QJM Advance Access originally published online on October 24, 2008
QJM 2008 101(12):985-986; doi:10.1093/qjmed/hcn144
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Kidney transplantation—the long term view
From the Oxford Kidney Unit, Churchill Hospital and Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
Address correspondence to Chris O'Callaghan, Nuffield Department of Medicine, University of Oxford, Oxford Kidney Unit, Churchill Hospital, Oxford OX3 7BN, UK. email: chris.ocallaghan{at}ndm.ox.ac.uk
Kidney transplantation is a routine and highly successful treatment for end-stage renal disease and transforms the lives of most recipients.1 However, in contrast to the transplantation of other major organs, the availability of artificial kidney function in the form of dialysis means that patients without kidney function can live for many years without transplantation. For this reason, the risks and benefits of kidney transplantation must be carefully weighed up against those of dialysis for each patient. Since the first kidney transplants were performed in the 1950s,2 there have been major advances in both transplantation and dialysis and the risks and benefits for both options have changed. Kidney transplantation has lifestyle advantages and is cheaper than dialysis, but there is a shortage of organs. The UK kidney transplant waiting list grew by 8% last year3 and in 2006, 16% of patients on waiting lists in the US died while waiting for an organ transplant.4
Early kidney transplant regimens relied on steroids and azathioprine to prevent rejection with some success, but the introduction of cyclosporin over 30 years ago substantially reduced rejection.5 Further refinements came from better matching, in particular the introduction of matching at the HLA-DR locus. More recently, new and potent immunosuppressive drugs have been introduced including tacrolimus, mycophenolate and sirolimus. Biological agents are also available to treat or prevent rejection and include the anti-interleukin 2 receptor antibodies, basiliximab and daclizumab and lymphocyte depleting antibodies, such as anti-thymocyte globulin and alemtuzumab.
These scientific advances have the potential to reduce rejection rates thus improving outcomes. However, in parallel with these developments, the demographics of transplant recipients have changed substantially. Large-scale registries provide national statistics on changes in outcome,4,6 but centres may differ in their practices and in their adoption of new developments. In a major retrospective review in this issue, Courtney and colleagues analyse the changes in renal transplantation in a large transplant centre serving the population of Northern Ireland over 40 years.7
A study of this type covering this time scale is remarkable and a testament not only to the authors, but also to the clinicians who prospectively documented clinical data from 1967 onwards on a database. The Belfast unit rose to prominence under the direction of Professor Mollie McGeown and their early results reflect the efforts that were made to optimize patient care. The authors have meticulously analysed a mass of clinical data and asked, whether the changes that have occurred have resulted in better or worse outcomes in their study population.
As might be expected with better immunosuppressive regimens, acute rejection rates fell over the decades. However, immunosuppression takes its toll in both the short and long term. In the short term, infection is a particular concern, especially with viruses such as cytomegalovirus. However, in the long term, the incidence of most cancers is increased in patients who are immunosuppressed.8 This is true of virus-associated tumours such as cervical cancers, but also of tumours for which no viral aetiology is recognized. Skin cancer is a particular problem with all transplant regimens. In the Belfast study, malignancy accounted for 14% of patient deaths and was more than twice as common in those who died with a functioning graft than those who lost their graft and returned to dialysis—presumably reflecting the higher immunosuppressive burden in those who died with a functioning graft. There was a worrying trend towards increased death from malignancy in the most recent decade, when more potent immunosuppression would be in use. Tumours often occur many years after transplantation and for this reason, the consequences of the newer more aggressive regimens may still not be fully characterized.
Further changes in kidney transplantation have come about with a widening of the criteria for transplantation. In the early days of transplantation, most recipients were young with only single organ disease. However, many patients undergoing transplantation now are older with multiple medical problems. The mean age of the Belfast patients at transplantation rose from 36 to 42 years over the study period, a trend which is likely to continue. As elsewhere in the world, there are more diabetic patients undergoing transplantation. Although diabetic patients have a better outcome with transplantation than with dialysis, they still have worse outcomes than non-diabetic patients.9 The authors did not study the weight of their patients, but obesity is rising in the population and there are indications that this is having the anticipated negative impact on patient and graft survival. A recent study from the Netherlands reported a 5-year graft survival of 61% in obese patients compared to 80% in non-obese patients.10
Some of the trends present in this study can clearly be extrapolated into the future. Average age at transplantation is likely to rise further and patients will have greater co-morbidity. The need to use organs that are not well matched will increase the use of aggressive immunosuppression, with its potential long-term consequences. Kidneys can now be transplanted across HLA types and even ABO blood group types, typically following desensitization, which may include plasmapheresis, intravenous immunoglobulin and rituximab.11,12 With organ shortages, spouses and friends of patients are increasingly becoming donors in living unrelated kidney transplantation. There is a growing need for immunological assays which will help clinicians to fine-tune immunosuppression by indicating when it is excessive or inadequate. In addition, the quest continues for therapies which will selectively suppress only the immune response against the transplanted organ. Whatever emerges in the future, it is to be hoped that clinicians will prospectively archive good quality clinical data to allow future studies to assess the impact of these changes.
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1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med (1999) 341:1725–30.
2. Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in identical twins. Surg Forum (1955) 6:432–36.
3. Transplant UK. Transplant Activity in the UK. (2008) Bristol, UK: Statistics and Audit Directorate, UK Transplant, NHS Blood and Transplant.
4. US Renal Data System, USRDS. Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. (2008) Bethesda, MD, USA.
5. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet (1978) 2:1323–7.[Web of Science][Medline]
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8. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA (2006) 296:2823–31.
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11. Takahashi K, Takahara S, Uchida K, Yoshimura N, Toma H, Oshima S, et al. Successful results after 5 years of tacrolimus therapy in ABO-incompatible kidney transplantation in Japan. Transplant Proc (2005) 37:1800–3.[CrossRef][Web of Science][Medline]
12. Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med (2008) 359:242–51.
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