Rachel J. Johnson

Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

Background. The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resulted in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. Methods. Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2R&agr;), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 months and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy endpoint was biopsy-proven rejection during the first 6 months posttransplant. Results. Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 &mgr;mol/L (95%, confidence interval [CI], 100.7 to 125.3 &mgr;mol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 &mgr;mol/L (95% CI, 135.0 to 173.0 &mgr;mol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2R&agr; saturation. Conclusions. This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2R&agr; blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.

Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK

BACKGROUND In the UK, kidneys are exchanged between centres on the basis of matching for HLA. We analysed various factors that might affect graft outcome to establish whether exchange of kidneys on this basis remains valid. METHODS 6363 primary cadaveric renal transplants carried out in 23 centres in the UK between 1986 and 1993 were used in the analysis. 6338 (99.6%) patients who underwent transplantation were followed up at 1 year. 5-year follow-up data were available for 2907 (97.8%) of the 2972 patients who survived to 5 years. We made random checks to validate the data. A multifactorial analysis with Coxs proportional hazards models was used to analyse factors that had a possible effect on graft outcome. To ensure that the analysis of matching was constant during the 8-year study, our analysis was based on the HLA antigens used for organ exchange (11 A locus antigens, 27 B locus antigens, and 12 DR locus antigens). We assessed overall outcome at 5 years and during three periods after transplantation at: 0-3 months, 3-36 months, and after 36 months. FINDINGS The following factors were significantly associated with graft outcome in the multifactorial analysis: year of graft, age of donor, age of recipient, whether the recipient had diabetes, cause of donors death, cold ischaemic time, transport of kidneys, transplant centre, and matching for HLA. The best outcome was achieved with kidneys that had no mismatches at HLA-A, HLA-B, and HLA-DR loci (000 mismatches). The next most favourable outcome was achieved with one mismatch at either A or B loci or one mismatch at both the A and B , but no mismatch at the DR locus (100, 010, or 110 mismatches). Age of the donor and recipient had a significant effect on transplant outcome: older age was associated with increased risk of graft failure. INTERPRETATION Various factors affect the outcome of primary cadaveric renal transplantation, particularly the age of the donor and the recipient. However, the effect of matching for HLA remains a strong one and fully justifies the continuing policy in the UK of exchanging kidneys on the basis of HLA matching, especially to recipients when there is a 000 mismatch for HLA between donor and recipient. On the basis of this analysis, a new allocation scheme for kidneys was introduced in the UK in 1998. During the first 9 months of the scheme, there has been a doubling of the number of HLA-000 mismatched kidneys transplanted.

Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study

BACKGROUND A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. METHODS We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged ≥18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). FINDINGS 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac-death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1·01, 95% CI 0·83 to 1·19, p=0·97), or in eGFR at 1-5 years after transplantation (at 12 months -0·36 mL/min per 1·73 m(2), 95% CI -2·00 to 1·27, p=0·66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. INTERPRETATION Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. FUNDING UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre.

Factors Affecting Graft and Patient Survival After Live Donor Kidney Transplantation in the UK

Background. The outcome after living donor renal transplantation is superior to that for deceased donor transplantation, but the results are not uniformly successful. The factors responsible for the variable outcome after living donor transplantation have not been well defined. Methods. UK Transplant Registry data were analyzed to determine the outcomes of 3142 first adult kidney transplants from living donors (71% genetically related and 29% unrelated) performed between 2000 and 2007 inclusive. Kaplan-Meier survival estimates were determined, and factors that might be associated with graft and patient survival were analyzed using Cox proportional hazards regression modeling. Results. Patient survival at 5 years was better for recipients of grafts from related than unrelated donors (97% vs. 93%, P=0.0002), but conversely graft survival was better in recipients of genetically unrelated grafts (93% vs. 89%, P=0.06). After adjustment for the factors found to influence graft and patient survival, these differences were no longer apparent. In contrast to the expectations, the degree of human leukocyte antigen-A, -B, and -DR mismatch did not influence graft survival. Increasing donor age (but not recipient age), recipient diabetes, and grafts from adult offspring were independently associated with poorer patient survival in the first 3 years after transplantation. Poorer graft survival was independently associated with donor age older than 59 years, and female recipients. Conclusions. Advanced donor age, but not human leukocyte antigen mismatch, is associated with poorer outcome after live donor kidney transplantation. However, the results of live donor transplantation remain superior to deceased donor kidney transplantation.BACKGROUND Mesenchymal stem cells (MSCs), also known as multipotent progenitor cells, release several factors that support cell survival and enhance wound healing. We hypothesized that MSC-secreted molecules would induce a trophic effect in pancreatic islet culture conditions. METHODS Pancreatic islets were co-cultured with MSCs, and ADP/ATP ratios, glucose stimulated insulin secretion (GSIS), and DNA fragmentation were evaluated to measure islet quality and viability in vitro. The induction of signal molecules related to the control of survival, function, and angiogenesis was also analyzed. Cell quality assays, DNA fragmentation assays, and islet transplantation into streptozotocin-induced diabetic mice were performed using MSC-conditioned medium (CM)-cultured islets. Furthermore, we identified soluble molecules within MSC-CM. RESULTS Islets co-cultured with MSCs demonstrated lower ADP/ATP ratios, and higher GSIS indexes and viability. Furthermore, co-cultured islets revealed higher levels of anti-apoptotic signal molecules (X-linked inhibitor of apoptosis protein, Bcl-xL, Bcl-2, and heat shock protein-32) and demonstrated increased vascular endothelial growth factor receptor 2 and Tie-2 mRNA expression and increased levels of phosphorylated Tie-2 and focal adhesion kinase protein. Islets cultured in MSC-CM demonstrated lower ADP/ATP ratios, less apoptosis, and a higher GSIS indexes. Diabetic mice that received islet transplants (200 islet equivalent) cultured in MSC-CM for 48 hr demonstrated significantly lower blood glucose levels and enhanced blood vessel formation. In addition, interleukin-6, interleukin-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC-CM. CONCLUSIONS These results suggest that the trophic factors secreted by human MSCs enhance islet survival and function after transplantation.

Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry.

Background. Maternal and fetal complications in pregnancies after renal transplantation have been highlighted in several reports, but information on their main predisposing factors is limited. The U.K. Transplant Pregnancy Registry was established in 1997 to obtain detailed information on pregnancies in female organ transplant recipients across the U.K. Methods. For each female kidney, liver, or cardiothoracic organ transplant recipient who had had a recent pregnancy, data on maternal and fetal factors and pregnancy outcomes were collected using forms completed by their transplant follow-up and obstetric units. For kidney transplant recipients, the factors that influence pregnancy outcome were studied using logistic regression, and the effect of pregnancy on graft function was analyzed. Results. There were live births in 83%, 69%, and 79% of pregnancies in cardiothoracic organ, liver, and kidney recipients, respectively. In 50% of live births from renal patients, delivery was preterm (<37 weeks), with 83% of the preterm infants delivered via caesarean. Preterm delivery was associated with maternal drug-treated hypertension and impaired renal function. A matched case–control study showed no evidence of increased renal allograft loss after pregnancy. A univariate survival analysis, however, suggested an association between drug-treated hypertension during pregnancy and poorer postpregnancy graft survival. In patients with prepregnancy serum creatinine (SCr) >150 &mgr;mol/L, a trend toward increased postpregnancy SCr was identified. Conclusions. Pregnancy is likely to end in a live birth in a majority of organ transplant recipients. In patients with greater prepregnancy SCr and/or drug-treated hypertension during pregnancy, however, subsequent renal function may be adversely affected.

Equity of access to renal transplant waiting list and renal transplantation in Scotland: cohort study

Abstract Objective To examine the access to the renal transplant waiting list and renal transplantation in Scotland. Design Cohort study. Setting Renal and transplant units in Scotland. Participants 4523 adults starting renal replacement therapy in Scotland between 1 January 1989 and 31 December 1999. Main outcome measures Impact of age, sex, social deprivation, primary renal disease, renal or transplant unit, and geography on access to the waiting list and renal transplantation. Results 1736 of 4523 (38.4%) patients were placed on the waiting list for renal transplantation and 1095 (24.2%) underwent transplantation up to 31 December 2000, the end of the study period. Patients were less likely to be placed on the list if they were female, older, had diabetes, were in a high deprivation category, and were treated in a renal unit in a hospital with no transplant unit. Patients living furthest away from the transplant centre were listed more quickly. The only factors governing access to transplantation once on the list were age, primary renal disease, and year of listing. A significant centre effect was found in access to the waiting list and renal transplantation. Conclusions A major disparity exists in access to the renal transplant waiting list and renal transplantation in Scotland. Comorbidity may be an important factor.

Effect of donor age and cold storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort study

BACKGROUND Use of kidneys donated after controlled circulatory death has increased the number of transplants undertaken in the UK but there remains reluctance to use kidneys from older circulatory-death donors and concern that kidneys from circulatory-death donors are particularly susceptible to cold ischaemic injury. We aimed to compare the effect of donor age and cold ischaemic time on transplant outcome in kidneys donated after circulatory death versus brain death. METHODS We used the UK transplant registry to select a cohort of first-time recipients (aged ≥ 18 years) of deceased-donor kidneys for transplantations done between Jan 1, 2005, and Nov 1, 2010. We did univariate comparisons of transplants from brain-death donors versus circulatory-death donors with χ tests for categorical data and Wilcoxon tests for non-parametric continuous data. We used Kaplan-Meier curves to show graft survival. We used Cox proportional hazards regression to adjust for donor and recipient factors associated with graft-survival with tests for interaction effects to establish the relative effect of donor age and cold ischaemia on kidneys from circulatory-death and brain-death donors. FINDINGS 6490 deceased-donor kidney transplants were done at 23 centres. 3 year graft survival showed no difference between circulatory-death (n=1768) and brain-death (n=4127) groups (HR 1·14, 95% CI 0·95-1·36, p=0·16). Donor age older than 60 years (compared with <40 years) was associated with an increased risk of graft loss for all deceased-donor kidneys (2·35, 1·85-3·00, p<0·0001) but there was no increased risk of graft loss for circulatory-death donors older than 60 years compared with brain-death donors in the same age group (p=0·30). Prolonged cold ischaemic time (>24 h vs <12 h) was not associated with decreased graft survival for all deceased-donor kidneys but was associated with poorer graft survival for kidneys from circulatory-death donors than for those from brain-death donors (2·36, 1·39-4·02, p for interaction=0·004). INTERPRETATION Kidneys from older circulatory-death donors have equivalent graft survival to kidneys from brain-death donors in the same age group, and are acceptable for transplantation. However, circulatory-death donor kidneys tolerate cold storage less well than do brain-death donor kidneys and this finding should be considered when developing organ allocation policy. FUNDING UK National Health Service Blood and Transplant; Cambridge National Institute for Health Research Biomedical Research Centre.

2509 Living Donor Nephrectomies, Morbidity and Mortality, Including the UK Introduction of Laparoscopic Donor Surgery

The worldwide expansion of laparoscopic, at the expense of open, donor nephrectomy (DN) has been driven on the basis of faster convalescence for the donor. However, concerns have been expressed over the safety of the laparoscopic procedure. The UK Transplant National Registry collecting mandatory information on all living kidney donations in the country was analyzed for donations between November 2000 (start of living donor follow‐up data reporting) to June 2006 to assess the safety of living DN, after the recent introduction of the laparoscopic procedure in the United Kingdom. Twenty‐four transplant units reported data on 2509 donors (601 laparoscopic, 1800 open and 108 [4.3%] unspecified); 46.5% male; mean donor age: 46 years. There was one death 3 months postdischarge and a further five deaths beyond 1 year postdischarge. The mean length of stay was 1.5 days less for the laparoscopic procedure (p < 0.001). The risk of major morbidity for all donors was 4.9% (laparoscopic = 4.5%, open = 5.1%, p = 0.549). The overall rate of any morbidity was 14.3% (laparoscopic = 10.3%, open = 15.7%, p = 0.001). Living donation has remained a safe procedure in the UK during the learning curve of introduction of the laparoscopic procedure. The latter offers measurable advantages to the donor in terms of reduced length of stay and morbidity.

Factors That Influence Access to the National Renal Transplant Waiting List

Background. Registry data can be used to examine whether there are differences between individual renal units in the proportion of dialysis patients listed for renal transplantation, to investigate possible reasons for any differences observed, and to discover whether highlighting these anomalies can influence practice. Methods. A cross-sectional study of 12, 401 prevalent adult dialysis patients from 41 renal units across England and Wales was performed. The proportion of patients registered on the deceased donor transplant waiting list was determined for each renal unit. Patient- and center-specific factors that influence the probability of being listed for transplantation were identified and used to adjust for differences observed between units. The annual change in the size of the transplant waiting list was examined before and after presentation of these data. Results. A total of 23.3% of patients were active on the transplant waiting list. Patient. Specific variables significantly associated with listing were age, primary renal disease, graft number, social deprivation, and ethnicity but not gender. Centre-specific variables included size of renal unit, size of living donor program, and listing practice for living donor transplantation. Whether the renal unit was also a transplant unit was not significant. After adjusting for these variables, there remained unexplained variation between renal units in the proportion of dialysis patients on the waiting list. An increase in the number of patients listed for transplantation has been observed since presenting these data. Conclusions. Differences in listing practice exist between centers that cannot be explained by the patient case mix or center characteristics examined.

Kidney donation after circulatory death (DCD): state of the art

The use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to markedly increase kidney transplants performed. However, this potential is not being realized because of concerns that DCD kidneys are inferior to those from donation after brain-death (DBD) donors. The United Kingdom has developed a large and successful controlled DCD kidney transplant program that has allowed for a substantial increase in kidney transplant numbers. Here we describe recent trends in DCD kidney donor activity in the United Kingdom, outline aspects of the donation process, and describe donor selection and allocation of DCD kidneys. Previous UK Transplant Registry analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, short- and medium-term transplant outcomes are similar in recipients of kidneys from DCD and DBD donors. We present an updated, extended UK registry analysis showing that longer-term transplant outcomes in DCD donor kidneys are also similar to those for DBD donor kidneys, and that transplant outcomes for kidneys from expanded-criteria DCD donors are no less favorable than for expanded-criteria DBD donors. Accordingly, the selection criteria for use of kidneys from DCD donors should be the same as those used for DBD donors. The UK experience suggests that wider international development of DCD kidney transplantation programs will help address the global shortage of deceased donor kidneys for transplantation.