apply to all donor kidneys (Table 8.4), the potential life donor must not be under emotional, social, or even financial pressures for the donation. The surgery for kidney retrieval has some morbidity, and a small but undeniable risk of mortality. There can be untoward psychological sequelae regardless of whether or not the transplantation is successful. Overall life expectancy is not impaired after kidney donation, but there seems to be a slightly increased risk of developing ESRD. Potential donors, therefore, have to be adequately counselled and need to understand all aspects of the sacrifice they are making.

The donor’s medical work‐up has to include split renal function studies, an intravenous urogram or computed tomography (CT), and renal arteriograms as well as a investigations aimed at identifying contraindications.

8.2.1 Cadaver Donor

The donor who is brain dead needs to be conditioned for safe procurement of organs in good condition. Blood volume has to be increased by intravenous fluids and diuresis and cardiovascular stability need to be maintained (e.g. mannitol, diuretics).

Anaesthesia is not required for organ removal in donors who are brain dead. However, occasionally there are spinal reflex movements which can be disturbing to the staff and are not helpful for promoting organ donation. It is better to avoid this altogether by relaxation.

Donor kidneys need to be removed with long renal vessels, intact hilar fat, and the fine vessels that supply the ureter. In a heart‐beating donor, there is usually no need for haste, unless there is circulatory instability.

A long midline incision is made from the xiphoid process to the symphysis, for multiorgan removal, the thoracic cavity needs to be opened as well. All organs should be inspected for malignancy or infection. The ascending colon and small bowel are mobilised by incising their peritoneal reflections and placed on the chest (Figure 8.1). The superior mesenteric and coeliac arteries are divided for access to the aorta well above the renal vessels (Figure 8.2). Aorta and vena cava are taped just above the bifurcations, the aorta is clamped at the level of the coeliac artery, and a tube is inserted (Figure 8.3). Cooled preservation solution (4 °C) is run in, usually 4 l, until the effluent from the vena cava is quite clear. The perfusion cools the organs and reduces their metabolism as well as oxygen demand. Secondly, the organs need to be flushed free of all blood which would otherwise clot in all small vessels.

The aorta and vena cava can be removed en bloc with the kidneys, or they can be split open in the midline and divided posteriorly before removal (Figure 8.4). The latter approach allows for close inspection of additional renal vessels because it is of utmost importance to secure all renal arteries and veins if there are several. The upper two‐thirds of the ureters are dissected, preserving their blood supply (Figure 8.5). The kidneys with their patch of aorta and vena cava are then removed and placed in a bowl of cooled perfusion fluid. A slice of splenic tissue is removed for tissue typing. The kidneys are then placed in sterile bags with perfusion fluid and packed into an ice‐cooled container for transportation.

As the feelings of relatives who may wish to see the deceased donor later need to be respected, wound closure should be diligent, including wound dressing, and furthermore, the body should be clean at the end of surgery.

8.3.1 The Major Histocompatibility Complex

Recognition of a transplanted organ as ‘non‐self’ is caused by the recipient’s immune system recognising antigens on the cell surface of donor cells. These antigens are found in vertebrates on most nucleated cells and are determined by a set of genes on chromosome 6, called the ‘major histocompatibility complex’ (MHC). There are also minor histocompatibility (miH) factors, which can lead to graft rejection between siblings, even when all the known antigens of the MHC have been correctly matched.

The genes of the MHC system are divided into classes I, II, and III. MHC class I proteins are cell surface glycoproteins consisting of two chains; the heavy chain activates CD8 T‐cells, and the light chain CD4 T‐cells. MHC class II proteins are expressed only on B‐cells, dendritic cells (DCs), and some endothelial cells. MHC class III genes encode for mediators such as tumour necrosis factors (TNF‐α and ‐β).

One‐half of the MHC genes come from the father, and the other half from the mother. Siblings and parents, therefore, have half their MHC antigens in common (Figure 8.15). With two alleles at each MHC locus, most individuals can express six different MHC class I proteins and eight different MHC class II proteins. Combined with the polymorphism at this locus, this means for unrelated individuals that MHC‐identical donors and recipients are extremely rare. Even if they are found, miH antigens are invariably different. Complete identity is only possible with monozygotic twins.

Patients who have been exposed to MHC antigens through previous transplantation, transfusions, or pregnancy often develop antibodies against those MHC antigens (preformed antibodies).

8.3.2 The Human Leucocyte Antigen System

In humans, the MHC is called the ‘HLA system’ because it was first studied on white blood cells.

The HLA system is a complex multigene family of more than 10 loci. The genes and their products are classified into two types: HLA class I and HLA class II. HLA class I genes are situated at the telomeric end of the 6p21.3 region of chromosome 6 (Figure 8.16). This region encodes the classic transplantation antigens HLA‐A, HLA‐B, and HLA‐C, which are expressed on nucleated cells. There are many other class I HLA loci.

The HLA class II region consists of three main loci (i.e. HLA‐DR, HLA‐DQ, and HLA‐DP). The gene products are expressed on cells with immune functions (i.e. B‐cells, activated T‐cells, and antigen‐presenting cells) and is induced during inflammatory processes.

Graft survival correlates with the number of HLA haplotypes shared by the donor and recipient. Therefore, HLA matching is done for organ allocation. However, there is large polymorphism of HLA proteins expressed because of variations of several or even single amino acids. This means that HLA specificities can be further subclassified by serological methods and even more so by DNA‐based typing methods.

8.3.3 The ABO Blood Group System

With cadaver donor transplantation, donor and recipient must have the same ABO blood group. Antibodies to the ABO blood group antigens are preformed or natural antibodies. ABO incompatibility between donor and recipient leads to hyperacute rejection.

According to the frequency of the different ABO blood groups in the population, there is a shortage of A donors, and patients with this blood group on average have a longer waiting time for a kidney, especially if they are rhesus negative.

In ABO‐incompatible live‐donor transplantation, the recipient’s ABO antibodies can be removed by repeated immunoadsorption and the use of B‐cell depleting drugs (rituximab) before transplantation. The later reappearance of these antibodies is generally not associated with rejection (i.e. accommodation) [14].

8.3.4 HLA‐Typing in Renal Transplantation

The number of HLA‐specificities that can be routinely tested is limited. These are the three class I antigens HLA‐A, HLA‐B, and HLA‐C and three class II types HLA‐DR, HLA‐DQ, and HLA‐DP. Because of the polymorphy of HLA‐antigens, this typing with broad specificity may result in ‘good matching’, but at a more specific level, several mismatches may actually be present [15].

More specific matching is not feasible for several reasons. The logistics of matching for such a diverse polymorphic antigenic system are complex; the increased ischemia time associated with an extensive matching process would lead to poorer outcomes, and there is a diminishing effect of HLA matching on transplantation outcome with modern more potent immunosuppressive regimens.

However, even with limited matching, the chance of finding an HLA identical recipient is small. It is higher if there is a large pool of recipients with their HLA status kept on a central register. The kidneys are sent to the best matched available recipient. Complete identity of the six HLA loci tested (a ‘full house’ organ) is desirable. In practice, for most renal transplantations, there are between one and three mismatches.

8.3.5 Cross‐Matching and Preformed Antibodies

Patients with donor‐specific sensitising have a high risk of hyperacute rejection, but this has been virtually eliminated by routine cross‐matching. This consists of testing donor lymphocytes and recipient serum for preformed antibodies. There are different techniques of cross‐matching, and there is an ongoing debate about which preformed antibodies are damaging and which are not. In most cases, IgG HLA class I and class II‐specific antibodies represent a contraindication to transplantation.

Highly sensitised patients are those with more than 85% of preformed antibodies. To find acceptable donors for such patients, ‘acceptable mismatch programs’ have been instituted by many programs defining minimal criteria (e.g. for the HLA‐DR locus). Another approach is allowing for paired live donor transplantation [16].

8.4.1 Reperfusion Injury

The first stage results from the severe physical assault that the organ is subjected to during harvest from the donor including the haemodynamic and neuroendocrine responses to brainstem death and transplantation into the recipient including many hours of preservation under artificial conditions. All these events sensitise the organ to ‘reperfusion injury’ when it is warmed rapidly on revascularization in the recipient.

During and shortly after the ischemia and reperfusion periods, a variety of genes become activated and inflammatory cells begin to infiltrate the graft. The effectors of this first nonadaptive and not antigen‐specific response are part of the innate immune system (i.e. activated endothelial cells, macrophages, and interleukins [IL‐1, IL‐6]) as well as complement factors. The inflammatory response also triggers the migration of bone‐marrow derived donor DCs out of the graft.

This early response does not constitute graft rejection, but the severity of the initial injury and the subsequent inflammatory reaction are central in the stimulation of antigen‐specific immunity later. A much damaged organ generates a strong ‘danger signal’, which initiates stronger responses when donor and recipient are antigenically different.

8.4.2 Adaptive Immunity

The next phase is characterised by presentation of donor antigens to infiltrating recipient T‐cells which then become activated, proliferate, and differentiate to a variety of other cells, which infiltrate the graft and destroy it unless effectively suppressed (Figure 8.17). The antigens that stimulate graft rejection are cell surface MHC (HLA) antigens and numerous miH systems. Incompatibility for either MHC or miH antigens lead to an immune response, but rejection is stronger with MHC incompatibilities [17].

8.4.3 Antigen Presentation

For a strong immune response, MHC antigens need to be presented to the recipient. Bone‐marrow derived DCs, which migrate from the graft into the recipient, are essential (direct antigen presentation). They present MHC class I and class II antigens, produce various costimulants and cytokines, and stimulate T cells, especially CD4⁺ and CD8⁺ cells. Recipient DCs, which infiltrate the graft, are also capable of recognising donor MHC antigens and presenting this antigenic information to immune system effectors (indirect antigen presentation).

8.4.4 Types of Immune Response

Activation of T‐cells requires several costimulatory signals for downstream intracellular activation, such as CD28. Following this, B‐cells, DCs, and monocytes are activated. A response develops, which is either predominantly cell‐mediated or humoral. Which of the two happens is largely cytokine‐regulated.

Interferon‐γ (IFN‐γ) is the prototypical cytokine, and if it dominates, the rejection will be cell‐mediated leading to the appearance of activated macrophages and specific circulating T‐cells. If IL‐4, ‐5, and ‐6 predominate, this will lead to humoral rejection. Thus, the local cytokine milieu seems to be important for determining which type of rejection occurs.

8.4.5 Migration of Activated Cells

Activated leucocytes migrate into the graft by adhering to the graft endothelium. This requires complex leucocyte‐endothelial interactions involving specific proteins (i.e. selectins, integrins, and immunoglobulins). Selectins control the first loose attachment of leucocytes (‘rolling’) along endothelial surfaces, which leads to the endothelial cells expressing IL‐8 and platelet‐activating factor. These lead to stronger leucocyte adhesion and arrest of the rolling process. L‐selectin and other proteins produced by the leucocytes enables extravasation.

Chemokines from the graft such as α‐chemokines (which attract neutrophils and T‐cells) and β‐chemokines (which attract monocytes/macrophages, DCs, and natural killer [NK] cells) support graft infiltration.

8.4.6 Graft Destruction

The immune response mounted depends on antibodies, unspecific cellular reactions as well as specific cytotoxic cells and cytokines. Antibodies can fix complement, especially complement component 4d (C4d), which recruits macrophages and activates endothelial cells. The point of entry, and therefore, the site of the most severe inflammatory reaction and destruction is the endothelial structure of the graft. Destruction of the small vessels of the graft occurs primarily and can be seen histologically while parenchymal changes are secondary to destruction of the vasculature.

8.4.7 Clinical Types of Rejection

There are three types of rejection: hyperacute, acute, and chronic.

8.4.8 Hyperacute Rejection

Hyperacture rejection is due to preformed antibodies (donor‐specific HLA class I antibodies) and can occur intraoperatively or within hours postoperatively. With hyperacute rejection, the graft kidney swells, takes on a dark colour, and infarcts within minutes of its circulation being restored.

Recipient antibodies against donor HLA antigens bind to the vascular endothelium of the graft, disrupt intercellular junctions, and induce the release of mediators leading to rapid uncontrollable activation of intravascular thrombotic and complement activation [18]. This results in intravascular coagulation and interstitial haemorrhage and destruction of the graft within minutes.

8.4.9 Acute Rejection

Acute rejection occurs any time after about one week up to three months. It is a result of cell‐mediated immunity in the majority of cases, whereby the graft is infiltrated by large numbers of activated T‐cells (cellular rejection). Clinically, the kidney swells, becomes tender, and its function declines. There may be systemic symptoms such as fever, malaise, or hypertension. Acute rejection can also, less commonly, be predominantly mediated by antibodies (humoral rejection).

Acute rejection can be initiated by failure to take the drugs, infection, or a blood transfusion. Transplant biopsy is required, showing dense cellular infiltration and oedema and can determine the type of rejection and its severity (i.e. Banff classification) [19].

8.4.10 Chronic Rejection

Chronic rejection can occur any at any time after transplantation and is a gradual deterioration in renal function which does not improve when the dose of immunosuppressants is increased. Biopsy shows interstitial fibrosis and tubular atrophy, which are the hallmarks of chronic rejection; there is also intimal fibrosis of arteries with hyalinization of glomeruli. Chronic rejection is a slow process which seems to occur in many renal transplants over the years and is held responsible for the slow but steady decline of transplant function starting many months or years after successful transplantation. It underlies the late graft loss seen in many patients [20].

8.5.1 Corticosteroids

Steroids reduce T‐cell proliferation and inhibit the production of IL‐2 and of Il‐1 and IL‐6 in macrophages. They also inhibit the migration of monocytes to areas of inflammation such as acute rejection. Prednisone and prednisolone are metabolised in the liver where prednisone is converted to prednisolone. Their half‐lives are increased in hepatic disease and shortened if taken together with drugs that induce hepatic enzymes. The sensitivity of lymphocytes to steroids can vary individually as well as under the influence of other immunosuppressants, accounting for the so‐called ‘steroid resistance’ seen in some patients.

Side effects of steroids are numerous, and considerable and most protocols today aim at tapering the steroid dose shortly after transplantation or using a steroid‐free maintenance protocol. Large‐dose steroid treatment is used in acute rejection.

8.5.2 Azathioprine

Azathioprine was used until cyclosporine became available. It is a derivative of mercaptopurine, is activated by hepatic metabolism, and inhibits purine synthesis, blocking DNA and RNA synthesis in lymphocytes and IL‐2 production. It is catabolised by xanthine oxidase, and thus, there is an interaction with allopurinol. Azathioprine has been largely replaced by mycophenolate, but it is an inexpensive drug still used in many countries.

8.5.3 Calcineurin Inhibitors: Cyclosporine and Tacrolimus

8.5.4 Mycophenolate Mofetil (MMF)

Mycophenolic acid (MPA), also a fungal product, inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH) and thereby the synthesis of guanosine nucleotides in T‐ and B‐cells. A synthetic analogue of MPA, mycophenolate mofetil (MMF), has better oral bioavailability. MMF is rapidly metabolised to an inactive glucuronide, but has a long half‐life (17 hours), but plasma levels need to be monitored. Gastrointestinal side effects (diarrhoea, indigestion, and reflux) and bone marrow toxicity occur. With MMF, viral infections are more common.

8.5.5 mTOR Inhibitors

Sirolimus and everolimus block T‐cell proliferation by inhibiting the mammalian target of rapamycin (mTOR) [22]. Sirolimus (rapamycin) is the product of a microorganism first isolated from soil from the Easter Island (Rapa Nui), giving it its name, and everolimus is a synthetic analogue. Both bind to an intracellular immunophilin (FK506‐binding protein) which forms a complex with a serine‐threonine kinase (mTOR). This is a key point in the cell cycle regulatory pathway. Both drugs block lymphocyte proliferation and IL‐2 transcription and inhibit tumour cell growth. The incidence of posttransplant malignancy is reduced. Specific side effects are changes in lipid metabolism, delayed graft function, bone marrow suppression, and disturbed wound healing [23].

Sirolimus has a long half‐life (60 hours), but everolimus has a short half‐life (16–18 hours). Both drugs are given orally. Dosing should be concentration controlled and metabolism is also by cytochrome P450 (CYP3A4).

8.5.6 Antibodies

Antibodies are used for the treatment of rejection. By immunising animals with human lymphocytes, heterogenous polyclonal sera can be obtained, which contain many antibodies with largely undefined specificities (i.e. antithymocyte globulin [ATG]). Polyclonal antibodies react with many different antigens and the animal proteins can cause allergic or anaphylactic responses. Fever, urticaria, rash, and headaches occur. The physiological half‐life of these antibodies is several weeks.

With cell hybridization, monoclonal antibodies (mAb), which suppress T‐cells and their subsets, are available. MAb preparations contain a single specific antibody and their action is more predictable. OKT3 (muromumab, murine anti‐CD3) is an IgG2a mouse antibody binding human CD3. It mediates complement‐dependent cell lysis and rapidly clears T‐cells from the circulation.

Polyclonal and monoclonal preparations with anti‐T‐cell antibodies are used for the treatment of steroid‐resistant rejection. Other specific mAbs are anti‐CD25 (daclizumab, basiliximab), anti‐CD25 (alemtuzumab), and anti‐CD20 (rituximab) which can be used for induction and rescue treatment. The B‐cell depleting effect of rituximab is used for ABO‐incompatible transplantation and for the treatment of humoral rejection.

8.5.7 Belatacept

Belatacept is a fusion protein and acts as a selective blocker of T‐cell‐costimulation. It binds to CD80 and CD86 on antigen‐presenting cells. This blocks the CD28‐costimulation of T‐cell activation [24]. It is given as an induction treatment and during the first weeks after transplantation. Ebstein‐Barr virus infections and posttransplantation lymphoproliferative disorder (PTLD) seem to occur more frequently with belatacept.

8.5.8 Side Effects of Immunosuppression

All immunosuppressive agents have side effects which occur with time even after years of treatment. Azathioprine causes bone marrow depression. Corticosteroids induce diabetes, osteoporosis, obesity, and other unwanted effects. MMF can cause leucopenia and thrombocytopenia. Tacrolimus is diabetogenic. Calcineurin inhibitors can provoke hypertension and are nephrotoxic. mTOR inhibitors cause gastrointestinal problems and disturbances in wound healing.

Infections and the development of malignancies are more common with immunosuppression. Infections with ubiquitous viruses (i.e. cytomegaly, herpes simplex, zoster, and BK virus) are common after renal transplantation, especially with MMF treatment. Urinary tract infections can lead to pyelonephritis and graft dysfunction. Infectious agents not dangerous to immunocompetent hosts can be life‐threatening in transplant recipients (e.g. pneumocystis).

The incidence of de novo malignancies is increased about 10‐fold with immunosuppression, the most common being skin cancers. The risk of malignancy is proportional to the immunosuppressive potency but lowest with mTOR inhibitors. A specific malignant disorder due to immunosuppression is the PTLD.

8.5.9 Immunosuppressive Treatment Regimens

Immunosuppressive treatment used can be characterised as induction, maintenance, or rescue therapies. Induction immunosuppression is intensive treatment used to suppress immune responsiveness at the time of transplantation. Maintenance treatment is less potent but is tolerable for long‐term use in a steady state. Rescue therapy is used with acute rejection and is – like induction therapy – intense and fairly toxic so that it cannot be given for prolonged periods of time.

8.5.10 Treatment of Rejection

The treatment of rejection requires biopsy, which will determine which type of rejection is present. First‐line treatment is by high dose steroids for three days. Failing this, humoral rejection requires plasmapheresis and perhaps rituximab. Second‐line treatment for cellular rejection is by antibodies (i.e. ATG, OKT3). In addition, the maintenance immunosuppressant may need to be changed [25].