Kidney Transplantation

Kidney Transplantation

TRANSPLANTATION Two models of non-heart-beating donation are being pursued: • One model (Wisconsin, USA) involves donor patients who do not meet crit...

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TRANSPLANTATION

Two models of non-heart-beating donation are being pursued: • One model (Wisconsin, USA) involves donor patients who do not meet criteria of brain death, but have irreversible injuries incompatible with life. Consent for organs are obtained from relatives and the patient is extubated in an operating theatre. As soon as asystole occurs, the organs are removed with the standard perfusion fluid and transplanted into a recipient as soon as possible. There has been a recent report of 5 patients having undergone this procedure with acceptable short-term results. • Another model was reported from the University of Lund, Sweden, where extensive debate between doctors and lay public (supported by detailed laboratory tests) led to a case report in March 2001. A team obtained consent from relatives of a 54-year-old man who had died from a myocardial infarction in the coronary care unit. Two chest tubes were inserted into the thorax and perfusate used to cool the organs. The relatives were allowed to stay with the deceased for one hour, following which the organs were removed in theatre. The lungs were then perfused with a combination of blood and perfusate and oxygenated on a ventilator for more than 8 hours. After satisfactory performance of the organs was confirmed, it was transplanted into a 54-year-old woman, who is alive and well 8 months after the procedure.

Kidney Transplantation Andrew McLaren Peter J Friend

Kidney transplantation is the optimal treatment of end-stage renal failure and is widely performed throughout the ‘developed world’ and in some ‘developing’ countries. It is an alternative therapy to long-term dialysis and, for most patients, is seen as a preferred option. Successful transplantation returns the patient to an almost normal quality of life, although it does require continued compliance with immunosuppressive and other therapeutic regimens. The life expectancy of transplanted patients is significantly improved and transplantation is more cost-effective than dialysis (see Raftery, page 100). End-stage renal failure affects 80–120/million population/year and approximately 50% of these will be suitable for transplantation. However, only about 1600 renal transplants (30/million population/year) are performed annually in the UK and consequently the waiting list is rising progressively, with over 5000 patients on the waiting list in 2002, a pattern that is being mirrored worldwide (see Mir/Park, page i).

The future Before these models are allowed to be reproduced in other countries, there must be an informed debate between doctors and the general public regarding what is acceptable, as some organs harvested may not be suitable for transplantation. Recipients for transplantation will also need to be included in the debate, deciding when they would choose to come off the waiting list for a NHBD organ. Most importantly, doctors will have to decide what options will be available for a recipient who accepts a NHBD organ that subsequently fails, as other organs may not be available for retransplantation. These newer modalities may challenge conventional practice but, if handled in a responsible way by doctors and patients, may hold the answer to extending the life of those who have no other choice, while possibly offering comfort to families that have been bereaved. u

Indications and assessment for kidney transplantation Kidney transplantation is suitable for appropriately assessed patients with chronic renal failure requiring dialysis or predicted to require dialysis within 6 to 12 months. It is not appropriate to treat patients with acute renal failure: this condition is usually reversible and is, therefore, treated with dialysis. The assessment of a patient for kidney transplantation has several objectives: • To ensure that the patient is likely to benefit from transplantation. The benefits in terms of quality and duration of life must exceed the risk to the patient. This becomes a critical issue in patients who are older and/or have significant other pathology, particularly cardiovascular or pulmonary disease or a history of malignancy.

FURTHER READING Aaronson K D, Schwartz J S, Chen T M Wong K L, Goin J E, Mancini D M. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997; 95(12): 2660–7. Kirklin J K, Young J B, McGiffin D C, Eds. Heart Transplantation. Edinburgh: Churchill Livingstone, 2002. Rose E A, Mosowitz A J, Packer M et al. The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg 1999; 67(3): 723–30. Shumway S J, Shumway N E, Eds. Thoracic Transplantation. Oxford: Blackwell Science, 1995. Steen S, Sjoberg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor. Lancet 2001; 357(9259): 825–9.

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Andrew McLaren is a Clinical Lecturer in surgery at the University of Oxford, Oxford, UK, from where he qualified in medicine. His research interests include the factors which influence the short- and long-term function of kidney transplants and organ preservation. Peter J Friend is Professor of Transplantation at the University of Oxford and Director of the Oxford Transplant Centre at the Churchill Hospital, UK. He is Consultant Surgeon in upper gastrointestinal and hepatobiliary surgery at the John Radcliffe Hospital, Oxford, UK. He qualified from Cambridge University and St Thomas’ Hospital, London, UK. He trained in transplant and general surgery at Addenbrooke’s Hospital, Cambridge, UK. He moved to Oxford to take up the post of Professor of Transplantation in 1999. His research interests are in immunosuppression, xenotransplantation and liver perfusion.

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• To establish that transplantation represents a justifiable use of a scarce resource. Organs from cadaveric donors are very scarce and it is thought that such organs should be allocated with consideration for the maximum benefit that can be obtained. • For patients with a potential living donor, the risk to the donor must be justified by the expected benefit of a successful transplant. In addition to the full history and examination that are performed prior to any proposed major surgical intervention, particular attention is paid to factors that are specifically important in the context of transplantation: • Infection: dental problems, chronic urinary tract sepsis, tuberculosis exposure. • Malignancy: a recurrence-free period of 5 years is usually recommended before transplantation, as immunosuppression may accelerate the progress of any residual tumour. • Sensitization is the formation of antibodies to the antigens of other people. Details are sought of any event by which this may occur e.g. pregnancy, blood transfusion or previous transplantation. • Cardiovascular disease is the most common cause of death post-transplant. An ECG is essential: more formal assessment with echocardiography, myocardial perfusion studies and coronary arteriography is used extensively. Therapeutic cardiac intervention may be performed prior to transplantation. Peripheral arterial disease should also be investigated with Duplex ultrasound and angiography as appropriate. • Poor compliance with drug regimens is an important factor in late transplant failure and this should be identified and addressed preoperatively.

metabolic derangement excluded. A neurological examination is performed to test the function of cranial nerves III, V, VIII, IX, XII. The patient is disconnected from the ventilator and the partial pressure of carbon dioxide allowed to rise to a level which would stimulate respiratory efforts in any patient with a functioning respiratory centre. The tests are carried out by two senior doctors who are not associated with the transplant team (usually anaesthetic, neurosurgical or neurological specialists) and repeated after an interval. After a potential donor has been declared brainstem dead, the issue of organ donation is raised with the family. In the UK, many people carry a donor card and/or have entered their name on the national organ donor register. Consent of the next-of-kin is, nonetheless, sought in all cases. Most heart-beating donors are suitable for donation of multiple organs: not only kidneys, but also liver, pancreas, heart, lung, corneas and, possibly, small intestine. Multi-organ retrieval The abdomen and chest are opened via a long midline incision from sternal notch to symphysis pubis. The liver and kidneys are partially dissected and, after dissection of the intrathoracic organs, the donor anticoagulated and cannulae placed in the distal abdominal aorta and portal vein (directly or via one of the mesenteric vessels) to perfuse the organs with cold perfusion fluid (e.g. University of Wisconsin or Marshall’s solution, see later). The liver is usually removed first, followed by pancreas and kidneys. Organs are retrieved and packed in sterile bags surrounded with ice for transport purposes. Before transplantation in the recipient centres, the kidneys are removed from the icebox, inspected and the final dissection performed: adherent fat and other tissue is removed, the artery and vein are dissected and vascular branches ligated.

Organ donation for kidney transplantation Donor sources (see Mir/Park, page i) The majority of donor organs in the UK are derived from cadaveric organ donors with established brainstem death (see Johnston/ Matta, page 96). These are ‘heart-beating donors’: donors who have died from intracranial pathology in whom the circulation is intact and who are maintained on a ventilator in an ICU. A small number of kidneys are retrieved from ‘non-heart-beating donors’: donors in whom the terminal event is irreversible cardiac arrest. An increasing number of kidney transplants are performed using organs from living donors. In the USA, over 50% of transplants are from live donors, whereas this figure is only 20% in the UK, though it is increasing.

The non-heart-beating donor Before the establishment of brainstem death criteria, the nonheart-beating donor was the only source of kidneys. The global shortage of organs for transplantation (see Mir/Park, page i) has led to a resurgence of interest in the use of kidneys from donors who have sustained circulatory arrest. Following cardiac arrest, the viability of the organs diminishes rapidly at body temperature, and an essential part of the retrieval is to cool the kidneys immediately. This is usually performed by a direct cannulation of the artery with a purpose-designed catheter. This has two balloons to isolate the segment of aorta supplying the renal arteries. The renal arteries (and mesenteric and celiac arteries) are perfused with cold preservation solution. The abdomen is then opened and the kidneys removed, perfused with preservation fluid and packed in sterile bags in an icebox.

The heart-beating donor and brain death (see Johnston/Matta, page 96) Following a catastrophic brain injury, brainstem function is destroyed. This includes the respiratory centre, leading to cessation of respiration followed by hypoxia and cardiac arrest. If respiratory function is artificially maintained on a ventilator, the heart will continue to function for a period and the circulation is maintained. The definition of death by absence of brainstem function is, therefore, a necessity of modern intensive care rather than just a requirement of transplantation. The UK guidelines for the determination of brainstem death are very specific and are based upon clinical parameters. The cause of coma must be determined and drugs, hypothermia and

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The living donor The availability of a living donor has several advantages for the recipient. The transplant can be performed when it is needed, possibly before the need for dialysis. The short- and long-term results of transplantation are better than cadaveric transplants of similar tissue match. The donor is usually a close relative, but unrelated donors are considered, provided that donation does not involve financial transactions.

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Potential donors undergo a thorough medical and psychological evaluation. Significant systemic disease normally excludes donation: this would include diabetes and cardiovascular or pulmonary disease. The function and anatomy of the kidneys are investigated. The left kidney is generally preferred because of the greater length of the renal vein. There are several techniques for live donor nephrectomy. Many surgeons prefer an extra-peritoneal approach, either antero-lateral or lateral, although an anterior trans-peritoneal approach may be used. Recently, laparoscopic nephrectomy has gained considerable popularity as it is associated with less pain, shorter hospital stay and an earlier return to work, which is particularly important for a previously fully fit donor.

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Organ preservation Organ preservation depends upon reducing cellular metabolism by cooling and infusing specialist preservation solution which prevents cell swelling and damage by osmotic injury. Most kidney transplant units use solutions based on either hypertonic citrate (Marshall’s solution) or potassium lactobionate (University of Wisconsin solution). Preservation times should be restricted to the minimum, as the degree of preservation injury is related to storage time. However, the logistics involved—transport, tissue typing, organ sharing (to optimize tissue matching) and admitting and preparing a patient for surgery—usually require a preservation time of 12–24 hours. Longer preservation times (up to 36 hours) are compatible with successful outcome, but with a higher short- and long-term failure rate.

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Transplantation immunology (see Callaghan/Bradley, page iii) Tissue typing The probability of rejection can be predicted from the antigenic disparity at the major histocompatibility complex. The clinically important antigens are found at the A and B loci (Class I) and DR locus (Class II) on chromosome 6. There is good evidence that better matching is associated with improved outcome, with reduced graft loss both in the early period (survival at 1 year) and long term (5 and 10 years, Figure 1). The tissue type is already available for all patients on the transplant waiting list. As soon as the tissue type from a donor is established (often from a blood sample taken before the organs have been retrieved), the preferred recipients can be identified. In the UK, the national organ sharing agreement requires that an organ which is identical (no mismatches) or ‘favourably’ matched (100, 010 or 110 mismatches at A, B or DR loci) should be transported to whichever transplant unit is responsible for the appropriate patient. Otherwise, the destination of the kidney is determined according to the local organ allocation protocol. Such protocols vary, but most base the selection on a combination of • closeness of tissue match • time on the waiting list • age discrepancy between donor and recipient.

sitization. These are detected by demonstrating antibodies in the serum of the recipient which recognize the lymphocytes of the donor either by cytotoxicity or fluorescence-activated cell sorter (FACS) analysis. If such antibodies are detected (a ‘positive cross-match’), the transplant is abandoned, as hyperacute rejection would be an almost inevitable consequence. The likelihood is that a positive cross-match can be predicted by the ‘panel reactive antibody’ (PRA) status: the proportion of a panel of volunteers to whose cells the prospective recipient has antibodies. Patients with a high PRA (>85%) are likely to be very difficult to transplant. Rejection Hyperacute rejection occurs when preformed antibodies in the recipient recognize and react to antigens expressed by the graft, resulting in graft loss. This process is rapid (minutes) and is prevented by ABO matching and cross-matching tests. Acute rejection is a T cell-mediated attack on the graft. Infiltrating cells target the glomeruli, tubular cells and vascular endothelium. This usually occurs between 5 days and one month postoperatively in 20–50% of transplants. Acute rejection is treated by a short course of high-dose immunosuppression (steroids or, if unsuccessful, anti-lymphocyte antibodies). Chronic rejection (chronic allograft nephropathy) occurs after 6 months, with insidious deterioration of renal function. Characteristic histological features include glomerulosclerosis and intimal thickening of small arteries. Although previous acute rejection is associated with the later development of chronic allograft nephropathy, non-immunological factors are also implicated (e.g. preservation injury, viral infection, drug toxicity).

Cross-matching Transplanted kidneys must be blood group-compatible with the recipient. It is also important to ensure that the proposed recipient does not have preformed anti-human leukocyte antigen (HLA) antibodies to the donor as a result of prior sen-

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Surgical aspects: the recipient operation The surgical principles of renal transplantation have altered little over the past four decades in which this operation has been performed. This is a heterotopic transplant, i.e. the transplanted organ is placed in a different location from the native kidney. In the standard operation, kidney transplants into adult patients are placed in the iliac fossa using an extra-peritoneal approach (Figure 2). This enables easy access to the iliac vessels and bladder. When a larger donor kidney is transplanted into a child, the patient’s aorta and inferior vena cava are frequently used as the site of anastomosis and an intra-peritoneal procedure performed. The patient is anaesthetized and a urinary catheter placed in the bladder. A curved, muscle-cutting incision is made in the iliac fossa and the extra-peritoneal plane to identify the external iliac vessels. The venous anastomosis is made first between donor renal vein and the external iliac vein. The arterial anastomosis is between the external iliac artery and donor renal artery, usually including a patch of donor aorta (Carrel patch). The kidney is allowed to reperfuse at this point and the ureter then anastomosed either directly to the dome of the bladder or via a submucosa tunnel. Several techniques designed to prevent ureteric reflux have been described, though there is no evidence that any is superior. A temporary, short double-J ureteric stent may be placed and there is evidence that this reduces ureteric complications.

and the postoperative progress is followed by monitoring urine output and biochemical renal function (creatinine). Deterioration in kidney function may be due to rejection, vascular complications, ureteric obstruction, drug toxicity or infection. Ultrasound is a valuable means of assessment, with Doppler assessment of the blood flow if necessary. Percutaneous biopsy (usually performed under ultrasound guidance) is the definitive investigation, but carries a small (1–2%) risk of haemorrhage or graft rupture. Immunosuppression is initiated at the time of transplantation. There are five broad categories of drugs in clinical use. They are generally used in combinations, acting at different stages of the immune response (to prevent rejection yet minimize dose-related side-effects) and are described below. Calcineurin inhibitors (e.g. ciclosporin, tacrolimus) block the intracellular signalling process that leads to cytokine release (especially interleukin-2, IL-2) after activation of T cells. Amplification of the immune response is therefore prevented. Specific side-effects include nephrotoxicity, neuropathy and diabetes. Drug levels are monitored by regular blood assays. Antiproliferative agents (e.g. azathioprine, mycophenolate) interfere with DNA synthesis and have a particular effect on rapidly dividing cells. Mycophenolate is more specific for lymphocytes and is more effective in suppressing rejection. Both drugs can cause bone marrow suppression; mycophenolate causes gastrointestinal disturbance.

Postoperative management Fluid management is critical in the early postoperative period: the patient may be anuric, polyuric or producing urine in a manner appropriate to the fluid balance. Fluid balance is assessed clinically and using urine output, central venous pressure and daily weight. The majority of transplanted kidneys function immediately,

Corticosteroids are effective immunosuppressants, acting via a variety of cellular effects and are still an important component of many protocols. Short- and long-term side-effects are numerous and dose-dependent. Modern immunosuppression therefore uses lower doses and many patients are weaned off steroids after a few months.

The extra-peritoneal approach

Cell cycle inhibitors (e.g. sirolimus) are the most recent addition to clinical practice. Sirolimus blocks the cell cycle to limit lymphocyte proliferation. Side-effects include hyperlipidaemia and delayed wound healing. Biological agents are given to reduce the risk of rejection during the early, high-risk period. Monoclonal antibodies that target the IL-2 receptor (a marker of activated T lymphocytes) may be given (dacluzimab, basiliximab) or polyclonal anti-lymphocyte antibodies. Induction treatment reduces the risk of rejection and enables the dose of the other drugs to be reduced, and toxic effects minimized. Other complications Delayed graft function: a considerable proportion (20–30%) of kidneys do not function immediately (‘delayed graft function’). This is because of injury to the kidney sustained before or during the transplant, leading to acute tubular necrosis (ATN, see Raftery, page 100). This creates problems both in fluid management and monitoring. The immunosuppressive protocol requires modification to reduce the risk of nephrotoxicity. Regular dialysis is needed until the ATN resolves. If this persists for more than a few days, a kidney biopsy is required to ensure that the problem has not been complicated by rejection.

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Infection Immunosuppression increases the susceptibility of kidney transplant recipients to infection. In the early postoperative period, there are risks from the bacterial pathogens that can complicate any surgical procedure. Later, there are risks from ‘opportunist’ infections, i.e. organisms that would not cause pathology in an immunocompetent individual. Cytomegalovirus (CMV) is common in the normal population, but the cause of considerable pathology among transplant patients. All patients and donors are tested for previous exposure. Previous exposure does confer some protection, although any immunosuppressed patient is at risk of CMV disease. However, the greatest risk exists for the seronegative recipient of a seropositive transplant. Infection typically presents with malaise, high spiking fever, neutropenia and abnormal liver function tests, or with localized disease in an individual organ (e.g. kidney, liver, lungs). Antiviral therapy (e.g. ganciclovir) may be used prophylactically to reduce the risk of CMV disease and also to treat patients in whom the disease has developed. Pneumocystis carinii can cause life-threatening pneumonia in immunosuppressed patients with a lymphocyte count <0.4 x 109. The risk is minimized by antibiotic prophylaxis and most transplant units treat recipients with co-trimoxazole (480 mg/day) for at least 3 months.

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Malignancy Many cancers are more common in immunosuppressed patients than in the general population. The increased risk is much greater for lymphoma (2% of renal transplants) and skin malignancy (up to 50% of patients at 10 years) which may be of viral aetiology (Epstein–Barr and human papilloma virus respectively). Malignancy is reduced by minimizing long-term immunosuppression, and for skin cancers, reducing sun exposure. Skin cancers can usually be managed by local excision. Treatment of post-transplant lymphoproliferative disorder is by careful withdrawal of immunosuppression and chemotherapy.

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Long-term survival The results of renal transplantation are dependent upon numerous factors relating to both the recipient and the donor (Figure 3). However, an overall graft survival rate of 85% at 12 months is expected following cadaveric transplantation and 90–95% following living donor transplantation. After 12 months, there is a continued attrition of grafts of 3–5% per year (Figure 4), the two major causes of late graft loss being chronic allograft nephropathy and patient death with a functioning graft.

Donor and recipient factors affecting transplant outcome Donor

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Cause of donor death (road traffic accident is the most favourable) Donor age Donor kidney glomerulosclerosis Cold ischaemia time

The future Kidney transplantation is the treatment of choice for end-stage chronic renal failure and early graft survival results have improved progressively. However, long-term graft attrition remains a major challenge and commits about 50% of patients to return to dialysis within 10 years. Much effort is being directed to understand the processes that lead to chronic allograft nephropathy. In addition, the prevention of early death in patients with functioning transplants is critically important and will require the development of drugs and other strategies that minimize cardiovascular risk factors. u

Recipient Pre-transplant Diabetes mellitus Cardiovascular disease Poor drug compliance Recipient age Post-transplant Human leukocyte antigen matching Delayed graft function Acute rejection Cytomegalovirus infection 3 SURGERY

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