Introduction

For many patients, the optimal treatment of their end-stage renal failure (ESRF) is kidney transplantation because it not only improves quality of life but may also confer survival benefits (EBM 25.1). Liver, heart and lung transplantation can be truly life-saving, as often no alternative treatments are available. The two main obstacles to transplantation are overcoming the recipient’s immune response and a shortage of donor organs.

Transplant immunology

The basis of transplant immunology is the host’s recog-nition of foreign tissue and its subsequent response to that. Our understanding of the molecular basis of this response has developed significantly over the last 50 years, which has allowed clinical transplantation to expand enormously. The process of transplant rejection, caused by infiltrating leucocytes, exhibits both specificity and memory and is prevented by lymphocyte depletion. The major histocompatibility complex (MHC) encodes the predominant transplant antigens responsible for acute rejection, and these are identical to serologically defined human leucocyte antigens (HLA).

The recipient’s immune response to the donor organ

Early events

Inflammation lies at the heart of the rejection process and is activated through early events around the time of transplantation. Brain-stem death and retrieval of organs, as well as cold ischaemic time (while the organ is stored on ice) and a period of warm ischaemia (while the vascular anastomoses are completed) stimulate an early inflammatory response to the transplanted organ. Reperfusion is associated with endothelial activation and the infiltration of inflammatory cells, particularly macrophages. The importance of this early ischaemia reperfusion injury (IRI) in shaping the patient’s subsequent course is illustrated by the superior outcome observed following living donor transplantation, despite more significant major histocompatibility (MHC) mismatching, and the adverse impact of a more prolonged cold ischaemic time on graft outcome. Indeed, the severity of this inflammatory injury modulates the subsequent alloimmune response, generating a ‘danger signal’ which primes the immune response to the transplanted organ. Thus, IRI impacts upon long-term outcome: it leads to a delay in primary graft function, increases acute rejection rates and reduces long-term graft survival (EBM 25.2). The crucial role of IRI in mediating transplant-associated injury has become more apparent as acute rejection rates fall with the introduction of new and highly effective immunosuppressive agents, and has led to an increasing interest in how IRI may be reduced through preconditioning strategies.

25.2 Impact of delayed graft function on long term outcome

‘Delayed graft function, defined as the requirement for dialysis during the first week following transplantation is associated with:

41% increased risk of graft loss at 3 years

Higher serum creatinine at 3.5 years

38% relative increased risk of acute rejection,

Compared with patients that have primary function’

Yarlagadda SG, Coca SG, Formica RN Jr, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant. 2009 Mar;24(3):1039-47. Epub 2008 Dec 22.

The afferent arm of the immune response

The immune response to the transplanted organ can be divided into afferent and efferent arms: the afferent arm includes presentation of donor antigen to recipient T cells, T cell receptor (TCR) binding and costimulation, which leads to T cell activation. The efferent arm describes the sequence of events that occurs as a result of T cell activation.

Antigen presentation

Donor MHC antigens are recognized as foreign (allo- recognition) by recipient T cells following presentation upon donor (direct) or recipient (indirect) antigen-presenting cells (APCs) (Fig. 25.1).

Fig. 25.1 Antigen presentation.

A Direct. B Indirect. (APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor)

T-cell receptor binding and costimulation

MHC antigen-binding to the T-cell receptor (TCR) in the presence of certain co-stimulatory molecules leads the T cells to undergo clonal expansion. Engagement of the TCR can result in a number of possible outcomes, depending on the costimulatory stimulus, and leads to T-cell proliferation, apoptosis or anergy. Costimulatory blockade is an interesting therapeutic strategy which has recently been introduced into clinical practice, with some benefit.

T-cell activation

Antigen binding and costimulation leads to the activation and clonal expansion of T cells. T cells differentiate into helper (CD4-positive) and effector (CD8-positive) cells that are able to secrete cytokines and kill target cells. Engagement of the CD4-positive T (helper) cells play a central role in initiating and amplifying the rejection response.

The efferent arm of the immune response

Donor organ damage can be mediated via cellular or antibody-mediated (humoral) mechanisms. The latter depends on B-lymphocyte maturation and the production of antibodies that activate complement. The former, also known as delayed-type hypersensitivity (DTH), involves cytotoxic T cells, natural killer (NK) cells, macrophages and neutrophils.

Immunosuppression

The challenge is to minimize the risk of graft rejection with as few side effects as possible. Various strategies are adopted: induction therapy, maintenance immunosuppression and treatment of rejection. The mechanisms of action of the common immunosuppressive drugs are outlined on Figure 25.2.

Fig. 25.2 Mechanisms of action of common immunosuppressive agents.

Organ donation

The shortage of organs for transplantation remains a major challenge to the transplant community, with demand consistently outstripping supply over many years (Fig. 25.3). Such a shortage has led to significant changes in practice over the last decade, with an increasing number of patients undergoing transplants from living donors, and from marginal or extended criteria deceased donors. These will be discussed in this section.

Fig. 25.3 Number of cadaveric donors and transplants in the UK, 1 April 1995 to 31 March 2009, and patients on the waiting lists at 31 March each year (ODT statistics).

Donor management

Specific criteria must be met in order to make the diagnosis of brain-stem death (Table 25.4). Events leading up to brain death may impact upon the quality of the retrieved organs. Initially, at the point of brainstem death, compression associated with coning results in hypertension and bradycardia, known as the Cushing reflex. An autonomic storm ensues, characterized by the massive release of catecholamines, with resultant hypertension and hypoperfusion. The effect on cardiac function is the deterioration of ventricular systolic function, the liver and kidneys are affected by hypoperfusion, and it is likely that these changes contribute to non-specific endothelial cell damage, which increases the immunogenicity of the organs.

Table 25.4 Criteria for diagnosis of brain-stem death

Thus the clinical management of the donor focuses on providing cardiovascular stability and maintaining organ function. The first principle is to ensure optimal fluid management, maintaining blood pressure with minimal inotropic support. The use of thyroxine replacement is controversial, and insulin may be required.

Multiorgan retrieval

Donors following brain death (DBD) are indistinguishable from other critical care patients so it is essential that the lead surgeon identifies the patient in the operating theatre prior to commencement of surgery. The preoperative check must also ensure complete documentation of brain-stem death tests, consent and donor blood group.

Organ retrieval begins with opening the abdomen (midline incision) and the chest (sternotomy). Once other pathology has been excluded and the liver mobilized, exposure of the inferior mesenteric vein and the aorta allows insertion of the perfusion cannulae (Fig. 25.4). Cold perfusion is commenced and the vena cava is divided in the mediastinum. Crushed ice is placed throughout the peritoneal cavity, with particular emphasis on the organs to be retrieved. The heart and lungs are excised. The pancreas is usually retrieved in conjunction with the liver. The kidneys are excised with ureters and the renal arteries on aortic patches. A portion of spleen and mesenteric lymph nodes are excised for the purpose of tissue typing and cross-matching, and the iliac vessels are excised and preserved for formation of conduits if necessary. The operation is completed by careful wound closure, application of dressings and patient cleaning. The procedure must be carefully documented in the patient’s notes.

Fig. 25.4 Multiorgan retrieval, showing placement of intra-abdominal cannulae.

(IMV = inferior mesenteric vein; SMV = superior mesenteric vein)

Organ preservation

Organ preservation is an important factor in ensuring viability of the organ and in optimizing outcomes. Following cessation of the blood supply, cell damage will occur due to the depletion of adenosine triphosphate (ATP) and a failure of the sodium potassium pump. This leads to cell swelling and anaerobic metabolism. Cold storage is the most commonly adopted method of organ preservation, and comprises intravascular flush with chilled preservation fluid to promote organ cooling, washout of blood components and rapid equilibration of the fluid with the tissues. Preservation fluids include Marshall’s, University of Wisconsin (UW) and Eurocollins solution. UW solution is the preservation solution of choice in liver and pancreas donors, whilst Marshall’s solution is used for kidney-only donors.

An alternative to cold storage is hypothermic machine perfusion, which may be associated with a reduction in delayed graft function, but no impact on graft survival has been observed. Although recent improvement in cold preservation fluids allows extended preservation times (e.g. kidneys up to 24 hours and livers up to 20 hours) prolonged cold ischaemia remains a significant cause of primary non-function or delayed graft function.

Until recently the vast majority of deceased donors were those who have been diagnosed as brain-stem dead following an intracerebral event. Due to the shortage of organs for transplantation, there has been an increase in the number of donations following circulatory death (DCD).

Donation after circulatory death

Recent years have seen the development of DCD programmes (previously known as non-heart beating donors) and this has resulted in the cincrease in numbers of deceased donors. Donors after circulatory death are categorized according to the Maastricht criteria (Table 25.5). The majority of such donors in the UK are category III donors, with successful outcomes for renal, liver, pancreas and lung transplant patients.

Table 25.5 Maastricht criteria for donation after circulatory death

The techniques for procurement for DCD vary: the essential principles are to flush and cool the organs as rapidly as possible. The open technique involves a rapid access laparotomy and cannulation of the aorta at its bifurcation. The inferior vena cava is vented and the aorta clamped just below or above the diaphragm. The alternative technique relies on the use of an intra-aortic balloon catheter which is placed via the femoral artery through a groin incision. Venous exsanguination is performed via the femoral vein.

Renal transplantation following donation after circulatory death is associated with increased rates of delayed graft function because of longer warm ischaemic periods, but the long-term outcome is comparable to DBD (EBM 25.3). An increasing number of liver transplants are being performed following DCD, and whilst concerns regarding increased risk of primary non-function have not been borne out, with careful selection of donors, the risk of biliary complications is higher than in DBD.

The extended criteria donor (ECD)

With the limited numbers of organs available for transplantation, donors who would have been previously declined are now being considered. Criteria include extremes of age, death from intracranial haemorrhage, organ-specific diseases such as excess alcohol intake or hepatitis, general co-morbidities such as diabetes, cerebrovascular accident or cardiovascular instability. The long-term outcomes of transplants performed from ECD are poorer than standard criteria donors, and the potential risks to the recipient must be weighed against the benefits. The risks of use of ECD are general and organ-specific. For liver transplants, the risk of primary non-function is increased in donors with severe fatty liver disease (steatosis). In kidney transplantation, there is in an increased risk of delayed graft function. Systemic risks from donors exist due to the possible transmission of infection and malignancy. The risk of transmission of blood-borne viral diseases such as hepatitis B, C or HIV is always present, and is minimized by predonation screening. Risk of malignancy is low, but there are documented cases of such.

Living donation

There has been an increase in the number of transplants being performed from living donors. These are mainly kidney transplants but increasing numbers of living donor liver transplants are being performed in the United Kingdom.

Operative approaches

Laparoscopic surgery has revolutionized living donor kidney transplantation in that it has made the operation more acceptable to the donor, when compared with the traditional flank approach. The main benefits to the donor are improved cosmesis and shorter recovery time. Hospital stay can be reduced by several days. However, it is a technically demanding procedure. There are various options depending on the expertise of the surgeon: the full laparoscopic approach may be performed by a transperitoneal or retroperitoneal approach, or it may be undertaken hand-assisted. The benefits of the hand-assisted approach are the use of the hand for retraction and the ability to rapidly control intraoperative haemorrhage. Open techniques include the traditional flank approach which may be rib-sparing or rib-dividing, or it can be performed via a mini-incision, which may have similar benefits to laparoscopic approaches.

Procedure-related morbidity and mortality

The mortality of donor nephrectomy is low, estimated at 1 in 3000 for all surgical approaches. Life expectancy for living donors is probably higher than the general population due to bias in the selection process. The risk of major complications such as pneumothorax, vascular or splenic injury is approximately 5%, and is 15% for all complications.

Renal transplantation

The optimal management for patients with end stage renal failure is a kidney transplant; it both improves quality of life, releasing patients from the limitations of dialysis, and increases survival. However, not all patients will benefit from transplantation, and consideration must be given as to the best use of the scarce commodity of donated organs. Thus patients undergo rigorous assessment prior to being listed for transplantation.

The operative procedure

Recipient operation

The Rutherford Morris incision is made in the iliac fossa, and the iliac vessels are exposed by retroperitoneal dissection. Lymphatics overlying the iliac vessels must be ligated and divided with care, to avoid the development of a postoperative lymphocoele. Following careful preparation of the recipient vessels, the anastomosis is performed between donor renal vein and recipient external iliac vein. The arterial anastomosis may be performed onto the recipient’s internal or external iliac artery, depending on the calibre of the donor renal artery and the positioning of the arteries (Fig. 25.5). If the internal iliac artery has been used on the contralateral side, this must not be used. The kidney is then reperfused, and the ureteric anastomosis performed between donor ureter and recipient bladder, over a double J stent. Insertion of the ureteric stent has been shown to reduce the risk of early ureteric complications such as urinary leak.

Fig. 25.5 Renal transplantation.

The renal transplant is placed retroperitoneally on to the iliac vessels with the ureteric anastomosis as shown.

Postoperative management

The patient should be managed in a high dependency unit by nursing staff who are experienced in the management of transplant recipients. During the early postoperative period, careful attention must be paid to fluid management. Whether or not the kidney has primary function will depend in part on the source of the kidney, and it is important that this is carefully noted. Primary function is expected in a transplant from a living donor, and so, if this is not the case, rapid and thorough investigation into the cause of delay is necessary. A kidney from a DCD has a high chance of delayed graft function, and so the early postoperative management will be different.

The mainstay of early postoperative management is, rigorous assessment and maintenance of fluids. A brisk diuresis is common and careful assessment and maintenance of volume status, blood pressure and serum electrolytes is crucial to optimize renal function. Delayed graft function (DGF) is defined as the need for dialysis in the first postoperative week and occurs in approximately 30% of all cadaveric transplants.

Complications

Early complications following renal transplantation may be general complications of major surgery, technical or immunological. The main immunological complications have been dealt with elsewhere in the chapter. Technical complications involve the vascular or ureteric anastomoses. Acute renal artery thrombosis is rare (incidence of approximately 1%), venous thrombosis has an incidence of 6%. Both must be recognized rapidly, using Doppler ultrasound, and require the patient to be returned to theatre immediately, if there is to be any chance of salvaging the transplant.

Urinary leaks occur less commonly now that ureteric stenting is adopted more widely: they present with falling urine output and increasing pain. They may be managed conservatively with prolonged urinary catheterization, but may require surgical intervention. Urinary tract obstruction can occur early or late. The diagnosis is confirmed by a percutaneous antegrade nephrostogram, during which a nephrostomy tube may be placed for temporary decompression. Subsequent percutaneous dilatation and insertion of a double J stent will often treat the stricture, with open surgery reserved for cases in which percutaneous management has failed.

Late vascular complications include renal artery stenosis, which occurs in 3–5% of patients and usually presents several months post-transplantation with hypertension and deteriorating graft function. The diagnosis is confirmed by angiography and the treatment of choice is angioplasty.

Fluid collections (lymphocoeles) around the transplant are a common finding on ultrasound scan but are only relevant if they become symptomatic or are causing urinary obstruction. Percutaneous drainage gives temporary symptomatic relief. Definitive management involves drainage of the lymphocoele into the peritoneal cavity and this fenestration can be performed laparoscopically.

Outcome

The 1-year renal graft survival is approximately 90% and patient survival exceeds this. However, there remains 2–5% perioperative mortality, as many renal patients have severe co-morbidity. The 5-year graft survival is around 70%, and at this time graft losses are commonly due to chronic allograft damage or to cardiovascular death in a patient with a functioning graft.

Recent developments in renal transplantation

The significant benefits that arise from living donor renal transplantation and the ongoing shortage of organs for donation have led to an expansion in renal transplant programmes to undertake higher risk transplants than would previously have been considered. In the United Kingdom the paired exchange programme has developed following changes in legislation in 2006. This programme exists for donor–recipient pairs who are unable to directly donate due to incompatibility, be it due to blood group or HLA incompatability, or to the presence of donor specific antibodies. Pairs are entered into the national programme to determine whether a paired exchange transplant is possible. These transplants are then undertaken in the two transplant centres simultaneously, and the kidneys are transported between centres.

In addition, an increasing number of ABO incompatible transplants are being performed across the United Kingdom. Recipients undergo a period of desensitisation, involving treatment with the anti-CD20 antibody, rituximab, and several rounds of plasma exchange. Anti-A or B antibody titres are monitored throughout treatment, and the transplant is performed when the titres are low. Despite the fact that the majority of recipients develop recurrent anti-A or B antibodies, antibody-mediated rejection is uncommon and the long-term results of ABO incompatible transplants are comparable to those that are compatible.

Liver transplantation

Patient assessment must be undertaken by a multidisciplinary team comprising surgeons, hepatologists, specialist anaesthetists and, where the patient demonstrates addictive behaviour, a specialist psychiatrist. In general patients should be expected to have at least a 50% chance of surviving 5 years post-transplantation. Table 25.9 demonstrates the criteria used to decide whether someone should receive a liver transplant in fulminant hepatic failure. To help assess priority for organ allocation, the model for end stage liver disease (MELD) was developed in the United States. This was originally developed to assess the prognosis of cirrhotic patients who underwent treatment for portal hypertension. It has also been shown to predict short-term outcome in patients awaiting liver transplantation and therefore is used both in the US and, sometimes with modification, in other countries for identifying those patients most in need of liver transplant (Table 25.10).

Table 25.9 Criteria for liver transplantation in acute liver failure

Table 25.10 Equation for determining MELD score

Living donation for liver transplantation

The liver is a remarkable organ which is able to regenerate if liver resection is performed. This property has allowed for a portion of liver to be removed either from an adult’s liver for a child or a larger portion removed to allow transplant into a small recipient. The first successful live donor liver transplant was done nearly 20 years ago, however this still remains a very controversial and complex area. Mortality in the donor is approximately 0.5% and risk of significant complications around 20%. Although this procedure has been accepted in a number of countries around the world, the extra risks both for donor and recipient make any decision to go ahead a very difficult one.

The operative procedure

The operation begins with preparation of the donor liver during ‘back-table’ dissection. All vessels are prepared and the liver examined carefully for any damage or underlying abnormality.

The recipient’s abdomen is opened either through a ‘Mercedes-Benz’ incision or through a midline incision which is curved to the right following the line of the costal margin (Fig. 25.6). There are many variations to the liver transplant operation and in the most common (Fig. 25.7) the liver from the recipient is removed but leaving the inferior vena cava intact. The new liver is attached to the recipient by joining together the inferior vena cava of the donor liver with the inferior vena cava of the recipient. This is called a ‘piggyback procedure’ and accomplished by performing a side-to-side anastomosis between the two vena cava. This is then followed by portal venous and hepatic arterial anastomoses (Fig. 25.8). The liver is reperfused with recipient blood and haemostasis carried out carefully. The donor gallbladder is then removed and an end-to-end common bile duct to common bile duct anastomosis performed unless there is a specific indication to perform a roux-en-Y hepaticojejunostomy (re-transplantation or primary sclerosing cholangitis in the recipient). Figure 25.9 shows a well-perfused liver following completion of the anastomoses.

Fig. 25.6 The Mercedes-Benz incision for orthotopic liver transplantation.

Fig. 25.7 Diagram demonstrating vascular and biliary anastomoses of a liver transplant.

Fig. 25.8 Hepatic artery anastomosis prior to reperfusion of liver.

Fig. 25.9 Liver transplant postperfusion.

Postoperative management and complications

Initially the patient tends to be managed in an intensive care setting and evidence of a functioning graft is based on the blood biochemistry of the recipient with falling blood lactate levels and return towards normal clotting signs of excellent function. Primary non-function or early dysfunction can occur and 2–5% of patients require urgent transplantation for non-function. As a liver transplant operation is a large procedure in patients with poor clotting, it is therefore very important to monitor the patients carefully for any evidence of bleeding. Re-exploration is often indicated. Vessel thrombosis, most commonly in the hepatic artery, can be detected on ultrasound and confirmed by arteriography. Suspicion of this serious complication necessitates re-exploration and it is possible that the patient may need a second transplant.

Rejection in the liver is much less common than with other organs for reasons which are not completely clear. Diagnosis of rejection is often made around day 7 with rising transaminases in the liver function tests. Biopsy may be performed to confirm the diagnosis and the rejection can be treated with daily boluses of methylprednisolone given over 3 days. It is rare, with modern immunosuppression, for acute rejection to cause complete failure of the graft.

Outcome

Many large single centre studies or information from registry data show that the 1-year survival for elective first liver transplant in adults is around 90%. European liver transplant registry data reports 5 years’ survival post-liver transplantation in adults at 66%. In comparison patients with acute liver failure fare less well with approximately 70% surviving at 1 year. The vast majority of recipients report a very good quality of life but there remains the need, in most patients, to take immunosuppression in the long-term. In common with the recipients of other transplant organs, patients can experience nephrotoxicity and other side effects from immunosuppressive medication. However without the liver transplant procedure, the outcome would have been certain death and so this procedure remains one of the miracles of modern medicine.

Pancreas transplantation

Transplantation of the pancreas offers the only treatment that reliably offers insulin independence and normal glucose metabolism for patients with type I diabetes mellitus. Islet cell transplantation may ultimately supersede solid-organ pancreas transplantation, but the latter remains the gold standard treatment.

The operative procedure

Back table preparation

The pancreas is retrieved en bloc with the spleen, and this is carefully excised on the back table, paying careful attention to the ligation and division of the vessels. The c of duodenum is carefully reduced and the ends both stapled and oversewn to avoid leakage. An arterial conduit is created: a Y graft is formed using donor iliac vessels onto the donor splenic and superior mesenteric vessels (Fig. 25.10). Figure 25.11 illustrates a pancreas graft just before implantation and shows the vascular reconstruction that is performed on the back table.

Fig. 25.10 Back table preparation of the pancreas graft.

Showing arterial Y graft using donor iliac vessels onto superior mesenteric and splenic arteries to create a single arterial conduit for anastomosis.

Fig. 25.11 Pancreas graft showing interposition Y graft prior to implantation.

Recipient operation

In SPK transplantation, the pancreas implantation is usually performed first due to the ischaemic intolerance of the pancreas relative to the kidney, and it is implanted intraperitoneally into the right side. The venous anastomosis is performed between donor portal vein and the distal inferior vena cava, and the arterial conduit constructed on the back table is anastomosed to the recipient common iliac artery. Reperfusion of the pancreas usually results in some haemorrhage, which has to be controlled with careful suture ligation of the small pericapsular vessels. Drainage of the exocrine secretions is achieved by a simple entero-enterostomy between donor duodenum and recipient small bowel.

Postoperative management and complications

Patients are often managed in the Intensive Care Unit postoperatively, where close monitoring and early identification of postoperative complications are likely to improve early outcome.

Pancreas transplantation is associated with a higher incidence and a greater range of complications than kidney transplant, due to a requirement for greater immunosuppression, in a high-risk diabetic population who have impaired infection resistance, poor healing and high levels of co-morbidity. Between one-fifth and one-quarter of patients require relaparotomy in the early postoperative period. Complications of pancreas transplant are outlined in Table 25.11. Risk factors for complications include increasing donor age, prolonged preservation time and donor and recipient obesity.

Table 25.11 Complications of pancreas transplantation

Infective complications

Systemic infection (opportunistic infections)

Local infections (peritonitis, localized collections, fistulae)

Vascular complications

Haemorrhage: early or late

Thrombosis: arterial or venous thrmobosis

Allograft pancreatitis

Ischaemia-reperfusion injury

Reflux pancreatitis

Rejection of a pancreas transplant alone has been notoriously difficult to diagnose, with no reliable early markers available. In SPK transplants, the diagnosis of rejection relies on monitoring renal function and undertaking renal biopsy when indicated. Acute rejection of the pancreas affects exocrine function first and gives rise to an inflammatory response, which may well be masked by the immunosuppressive regimen. Dysfunction of islets occurs as a late sign of rejection, which may then be less amenable to treatment.

Pancreatic islet transplantation

Transplantation of islets alone offers an attractive alternative to whole pancreas transplantation and is associated with less serious morbidity. There is no doubt that islet transplantation can be effective. It has been shown to have led to long-term insulin independence in a small number of patients and in other patients, it renders their diabetic control more predictable to manage with reduced insulin requirements. One challenge that needs to be overcome is the requirement for several pancreata in order to isolate sufficient islets to treat one patient.

Heart and lung transplantation

Summary

Solid organ transplantation provides excellent treatment for patients with end-stage organ failure, with 1-year graft survival exceeding 80% for most organs. The advantage of transplantation must be weighed against the price of immunosuppression and it is important that potential recipients are fully counselled. One of the greatest challenges facing transplantation is the shortage of organs for donation and this chapter has described specific strategies aimed at combating this: namely, use of marginal donors, living donors and donors after cardiac death.