Organ and tissue transplantation

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CHAPTER 21 Organ and tissue transplantation

Classification 466

Organ and tissue donors 466

Organ preservation 472

Siting of the transplant 472

Rejection 473

Immunosuppression 473

Specific organs 476

General complications 480

Transplantation has developed from an experimental procedure over 50 years ago, to an established therapeutic option for most types of end-stage organ failure. For kidney, heart and liver transplantation, a 1-year graft survival in excess of 85% can be expected.

Organ and tissue donors

Organs and tissues may be obtained from:

• deceased donors – donation after brain death (DBD; heart beating donors) or donation after cardiac death (DCD; non-heart beating donors)

• living donors.

Deceased donors

As the organ shortage became more severe, it was realized that ideal requirements for selection of organ donors were not feasible. Selection criteria for solid organ donors have therefore recently been relaxed. Organs that long ago would not have been considered for transplantation, are currently being used, bringing in a new class of organ donor termed the ‘expanded criteria donor; ECD’ formerly known as ‘marginal’ donor. ECD is any brain-dead donor aged >60 years or a donor aged >50 with two of the following conditions: a history of hypertension; a terminal serum creatinine level >150 μmol/L, or death resulting from a cerebrovascular accident. Selection of liver and heart and heart/lung donors depends on size match with the recipient. Also, no attempt is made to match other than on blood group compatibility with these organs. HLA typing and cross-matching are not currently undertaken.

Obtaining permission for deceased organ donation

1. A potential donor should be identified by the consultant in charge of the patient.

2. Contact may be made with a transplant team prior to establishment of brainstem death to assess if the donor is suitable for organ donation.

3. The first set of brainstem death criteria are carried out. If they are satisfied, the question of organ donation may be raised with the relatives. Consent should not be obtained until two sets of brainstem death criteria have been obtained.

4. If the relatives wish to know more about what is involved in transplantation, the Transplant Coordinators will speak to them and explain the details.

5. Blood is taken for tissue typing, blood group, HIV and hepatitis B and C screening.

6. Confidentiality must always be maintained.

7. Bereavement counselling and follow-up support should be arranged for the family; the Transplant Coordinators can also help with this.

Donation after cardiac death (DCD)

This type of organ donation applies to renal transplantation and liver transplantation only but tissues such as heart valves, corneas, bone, etc. can also be removed from this type of donor. The distinction between a DBD and DCD donor lies in the mode of death. DBD donors usually die from an intracranial catastrophe (→ Table 21.1), the mode of death being classified as ‘brainstem death’. In DCD donors, the patient dies from a cardiorespiratory arrest, their death being classified as a ‘cardiac death’. After death, kidneys are viable for around 30 min (maximum of 45 min in young donors).

There are four types of DCD donors (Maastricht criteria). They may be classified as controlled (cardiac arrest is anticipated and gives time for organization of necessary resources; category III) or uncontrolled (donor dies without warning, thus the ischaemic time is longer as resources are not readily available; categories I, II and IV). The groups of DCD donors are classified as follows:

I. Dead on arrival at hospital

II. Unsuccessful resuscitation

III. Awaiting cardiac arrest

IV. Cardiac arrest in brainstem dead patient.

Brainstem death

This is covered in Chapter 18, as this is the province of doctors independent of the transplant team.

Living donors

This type of organ donation relates chiefly to renal transplantation, although it is now possible to transplant segments of pancreas, segments of liver and lobes of lung from living donors. At the present time, more than 30% of transplants in the UK are carried out from living donors owing to the shortage of deceased donors. Living donation, like deceased donation, is regulated by the Human Tissue Authority under the Human Tissue Act 2004.

Organ donation and transplantation is governed by the Human Tissue Act 2004, which supercedes the Human Organ Transplant Act 1989. The Human Tissue Authority (HTA) was established in 2005 to implement the provisions of the Act, which came into force in 2006.

Categories of living donation established under the Act are:

1. Directed (i.e. the organ is directed to a known recipient)

— genetically related (formerly living related)

— emotionally related (living unrelated)

— paired.

2. Non-directed (i.e. the organ is for a recipient whose identity is unknown as with deceased donation)

— domino

— altruistic.

Directed

Genetically and emotionally related

This is donation to a known person, i.e. brother to sister, parent to child, husband to wife or between friends. Under the Human Tissue Act, the approval process is the same for directed genetically and directed emotionally related organ donation. Both will be dealt with by a local independent assessor who is trained and accredited by the HTA and who will assess all donor/recipient pairs, and where the requirements have been met, will give approval for the transplant to proceed.

Paired donation

This relates to circumstances where a close relation, friend or partner is fit and able to donate but is not well-matched to the potential recipient. That couple can be matched to another couple in a similar situation so that both people in need of a transplant receive a well-matched organ, i.e. Mrs A wants to give Mr A a kidney. Mrs B wants to give Mr B a kidney. Mrs A does not match Mr A. Mrs B does not match Mr B but Mrs B matches Mr A and Mrs A matches Mr B. In these circumstances, Mrs B gives a kidney to Mr A, while Mrs A gives a kidney to Mr B. Hopefully, everyone lives happily ever after!

Non-directed

Tissue matching

ABO compatibility

In the past, ABO compatibility has been essential. However, currently, ABO-incompatible transplants are being carried out with good success (see below.)

Histocompatibility matching

Human leukocyte antigens (HLA) are encoded on the short arm of chromosome 6; these code for the antigens involved in transplant rejection. Class I molecules consist of HLA-A, B, and C; Class II molecules consist of HLA-DP, DQ and DR. HLA-A, B and DR are generally considered the most important, a perfect match at the DR locus being associated with improved graft survival in deceased donor renal transplants. Each locus is highly variable and thus gives rise to numerous combinations. The HLA matching of patients is expressed as the HLA ‘mismatch’ – this describes how well matched the kidney is.

Some examples of HLA matching are given below:

a. A6, A3 B27, B15 DR3, DR15 Donor

A2, A3 B7, B8 DR3, DR12 Recipient

b. A1, A24 B8, B44 DR4, DR15 Donor

A1, A3 B27, B15 DR4, DR15 Recipient

In example (a) the recipient is a 1-2-1 mismatch. In example (b) the recipient is a 1-2-0 mismatch.

Cytotoxic cross-match

It must be negative. The recipient’s blood is tested for cytotoxic antibodies against antigens on donor T lymphocytes using either complement-dependent lymphocytotoxicity or flow cytometric crossmatch techniques. If such antibodies are present, they would attach to and destroy the transplanted kidney, and therefore the donor is unacceptable.

ABO-incompatible living donor kidney transplantation

The presence of anti-A/B blood group antibodies has been considered a contraindication to transplantation for the risk of hyperacute rejection. Currently, kidney transplants between ABO-incompatible donor and recipients are carried out by removing the antibodies pre-transplantation, by either immunoabsorption or plasmapheresis until a low level of antibody (1:8) is reached. The patient then receives rituximab (anti-CD20 monoclonal antibody against B cells) or intravenous immunoglobulin. Induction with anti-thymocyte globulin or basiliximab in combination with tacrolimus, mycophenolate mofetil and prednisolone followed by maintenance with last three drugs has produced a 1-year graft survival of over 95%. Frequent monitoring of antibody levels, low threshold for biopsy and aggressive treatment for antibody-mediated rejection is needed for good outcome. Similar strategy is adopted for renal transplantation in highly sensitized recipients in the presence of positive cross-match.

Organ preservation

Organs are perfused with a balanced salt solution, e.g. hyperosmolar citrate or University of Wisconsin solution at 4°C, and are stored surrounded by the same solution in sterile bags, which in turn are surrounded by crushed ice. Kidneys may also be preserved by hypothermic pulsatile perfusion on a machine. This is ideal for kidneys taken from DCD donors.

Warm ischaemic time

This is the time from cessation of circulation until perfusion with cold preservative. In DBD donors, this time is theoretically zero.

Cold ischaemic time

This is the time from perfusion with ice-cold preservative until circulation is re-established in the recipient. Table 21.2 shows appropriate times for warm and cold ischaemic time for different organs.

TABLE 21.2 Warm and cold ischaemic times

Organ	Warm	Cold
Kidney	30 min	Up to 48 h
Heart	0	Up to 4 h
Heart/lung	0	Up to 4 h
Lung	0	Up to 4 h
Liver	0	Up to 18 h
Small bowel	0	As soon as possible
Pancreas	0	Up to 12 h

Siting of the transplant

Orthotopic

The organ is situated in the place where the diseased organ had been, e.g. heart and liver transplantation.

Heterotopic

The new organ is placed in a different site from the native organ, e.g. renal transplantation – the kidney is placed in the iliac fossa.

Rejection

There are four types of rejection.

Hyperacute

This occurs with ABO incompatibility or preformed cytotoxic antibodies. It occurs on the operating table and in the case of the kidney it is seen to be flaccid, cyanotic and eventually thromboses. Nephrectomy is required, often at the time of transplantation or within 24 h.

Accelerated acute rejection

Rapid onset within a few days after transplantation. It results from prior sensitization to HLA antigens. Injury to the kidney results from antibody-mediated responses.

Acute rejection

This is the most common form of rejection and occurs within 3 months of transplantation. Two distinct types are seen:

Cellular

>90% of cases of acute rejection. Damage is predominantly cell-mediated and is easily reversed by appropriate treatment (see below).

Vascular

5–10% of acute rejection episodes are due to antibodies directed against graft endothelial cells. This type of acute rejection tends to be more severe and less responsive to treatment.

Chronic allograft nephropathy (chronic rejection)

This is the commonest cause of late graft loss. The process is not fully understood and it is thought to be due to a number of immune and non-immune factors. Clinical manifestations include proteinuria, hypertension and progressive deterioration of renal function. Histology shows interstitial fibrosis, tubular atrophy, glomerulosclerosis and obliterative arteriolopathy. Management includes use of least nephrotoxic immunosuppressive drugs, control of hypertension and proteinuria with ACE and ARB-inhibitors.

Immunosuppression

All transplant patients require immunosuppression for life. Large doses are given in the perioperative period but these are gradually scaled down to maintenance dose over a few months post-transplant. Drugs used include corticosteroids, antiproliferative drugs, e.g. azathioprine and mycophenolate mofetil (MMF), calcineurin inhibitors (CNIs), e.g. ciclosporin and tacrolimus, and mTOR inhibitor, e.g. sirolimus and everolimus. Rejection episodes are treated with pulsed doses of methylprednisolone, polyclonal (ALG or ATG) or monoclonal (OKT3 and rituximab) antibodies. Polyclonal or monoclonal (basiliximab and daclizumab) antibodies are being used routinely as induction agents in combination with other agents. The immunosuppressive agents are tailored to the individual recipient based on the degree of HLA-mismatches, sensitization and graft function. The most commonly used regimen includes basiliximab, tacrolimus, MMF and prednisolone combination

Corticosteroids

Prednisolone is usually used in combination with CNI and antiproliferative agents. It has multiple anti-inflammatory effects as well as immunosuppressive effects, the latter mainly the result in inhibition of cytokine (IL-1 and TNF-α) production and non-specific effects on cell-mediated and humoral immunity. A high dose of prednisolone is given during transplantation (500 mg i.v., followed by 0.3 mg/kg body weight/day), which is gradually decreased to 5 mg/day over a 6-month period and continued long term. Several early steroid withdrawal or sparing regimens have shown to avoid the side-effects of steroid therapy without compromising the graft outcomes. Pulsed doses of methylprednisolone are an effective treatment for acute rejection episodes. The side-effects of corticosteroid include cushingoid features, hypertension, peptic ulceration, poor wound healing, acne, easy bruising, osteoporosis, myopathy, cataracts, stunted growth, pancreatitis, avascular necrosis of bone, hyperglycaemia and diabetes.

Antiproliferative drugs

These include azathioprine, which was the first widely used immunosuppressive drug, and the newer drug, mycophenolate mofetil (MMF). Azathioprine is metabolized to 6-mercaptopurine by the liver and this in turn inhibits DNA and RNA synthesis by interfering with purine metabolism. In so doing, it inhibits proliferation of lymphocytes in response to antigenic stimulation and impairs antibody response. Side-effects include nausea and vomiting, rashes, agranulocytosis, leukopenia, hepatic dysfunction, malignancy (especially skin malignancies and lymphoid tumours). MMF has a greater effect than azathioprine in preventing rejection, the active compound being mycophenolic acid. It blocks the proliferation of T and B cells by the reversible inhibition of the enzyme inosine monophosphate dehydrogenase (IMPDH). This enzyme is involved in the synthesis of guanosine nucleotides, which are required for DNA and RNA synthesis; lymphocytes are preferentially affected as other cells have salvage pathways. In addition, MMF has been shown to prevent smooth muscle proliferation that might have additional benefit in preventing chronic allograft nephropathy. The main side-effects of MMF include haematological effects (anaemia and leukopaenia) and gastrointestinal effects, particularly abdominal pain, diarrhoea and, in some cases, gastrointestinal haemorrhage. The GI side-effects are managed by reducing the dosage of MMF, increasing the frequency of administration (four times instead of twice daily), or by switching to the newer product, mycophenolate sodium.

Calcineurin inhibitors

These include ciclosporin and tacrolimus. Ciclosporin is a fungal metabolite that inhibits the enzyme calcineurin, thereby preventing the dephosphorylation and translocation of the nuclear factor of activated T-cells (NF-AT), which is essential for interleukin-2 (IL-2) gene transcription within the nucleus. This prevents IL-2 production, which is essential for the proliferation and clonal expansion of cytotoxic T lymphocytes. It has considerably improved the results of organ transplantation since its introduction in 1983. The dose is titrated to trough level in the blood. Side-effects include nephrotoxicity, hypertension, hirsutism, tremor, gingival hyperplasia, hepatotoxicity, hyperlipidaemia and gout. Tacrolimus is 100 times more potent than ciclosporin and has a similar mechanism of action to ciclosporin. Tacrolimus is proven to be more effective in reducing the incidence of acute rejection and prolonging the graft survival, compared to ciclosporin. This has led to a wider use of tacrolimus in solid organ transplantation. The side-effects of tacrolimus are similar to those of ciclosporin except that there is a lower incidence of hirsutism and gingival hyperplasia with tacrolimus, but is more neurotoxic and diabetogenic compared to ciclosporin. The incidence of BK polyoma virus has increased with the use of tacrolimus.

mTOR inhibitors

Sirolimus and everolimus are potent immunosuppressive agents that impair T cell proliferation by inhibiting the mammalian Target of Rapamycin (mTOR) and thereby IL-2 gene transcription. This results in cell cycle arrest in late G1 phase. They also inhibit proliferation of smooth muscle cells, fibroblasts and tumour cells in vitro and in animal tumour models. Sirolimus, in combination with ciclosporin, has reduced acute rejection rate significantly and has proven useful in the management of chronic allograft nephropathy. Side-effects include electrolyte abnormalities, thrombocytopaenia, hypercholesterolaemia and hypertriglyceridaemia, wound dehiscence and lymphocele.

Polyclonal antibodies

Polyclonal antibodies are produced by immunizing horses or rabbits with human lymphoid tissue/thymocytes. The resulting immune sera are then harvested. Two types are used:

• Antilymphocyte globulin (ALG)

• Antithymocyte globulin (ATG).

They can be used for induction of immunosuppression and the treatment of rejection. Severe depletion of both T and B lymphocytes occurs following their administration through complement mediated and antibody-dependent cellular cytotoxicity. Complications include anaphylaxis and a high incidence of viral infection, particularly CMV.

Monoclonal antibodies

Monoclonal antibodies in clinical use are:

• Anti-CD3 (cluster of differentiation-3) antibodies – OKT-3

• Anti-IL-2 receptor (IL-2R) antibodies – basiliximab and daclizumab

• Anti-CD20 antibody – rituximab.

OKT-3 is directed against the CD3 antigen of T lymphocytes, binding leading to a reduction in the number of CD3 +ve T lymphocytes in the circulation. It can be used for induction immunosuppression and in the treatment of steroid-resistant acute rejection. Release of cytokine following lympholysis results in fever, hypotension, pulmonary oedema and fatal myocardial depression. Administration of antihistamines, steroid and antipyretic is needed to ameliorate these manifestations. There is a higher incidence of herpes virus reactivation, opportunistic infections (cytomegalovirus and fungi), and Epstein–Barr-associated lymphoproliferative disorders and B cell lymphomas.

Anti-IL-2R antibodies bind to the IL-2 receptor and thus inhibit IL-2 mediated responses. They are given preoperatively in combination with ciclosporin and prednisolone in high-risk sensitized patients in an attempt to decrease acute rejection. They are not used in the treatment of acute rejection. Side-effects have not been reported.

Anti-CD20 monoclonal antibody is used in transplants involving ABO incompatibility. It is also used as induction therapy in highly sensitized patients prior to kidney transplantation and as rescue agent to treat antibody-mediated rejection.

Specific organs

Kidney transplant

Recipient

Almost any kidney disease is suitable for transplantation. Some diseases may recur in the transplant kidney, e.g. mesangio-capillary glomerulonephritis, focal segmental glomerulosclerosis and IgA nephropathy. If malignancy was the cause of renal failure, e.g. bilateral nephrectomy for Wilms’ tumour or renal carcinoma, a period of time should be allowed for recurrence to occur. If it does not occur within that time period, then the patient is reassessed for transplantation.

Donor

HLA typing is essential. Cross-match should be negative. Kidneys can be safely kept for 36 h, and occasionally up to 48 h.

Operation

This is heterotopic, the kidney being placed extraperitoneally in either the RIF or the LIF. The renal vein is anastomosed to the external iliac vein. The renal artery is anastomosed either end-to-end to the internal iliac artery or end-to-side to the external iliac artery. The ureter is anastomosed to the dome of the bladder. Some 80% of kidneys from BDB donors function immediately; 20% show delayed function due to ATN and require dialysis until the kidney begins to function. Kidneys DCD donors show a delayed function rate of around 70%.

Diagnosis of rejection

• Clinical: general malaise, fever (rare), increased weight, decreased urine output

• Laboratory: increased serum creatinine, decreased creatinine clearance

• Radioisotope scan: MAG3 scan shows reduced perfusion

• Biopsy: core biopsy with a Tru-cut needle. This is the Gold Standard.

Results

• 85–90% 1-year graft survival

• 75% 5-year graft survival.

Liver transplant

Recipient

Those with primary biliary cirrhosis, sclerosing cholangitis, chronic hepatitis, alcoholic cirrhosis, metabolic disease, biliary atresia in children. Hepatic resection where possible is preferred for malignant disease owing to the high recurrence rate post-transplant. Fulminant hepatic failure following hepatitis or drug overdose may be treated by liver transplantation.

Donor

Blood group match. No HLA or cytotoxic crossmatch currently undertaken. Size compatibility required. Preservation can be undertaken for up to 20 h using University of Wisconsin solution. Liver reduction techniques have been developed based on segmental anatomy of the liver such that parts of adult livers may be used in paediatric patients. Living related liver transplantation may also be undertaken, usually using the left lateral segment.

Operation

This is an orthotopic operation. The recipient’s liver is removed. The donor vena cava is anastomosed to the recipient vena cava above and below the liver. The portal veins are anastomosed end-to-end. The donor hepatic artery on a patch of aorta is anastomosed to the common hepatic artery. End-to-end biliary tract anastomosis across a T tube is carried out.

Diagnosis of rejection

Reduced bile output of poor quality down the T tube. Deteriorating LFTs. Biopsy.

Results

• 1-year graft survival depends upon the underlying liver disease. For chronic liver disease the 1-year graft survival is in excess of 80% but for fulminant hepatic failure is around 50%.

• 5-year graft survival. This is around 70% for chronic liver disease but only around 45–50% for fulminant hepatic failure.

Some individuals have lived for more than 25 years after liver transplantation. Late graft loss is less common than for other forms of solid organ transplantation. About 20% of liver transplants at 5 years post-transplant appear to accept their liver grafts without the need for continuing immunosuppression. However, there are no criteria for defining this group prospectively.

Heart and heart/lung transplant

Recipient

End-stage heart disease with survival of 1 year unlikely, e.g. viral myocarditis, cardiomyopathies, severe IHD. Heart/lung transplants are usually carried out for cardiac problems associated with pulmonary vascular hypertension. The four possible lung transplant operations are heart/lung, double lung, sequential single lung, or single lung transplantation. The procedure used depends upon the lung condition. The commonest causes for lung transplantation in general are cystic fibrosis, bronchiectasis, primary pulmonary hypertension, emphysema, and idiopathic pulmonary fibrosis.

Donor

Blood group match. No HLA or cytotoxic crossmatch. Size compatibility important. A safe time limit for cold ischaemia for the heart is 4–6 h. The lungs are less tolerant of ischaemia than the heart. The lungs are usually ventilated with 80% oxygen and kept semi-inflated during storage.

Operation

Heart

This is an orthotopic operation, the recipient’s heart being removed. The recipient pulmonary veins are anastomosed to the left atrium and the recipient right atrium to the donor right atrium. The aorta and pulmonary arteries are anastomosed end-to-end to the corresponding recipient vessels. The operation is carried out on cardiopulmonary bypass.

Lung

The technique depends upon whether it is a double lung transplant, sequential single lung transplant, or single lung transplant. A single lung transplant offers the advantage of maximum use of donor organs and relative technical simplicity. Cardiopulmonary bypass is not required. The main disadvantage of the single lung transplant is that there is only a limited amount of lung tissue and complications may result from the remaining diseased lung. The operation is therefore unsuitable for infective lung conditions such as bronchiectasis or cystic fibrosis.

Diagnosis of rejection

Heart

Cardiac arrhythmias. Regular endomyocardial biopsies via forceps inserted via the external jugular vein and guided to the endocardium under radiographic control.

Lung

Acute rejection is characterized by fever, lethargy, hypoxia and infiltrates on CXR. The diagnosis is confirmed by biopsy (bronchoscopic and transbronchial).

Complications

Heart

Cardiac arrhythmias and death. Sepsis. Chronic rejection with small vessel disease and recurrent angina.

Lung

Late complications include infection, obliterative bronchiolitis and malignancy.

Results

Heart, heart/lung

• 85% 1-year graft survival

• 73% 5-year graft survival.

Lung

• 70% 1-year graft survival

• 50% 5-year graft survival.

Pancreatic transplantation

Recipient

These are juvenile-onset diabetics who have concomitant renal failure and require kidney transplantation in addition. The aim is to prevent the development of other microangiopathic complications. The kidney and pancreas from the same donor are usually transplanted simultaneously, one organ into the RIF, the other into the LIF. The use of pancreatic transplantation alone to attempt to prevent the complications of diabetes is increasing.

Donor

Blood group match. No history of diabetes. No family history of diabetes. Normal blood sugar.

Operation

This is usually a heterotopic transplant, the pancreas being placed in either the right or the left iliac fossa. The majority of pancreatic transplants are whole pancreatic transplants with bladder or enteric exocrine drainage. The pancreas is removed with a duodenal segment, the latter being anastomosed to the bladder or the terminal ileum. The vascular anastomoses are based on the splenic artery, superior mesenteric artery and portal vein. These are anastomosed to the iliac vessels.

Diagnosis of rejection

Isotope scans. Reduction in urinary amylase where the pancreas is drained into the bladder. Biopsy.

Complications

Bleeding, graft thrombosis, graft pancreatitis, pancreatic fistulae, peri-graft collections, fibrosis.

Results

According to the expertise of the centre where the transplant is carried out, there is a 50–80% 1-year graft survival. In centres with considerable experience of pancreatic transplantation, where the pancreas and kidneys are transplanted simultaneously the 1-year graft survival is 80%, with a 5-year graft survival of 65%. Where pancreas transplantation alone is carried out, the 1-year graft survival is only around 50%.

The poor results and complications have encouraged an attempt to transplant isolated islets of Langerhans. These are injected via the portal vein into the liver. Encouraging results are being reported.

Small bowel transplantation

Approximately 300 small bowel transplants have been performed worldwide. The main indication is intestinal failure (usually from short bowel syndrome) where complications secondary to total parenteral nutrition (TPN) have developed, i.e. no vascular access. The surgical technique may be via an isolated intestinal graft (superior mesenteric artery and vein anastomosed to the recipient aorta and IVC, respectively, the intestine being anastomosed to the native bowel and the distal end brought out as a stoma). Alternatively, a liver–intestine graft may be carried out. A few cases of living donation have been reported. The main complications are graft thrombosis, rejection, sepsis and GVH disease. Graft survival is around 60% at 1 year.

General complications

These include infection and malignancy.

Infection

Infection post-transplant may be dangerous and life-threatening and is related to use of immunosuppression. Infections may be bacterial, viral, fungal or protozoal. These include:

• Bacterial, e.g. coliform urinary tract infections, septicaemia, chest infections, e.g. Staph. pneumoniae, tuberculosis

• Viral, e.g. herpes simplex (cold sores on lips), herpes zoster, CMV, the latter giving rise to pneumonia, encephalitis and deterioration of graft function and BK polyoma virus leading to interstitial nephritis and ureteric strictures

• Fungal, e.g. oral, oesophageal and vaginal candidiasis, aspergillosis, Pneumocystis carinii

• Protozoal, e.g. toxoplasmosis.

Management of infection

When a transplant patient develops a fever and rejection has been excluded, aggressive investigation should be undertaken to elucidate the cause. Investigations include swabs of wound discharge, urine cultures, sputum cultures, blood cultures, viral studies, CXR, USS, CT scan, bronchoscopy, bronchial washings, lung biopsy. Treatment may have to be started on a ‘best guess’ basis. Appropriate therapy should be started as soon as laboratory confirmation of the diagnosis has been obtained. In severely ill patients with overwhelming infection, immunosuppressive drugs should be reduced or stopped until the infection is under control.

Malignancy

The incidence of malignancy is increased in all immunosuppressed transplant patients and therefore long-term follow-up is mandatory. Primary cancers develop in 5% of all recipients. There is a 100-fold increase compared with age-match controls. Altered immunity with depressed tumour surveillance is an aetiological factor.

Skin cancers are the most common, followed by non-Hodgkin’s lymphomas. In ciclosporin-treated patients, non-Hodgkin’s lymphoma occurs earlier in the post-transplant patient than with steroid and azathioprine therapy. Other cancers occur more commonly in transplant patients than in the general population.

Malignancy in transplant patients should be treated by standard methods. A decision to withdraw immunosuppression as part of the treatment of cancer is difficult. In general, patients with localized disease should be continued on immunosuppressive therapy, while the development of metastases is an indication for withdrawal of immunosuppression. However, decisions must depend on a careful consideration of the individual case.

Long-term follow-up of transplant patients

Any patient who has had a transplant should be followed up long-term by the Transplant Unit. Patients remain on immunosuppression for life and long-term complications may develop. Surveillance for development of malignancies is important. Other important factors involve prompt and appropriate treatment of infection; advice on vaccination procedures (live vaccine should never be given to immunosuppressed patients); contact with infectious disease; travel abroad; pregnancy.

Churchills Pocketbook of Surgery

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