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QJM Advance Access originally published online on October 16, 2008
QJM 2008 101(12):967-978; doi:10.1093/qjmed/hcn136
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© The Author 2008. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The evolution of renal transplantation in clinical practice: for better, for worse?

A.E. Courtney, P.T. McNamee and A.P. Maxwell

From the Regional Nephrology Unit, Belfast City Hospital, Belfast, BT9 7AB, UK

Address correspondence to Dr Aisling E. Courtney, Regional Nephrology Unit, Belfast City Hospital-Level 11, Lisburn Road, Belfast, BT9 7AB, UK. email: aecourtney{at}doctors.org.uk

Received 4 June 2008 and in revised form 3 September 2008


   Summary
Top
 Summary
Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 FUNDING
 Acknowledgements
 References
 
Background: Kidney transplantation is the optimal form of renal replacement therapy for most patients with end-stage renal disease. Attempting to improve graft and recipient survival remains challenging in clinical practice.

Aim: To identify the factors that have significantly changed over the past four decades and assess their impact on renal transplant outcomes.

Design: Retrospective review of all renal transplant procedures in a single UK region.

Methods: All 1346 renal transplant procedures performed between 1 January 1967 and 31 December 2006 were reviewed. Clinical data, histological reports and outcomes were available from a prospectively recorded database. The study period was divided into four decades to assess the changes in renal transplantation over time.

Results: Significant changes that have occurred include an increase in donor and recipient ages, a greater proportion of recipients with diabetic nephropathy, a longer wait before the first transplant procedure, a fall in the incidence and impact of acute rejection, a smaller proportion of deaths due to cardiovascular disease, (P < 0.001 for all) and a trend to increased deaths from malignancy (P = 0.06) over time. In multivariate analysis, death censored graft survival was significantly influenced by the era of transplantation, donor and recipient ages, living vs. deceased donor status, and histological evidence of acute rejection, chronic allograft nephropathy, or disease recurrence. Significant factors in recipient survival were the era of transplantation, recipient age, a primary renal diagnosis of diabetic nephropathy or unspecified chronic renal failure, and biopsy proven acute rejection.

Conclusions: There have been major changes in the clinical practice related to renal transplantation over the past four decades; some have been beneficial and others detrimental to survival. Regular review of outcomes is essential to guide renal services development and maximize graft and recipient survival.


   Introduction
Top
 Summary
 Introduction
Patients and methods
 Results
 Discussion
 Conclusion
 FUNDING
 Acknowledgements
 References
 
The first successful renal transplant in the UK took place in Edinburgh in 1960,1 and despite substantial early challenges2 several other centres started renal transplant programmes in that decade. There have been considerable advances in the understanding of immunobiology, immunopharmacology and the optimization of graft preservation allied to improvements in surgical technique in the intervening period. Renal transplantation is the optimal form of renal replacement therapy (RRT) for many patients with end-stage renal disease (ESRD).3

Nevertheless, barriers to the long-term survival of both transplanted kidneys and renal transplant recipients persist. While almost all UK transplant centres have 1-year graft survival rates exceeding 90% for first adult deceased donor kidney transplants, the average 5-year graft survival rate is still only 81%.4

We analysed all renal transplant procedures performed in a single UK region (Northern Ireland) over 40 years from 1967 and identified the significant changes that have occurred in this time period in donor and recipient characteristics, immunological risk, and graft and recipient outcomes. We considered how these may impact renal transplant survival and future clinical practice.


   Patients and methods
Top
 Summary
 Introduction
 Patients and methods
Results
 Discussion
 Conclusion
 FUNDING
 Acknowledgements
 References
 
Patients
All renal transplant procedures in Northern Ireland (NI), population 1.75 million, are performed in the Regional Nephrology Unit, Belfast City Hospital which opened in 1967. All kidney transplants from 1 January 1967 until 31 December 2006 inclusive were analysed. Clinical variables and outcomes on all recipients are detailed on a prospectively recorded database, the Northern Ireland Regional Renal Transplant database. Data included are donor age, gender and whether deceased or living; recipient age and gender; the primary renal disease, duration of RRT prior to transplantation, and number of previous kidney transplants; HLA matching and ischaemic time; graft and recipient survival; and the cause of death. Follow-up analysis was continued until 20 April 2007.

Until 1989 all transplant recipients received dual immunosuppressive drug therapy with prednisolone and azathioprine. Calcineurin inhibitor based maintenance therapy (with ciclosporin and later tacrolimus) was then introduced for subsequent transplant recipients. After mycophenolate mofetil became available in 1998 a quarter of patients had calcineurin inhibitor free maintenance regimens.

The study was performed with approval from Queen's University, Belfast Research Ethics Committee.

Time periods
The data were categorized into decades one to four. The first period was 1 January 1967 to 31 December 1976, the second 1 January 1977 to 31 December 1986, the third 1 January1987 to 31 December 1996, and the fourth 1 January 1997 to 31 December 2006. Although this division into decades is arbitrary it represents a pragmatic approach to studying trends in several variables that impact on renal transplantation outcomes over the past 40 years.

Primary renal disease
These were recorded for all patients using the European Dialysis and Transplant Association coding system. For the purposes of analysis they were grouped into six categories: glomerular disease, chronic pyelonephritis/interstitial nephritis, polycystic kidney disease (PKD), diabetic nephropathy (DN), chronic renal failure (CRF) not otherwise specified and other miscellaneous causes.

Histological assessment
All renal transplant histological specimens from this UK region are examined in the Histopathological Laboratory, Royal Victoria Hospital, Belfast and the reports are sequentially recorded. Three consultant renal histopathologists have provided this service in the four decades of renal service provision in NI.

All records were reviewed and where a histological report was available the diagnosis was added to the database. Features consistent with chronic allograft nephropathy in specimens prior to the introduction of this nomenclature were classified accordingly.

The causes of graft loss were further categorized for comparative purposes: vascular or technical complications including infarction; acute rejection; chronic transplant pathology including chronic allograft nephropathy, calcineurin inhibitor toxicity, and interstitial fibrosis and/or glomerulosclerosis not otherwise defined; miscellaneous histological diagnoses including recurrent disease; and non-diagnostic histological findings or no histological assessment.

Statistical analysis
Descriptive analysis of the demographics and clinical variables are reported as mean ± SD or median values with interquartile range (IQR) as appropriate to their distribution. Skewed data were modified by log transformation for further analysis as necessary. Comparison analysis across the four decades of transplantation was performed using the chi-squared test and Fisher's exact test for categorical variables, and the one-way Analysis of Variance with post-hoc t-test for continuous variables. Logistic regression analysis with stepwise elimination was employed to determine significant factors in the incidence of acute rejection.

Graft and recipient survival was analysed by the use of Kaplan–Meier survival plots. The characteristics associated with graft survival were investigated by means of the log-rank test. All factors that were significant at the 10% level, or improved the precision of the estimates, were then incorporated into a Cox proportional hazards model to determine any potential correlation between these variables. Non-significant factors were sequentially eliminated. Comparable analyses were performed for recipient survival. Evidence of effects modification was sought using era as a linear interaction term.

Data was complete for all variables except for donor age and gender (97.9% complete) and the degree of HLA mismatch (97.5% complete). These were missing at random and excluded from analyses as appropriate. Values of P < 0.05 were considered statistically significant. SPSS for Windows® (SPSS® Inc., Chicago, IL, USA) version 15.0 was employed for all analyses.


   Results
Top
 Summary
 Introduction
 Patients and methods
 Results
Discussion
 Conclusion
 FUNDING
 Acknowledgements
 References
 
There were a total of 1346 renal transplant procedures performed in 1169 patients in the Belfast City Hospital in the study period. In the first decade 103 transplants occurred, this number rose to 344 in the second decade, peaked in the third at 484, and in the final decade there were 415 procedures. Table 1 details the transplant data in the four time periods.


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  		Table 1 Characteristics of renal transplantation over four decades

 
Demographics
Donor characteristics
Donor age. The donor age was known for 1318 (98%) of procedures and ranged from 1 to 75 years with a mean 35.6 ± 16.5 years overall. There was no change, with a mean age of 32.3 years, between the first two decades, but this rose to 35.4 years in the third (t = 2.64, P = 0.009), with a further significant increase to 39.6 years (t = 3.71, P < 0.001) in the last decade.

Donor gender. Of the 1319 (98%) transplants with donor gender data, 799 (61%) were male. The proportion of female donors rose significantly across the four eras from 28% to 46% ({chi}2 = 13.6, P = 0.003).

Donor type. Deceased donor organs accounted for 1259 (94%) of transplants. The proportion of living donor transplants differed significantly but not consistently across the four decades of transplantation: 5%, 10%, 4% and 7%, respectively ({chi}2 = 12.4, P = 0.006).

Recipient characteristics
Recipient age. There were no missing data and the range was 2–78 years. The overall mean was 40.0 ± 15.5 years with a significant increase across the four decades from 36.2 to 42.3 years (t = 3.68, P < 0.001).

Recipient gender. There were 848 (63%) male recipients with no significant percentage change over the study period ({chi}2 = 2.05, P = 0.56).

Recipient renal replacement therapy. The median duration of RRT prior to transplantation was 15 (range 0–302 and IQR 7–32) months. Forty-eight (4%) patients had pre-emptive transplantation and a further 18 patients received a kidney transplant within a month of commencing dialysis.

The median duration of RRT was 13 (range 0–121) months in the 1169 (87%) first transplant procedures; 57 (range 6–302) months in the 156 persons who received a second graft; 113 (range 15–235) months for the 19 third organ transplants and 164 (range 136–192) months for the two cases who received a fourth kidney.

The duration of RRT prior to receiving a first transplant rose significantly between decades two and three (12–18 months, t = 5.23, P < 0.001), and three and four (18–28 months, t = 7.25, P < 0.001).

Recipient primary renal disease. All recipients had a primary renal diagnosis; 355 (26%) had glomerular disease, 277 (21%) chronic pyelonephritis/interstitial nephritis, 160 (12%) PKD, 102 (8%) DN, 206 (15%) CRF not otherwise specified and 246 (18%) miscellaneous causes. No immunoglobulin A (IgA) nephropathy was recorded in the first decade since this predated immunofluorescent techniques but the proportion of glomerular disease fell from 47% to 25% ({chi}2 = 25.5, P < 0.001). The percentage of patients with pyelonephritis/interstitial nephritis was constant ({chi}2 = 2.3, P = 0.51). The proportion with PKD has been comparable (12–13%) across the last two decades though it accounted for 17% of cases in the first decade (overall {chi}2 = 7.5, P = 0.06). Persons with diabetic nephropathy were not represented in the early years of transplantation but rose from 5% of recipients in the second decade to 10% in the fourth ({chi}2 = 16.3, P = 0.001).

Immunological factors
HLA A-B-DR. Data were available for 1312 (97%) transplants, but 194 preceded recognition of the DR locus and had only HLA A-B matching. Excluding this cohort of patients, the degree of matching significantly improved over the study period ({chi}2 = 770, P < 0.001); in the second decade 18% of transplants had more than three mismatches compared to 6% in the fourth decade.

HLA-DR. Fifty-five organs (5% of those with available DR status), were transplanted across two mismatches at the DR locus; 46 in the second decade making this period significantly different from the following two decades ({chi}2 = 167, P < 0.001).

Ischaemic time
The ischaemic time (IT) was recorded for 1257 (93%) of procedures and in 905 (72%) cases it was <24 h. However, in the third decade the IT of almost half of the transplants exceeded 24 h, and while there was a significantly shorter IT in the fourth decade (considering it as a continuous variable t = 5.4, P < 0.001) it remained substantial longer than in the first 20 years.

Histological reports
There was histological assessment of 690 (51%) of grafts but a marked variation in biopsy practice; only 19 (18%) of organs in the first decade had a biopsy compared to 325 (67%) in the third decade (overall {chi}2 = 123.8, P < 0.001). The number of kidneys biopsied (158, 38%) and the incidence of chronic pathology in the final decade were impacted by the shorter duration of follow-up.

Acute rejection. Acute rejection (AR) was diagnosed in 279 (21%) of renal transplants; the majority of episodes (243, 87%) occurred within 6 months of engraftment with 10% (29) arising more than a year after transplantation. Each graft was considered only once and the time determined by the earliest biopsy to demonstrate rejection.

In the first decade AR was diagnosed clinically and not histologically. Excluding this era, there was a decrease in AR rates from 29% to 16% ({chi}2 = 19, P < 0.001) in subsequent decades. In regression analysis including the variables HLA matching, number of previous transplant procedures, RRT duration, IT and transplant decade, the DR mismatch was the most influential factor in the incidence of AR (P = 0.004). The era of transplantation was the other variable to retain significance (P = 0.02).

Chronic allograft nephropathy. Chronic allograft nephropathy (CAN) was documented in 70 (5%) of kidneys. There were significant differences across the four decades ({chi}2 = 15, P = 0.002) but interpretation is limited by the biopsy practice in the first era and the duration of follow up in the final era.

Calcineurin inhibitor toxicity. Features consistent with chronic calcineurin inhibitor (CNI) toxicity were predominant in 55 (4%) of cases with obviously significant differences with time ({chi}2 = 55, P < 0.001) since CNI agents were not routinely used in NI until 1989.

Recurrent disease. Forty-six (3%) of grafts were reported to have primary disease recurrence. There were significant differences across the four decades ({chi}2 = 55, P < 0.001) but no account was taken of the probable confounders of biopsy practice, early non-identification of IgA nephropathy and duration of follow-up in the final decade.

Graft loss
In the follow-up period 747 grafts failed; 330 recipients died with a functioning transplant, and 417 (31% of total) recipients returned to dialysis therapy. A histological reason for graft loss was available for 271 (65%), detailed in Table 2. The trends in major causes of graft loss across the four decades are summarized in Table 1.


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  		Table 2 Causes of renal transplant loss

 
Infarction/technical complications. The last two decades had a greater proportion of grafts lost due to infarction or technical complications ({chi}2 = 14.5, P = 0.002).

Acute rejection. Excluding the first era from analysis, there was a reduction in graft loss due to AR in subsequent decades ({chi}2 = 8, P = 0.02); falling from 20% to 12% between the second and third decades (P = 0.04), to 7% in the fourth decade (P = 0.44). In regression analysis, (comparable to that described for all AR diagnoses), the era of transplantation remained significant (P < 0.001).

Chronic allograft nephropathy. In 61 grafts the primary cause of failure was consistent with CAN with no significant difference across the study period ({chi}2 = 6.2, P = 0.1).

Calcineurin inhibitor toxicity. Twenty kidney transplants failed primarily due to chronic CNI toxicity. The incidence was comparable between the third and fourth decades ({chi}2 = 1.6, P = 0.17).

Recurrent disease. Recurrent disease accounted for graft loss in 27 cases with a significant difference between the second (3% of graft losses) and third (11%) eras ({chi}2 = 6.7, P = 0.01).

Mortality
There were 552 deaths; 330 (60%) died with a functioning transplant and 222 (40%) died after a return to maintenance dialysis therapy. This proportion was comparable across the forty years of this study ({chi}2 = 0.76, P = 0.86). Table 1 details the known causes of death in each decade.

Cardiovascular disease. Cardiovascular disease (CV) comprised ischaemic heart disease, cerebrovascular disease, aortic aneurysm rupture, visceral ischaemia, sudden cardiac death and cardiac failure. It accounted for 240 (43%) of deaths, and a similar proportion between those who died with a functioning graft or after a return to dialysis. There was a significant fall in the percentage of CV deaths between decades two and three ({chi}2 = 5, P = 0.02), and between decades three and four ({chi}2 = 7, P = 0.08).

Malignancy. This was responsible for 75 (14%) of deaths, and a significantly greater proportion of those that died with a functioning graft compared to those who returned to dialysis therapy (18% vs. 7%, {chi}2 = 14, P < 0.001). There was a trend to increased deaths from malignancy in persons transplanted in the fourth decade ({chi}2 = 8, P = 0.06) despite the shorter follow-up period.

Infection. Overall 54 (10%) of deaths were attributed to infection. This was comparable between those who died with and without a functioning graft ({chi}2 = 2, P = 0.22), and across the four decades of the study period ({chi}2 = 1, P = 0.75).

Survival
At the end of the study 599 (44.5%) of transplants were still functioning and 747 (55.5%) had failed, of whom 417 (55.8%) had returned to dialysis therapy and 330 (44.2%) had died with a functioning graft. The median follow-up period was 9.5 (range 0–36.6) years. The estimated median graft survival overall was 10.8 years (IQR 0.3–21.8), and recipient survival was 17.8 years (IQR 8.0–33.3).

Graft survival
Table 3 details the characteristics of renal graft survival. The age of the donor, type of donor, age of recipient, diabetic nephropathy as the primary disease, histological evidence of AR or CAN, and the era of transplantation were all highly significant influences on graft survival (P < 0.001).


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  		Table 3 Characteristics of renal transplant survival

 
There was a difference of 6.8 years in the median graft survival between donors younger and older than 60 years of age, (donors older than this are considered as extended criteria donors). The survival between male and female donors was comparable but the outcomes of living donors were significantly better. As expected graft survival was significantly better in younger recipients.

Kidneys transplanted in the second decade did substantially worse than kidneys transplanted in the other eras (median survival 7.7 years, P = 0.001), and those transplanted in the fourth decade had a much better estimated survival (P < 0.001).

Other factors that conferred a significantly worse outcome were unspecified CRF as the primary renal diagnosis (P = 0.009 compared to all other primary disease categories); and greater than three mismatches at the HLA A-B-DR loci or two mismatches at the DR locus (P = 0.002). Those kidneys with an ischaemic time of 24 h or longer tended to have a shortened graft survival (P = 0.06). Prior RRT duration and the number of previous grafts were not significantly influential on outcome (data not shown).

Cox proportional hazard model. Age, RRT duration prior to transplantation, HLA A-B-DR and HLA-DR mismatching, and IT were considered as continuous variables for this analysis and the characteristics that retained significance in terms of graft survival are detailed in Table 4.


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  		Table 4 Cox regression analysis for renal transplant survival. Hazard ratios for all factors that retained significance in analysis

 
The era of transplantation, donor and recipient age, donor type (deceased or living), primary renal disease of DN or CRF not otherwise specified, and histological evidence of AR or CAN were all influential factors (P <= 0.02) in overall graft survival.

When the data were censored to exclude those who died with a functioning graft the same factors retained significance with the exception of the primary renal diagnosis. Histological disease recurrence was also a significant influence on graft survival in this cohort. The hazard ratios for donor and recipient age appear small, but reflect the incremental risk of graft loss per year increase in age.

Consideration of the decade of transplantation as an interactive term demonstrated that the impact of AR on death censored graft survival was modified by the era studied ({chi}2 = 6.8, P = 0.009). There was no significant interaction between the decade of transplantation and the other significant variables with overall graft survival or death censored graft survival (data not shown).

Recipient survival
Table 5 displays the results of the log rank test analysis. Donor age, donor type, and recipient age were highly significant influences on recipient survival (P < 0.001). Recipients aged over 60 years at the time of transplantation had a median survival that was 11.6 years shorter than recipients under 60 years.


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  		Table 5 Characteristics of renal transplant recipient survival

 
Those transplanted in the second decade survived significantly less time, whilst those in the fourth decade are estimated to live significantly longer.

The primary renal disease was important; persons with diabetic nephropathy and CRF not otherwise specified had poorer survival (P < 0.001), whereas persons with glomerulonephritis (P = 0.001), chronic pyelonephritis/interstitial nephritis (P = 0.002), and PKD (P = 0.03) lived longer.

Poorly matched kidney transplants (more than three mismatches at HLA A-B-DR loci or two mismatches at HLA-DR locus), were also associated with reduced survival, as was histological evidence of AR, CNI toxicity or recurrent disease. Prior RRT duration and the number of previous grafts were not significantly influential on outcome (data not shown).

Cox proportional hazard model. Similar analysis was conducted as that described previously for graft survival and the hazard ratios are displayed in Table 6. Factors that independently had a highly significant impact on life expectancy (P < 0.001) were recipient age, a primary renal diagnosis of DN or CRF not otherwise specified, biopsy proven AR, and the era of transplantation. There was no significant effect modification between the decade of transplantation and any of these variables (data not shown).


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  		Table 6 Cox regression analysis for renal transplant recipient survival. Hazard ratios for all factors that retained significance in analysis

 
Results summary
There were significant differences with time over the study period: in later years donors were older and more likely to be female; recipients were older, more likely to have DN, and had to wait longer for a transplant; there was improvement in the degree of HLA-A-B-DR mismatching and a reduction in ischaemic time in the fourth decade; the incidence of biopsy proven AR and graft loss due to AR both fell independently of HLA matching improvement; CNI toxicity became relevant in the second half of the study period; there was a fall in the proportion of deaths due to cardiovascular disease and a trend to a rise in deaths due to malignancy. In multivariate analysis death censored graft survival was significantly impacted by the era of transplantation, donor and recipient ages, living or deceased donor status, and histological evidence of AR, CAN, or disease recurrence. The era of transplantation, recipient age, a primary renal diagnosis of DN or CRF not otherwise specified, and biopsy proven AR significantly impacted recipient survival.


   Discussion
Top
 Summary
 Introduction
 Patients and methods
 Results
 Discussion
Conclusion
 FUNDING
 Acknowledgements
 References
 
The outcomes of the first 100 transplants (91 first transplants, 96 deceased donors) in NI were reported in 1977.5 The 5-year graft survival was 82%, which compares to 75% for deceased donor grafts in Belfast in the latest Renal Registry report.4 This reflects excellent comparative survival figures from the early period of transplantation in Belfast, and current results that are not significantly different from other UK transplant centres. It raises the question whether the evolution in the clinical practice of renal transplantation over the past four decades has been for better or for worse.

What is apparent is that in our region of the UK those transplanted in the second decade had the poorest outcomes with a median graft survival of just 7.7 years which was significantly worse than the other three time periods (P = 0.001), and the estimated graft survival in the fourth decade is now significantly better (P < 0.001). In our centre, there is a substantial survival benefit associated with the later eras of transplantation that is independent of other factors that are known to influence survival. This is despite the changing demography of the transplant recipients that might be expected to be associated with a poorer outcome.

Trends in renal transplantation—negative effects on outcome
There were significant changes in terms of age and incidence of DN in our population over the study period, and these factors independently had a detrimental impact on survival in multivariate analysis.

The mean ages of donors and recipients have risen significantly. Both have been demonstrated to be associated with reduced survival.6–9 The cut-off value at 60 years was arbitrary but relevant as potential deceased donors that are older than this are considered as extended criteria donors.10 Kidney transplants from such extended criteria donors are associated with a significantly reduced expected graft survival compared to standard donor kidneys. In our Cox proportional hazard model, age was considered as a continuous variable and there was a statistically significant decrease in death censored graft survival with each additional year in donor age. The age of the recipient was also an important influence on both death censored graft survival and recipient survival. In the first decade of transplantation in NI only seven recipients were older than 50 years of age, a reflection of the strict rationing policy at that time. It is clear that the advantage associated with successful transplantation compared to maintenance dialysis persists even in the older population11 and since over half of all incident patients commencing RRT in the UK are over 65 years of age4 there is likely to be increasing demand for equity of access to the transplant waiting list from older people.

Similarly the proportion of individuals whose primary renal disease is DN that have received a kidney transplant is also increasing. These individuals were precluded from dialysis and transplantation in earlier years, but as a proportion of the incident transplant population they have doubled from 5.2% in the second decade to 10.4% in the fourth. The outlook for such individuals is poor on dialysis4 but remains significantly worse when compared with other primary diagnostic groups after transplantation.12 Our results concurred with this. However the global epidemic of type 2 diabetes mellitus is contributing to the growth of the ESRD population. DN is now the most frequent specific primary renal diagnosis in those commencing RRT in the UK.4 The demand for transplantation is this group is projected to continue to rise.

Trends in renal transplantation—positive effects on outcome
Over the study period there was a significant reduction in the incidence of AR and an increase in proportion of living donor kidney transplantation. Both factors were independently associated with better survival outcomes in multivariate analyses.

AR has long been recognized as being of importance in renal graft survival13 and in our study it was independently influential on both death censored graft survival and recipient survival. The overall incidence of, and proportion of grafts lost due to AR is falling independently of the degree of HLA matching in our population. We limited our analysis of AR to those episodes confirmed by renal biopsy (consistent with other international reports). The inclusion of empirically treated AR (without histological confirmation) would have overestimated the true incidence. It is likely that the introduction of more potent immunosuppressive medication has resulted in a decline in both the incidence and impact of AR episodes. This is suggested by the significant interaction between AR and the decade of transplantation; the influence of AR on death censored graft survival differed across the eras considered. However there has been a rise in the proportion of deaths related to malignancy in the most recent decade. If this heralds an increase in absolute numbers and not just in proportion of cancer related deaths then the policy on immunosuppression and HLA-matching should be reviewed.

The death censored graft survival of organs from living donors was significantly better than kidneys from deceased donors. This factor did not retain statistical significance in multivariate analysis of recipient survival. The effect on graft survival would be expected to be of greater magnitude than recipient survival and the absence of a statistically significant impact may reflect the small numbers in our population rather than an absence of effect. The increasing disparity between the number waiting for a renal transplant and the static nature of the deceased donor organ pool has led to a greater emphasis within the UK on encouraging and facilitating living donation, including in 2008 the development of an 18-week commissioning pathway for living donor transplants in England.14

Trends in renal transplantation—neutral effects on outcome
Several factors changed significantly over the period of the study that may have been expected to have independently influenced survival, such as donor gender, duration of RRT prior to transplantation, the degree of HLA matching, and the peri-operative ischaemic time. In our study none of these factors independently impacted on survival outcomes in multivariate analyses.

An immunological distinction between genders is considered to account for the poorer outcomes associated with female grafts in some reports.15 However even in the largest registry studied16 the magnitude of effect was small and limited to certain subgroups.

An incremental decrease in graft and patient survival has been associated with increasing duration of dialysis therapy prior to transplantation.17 This was not seen in our population and may reflect that overall the mean duration of RRT prior to a first transplant was 19 months, and that those who waited longer are primarily in the fourth decade so the potentially poorer outcomes associated with this have not yet been realized given the shorter follow-up time for these recipients.

The degree of HLA matching and the peri-operative ischaemic times are surrogate markers for immunological and non-immunologically mediated damage to the graft, so the inclusion in multivariate analyses of actual histological diagnoses such as AR and CAN meant that these factors were not independently associated with survival outcomes.

Trends in renal transplantation—international
The prospective nature and comprehensiveness of the Northern Ireland Regional Renal Transplant database over 40 years minimizes some of the limitations associated with single centre studies. Also the variation in the practice of transplantation medicine both nationally and internationally must be considered in the interpretation of data from all centres or registries. For example the incidence of CAN and chronic CNI toxicity may be considered low in our cohort but we do not perform protocol biopsies and a renal biopsy is considered only if there is a clinically significant deterioration in graft function. Additionally in over one-third of cases of death censored graft loss no histological assessment was performed. However our results are broadly consistent with reported registry data trends in transplantation internationally. Analysis of results in the USA demonstrated very substantial improvements in 1-year graft and recipient survival from the 1960s until the 1990s18 with modest if any improvement in long-term graft survival since then, and a decline in patient survival in the most recent cohort 2000–2004.19 This is concurrent with a substantial rise in recipient age at transplantation. Data from Australia and New Zealand for the period 1993–2004 was comparable with our own in terms of older donors and recipients, longer waiting period before transplantation, and a reduction in the incidence of acute rejection and of deaths due to cardiovascular disease.20 In this period there was improvement in graft but not recipient survival. The passage of time will determine whether the projected increase in both categories in the fourth decade in our population will be realized.


   Conclusion
Top
 Summary
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
FUNDING
 Acknowledgements
 References
 
Renal transplantation is established in the domain of ‘normal’ medical practice, and is increasingly important given the rising prevalence of ESRD. It offers the best option for most individual patients with improved quality of life and survival, and it is the most cost-effective form of renal replacement therapy.21 Relaxation of the initially stringent acceptance criteria for transplantation has led to increasing numbers and a changing demography of the population wait listed for renal transplantation. Some of these factors are associated with reduced graft and recipient survival but have been off-set with improvements in practice, such as a reduction in the incidence and impact of acute rejection. However the use of more powerful immunosuppressive regimens that have contributed to this may be associated with detrimental effects that will be fully realised with further follow up, e.g. increased graft loss due to polyoma viral infection (BK nephropathy) and malignancy related death. Continued vigilance and regular review of the evolving clinical practice patterns in renal transplantation are necessary to maximize both graft and recipient survival outcome.


   FUNDING
Top
 Summary
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 FUNDING
Acknowledgements
 References
 
Dr A.E. Courtney is supported by a Northern Ireland Kidney Research Fund clinical fellowship.

Conflict of interest: None declared.


   Acknowledgements
Top
 Summary
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 FUNDING
 Acknowledgements
References
 
We are grateful to Dr C.C. Patterson for his statistical advice. We thank the clinicians and nursing staff for their dedicated care of renal transplant recipients and for helping with prospective data entry into the Northern Ireland Regional Renal Transplant database. We also thank staff in the Pathology Laboratory, Royal Victoria Hospital and the Northern Ireland Histocompatibilty and Immunogenetics Laboratory, Belfast City Hospital for help extracting renal biopsy information and tissue typing data respectively.


   References
Top
 Summary
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 FUNDING
 Acknowledgements
 References
 
1. Woodruff MF, Robson JS, Ross JA, Nolan B, Lambie AT. Transplantation of a kidney from an identical twin. Lancet (1961) 1:1245–9.[Medline]

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