Christopher Dudley

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.

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.

Chronic renal failure in kidney transplant recipients. Do they receive optimum care? : Data from the UK renal registry

We report the prevalence of chronic kidney disease (CKD) and related complications in a national cohort of RTR (n = 9542), and compare this with dialysis patients. The majority of RTR were classified as having CKD stage 2T (21.6%) or 3T (57.5%) with 15.7% classified as CKD stage 4T and 3.1% as stage 5T. Only 2.1% of RTR were in CKD stage 1T. The proportion of patients with stage 4T and 5T CKD who lost their graft in the following year was 8% and 49%, respectively. The prevalence of anemia (hemoglobin <11 g/dL) increased from 4.4% in stage 1T to 51.5% in stage 5T and compared with 30% in dialysis patients (p < 0.0001). Hypertension, hyperphosphatemia, elevated Ca × PO4, raised iPTH and hypoalbuminemia rose with increasing CKD stage. For many variables, the achievement of standards was lower in stage 5T RTR than in dialysis patients. There were center differences in median estimated glomerular filtration rate and percentage of patients with hemoglobin <11 g/dL (p < 0.0001). In conclusion, many patients in stage 4T–5T have CKD‐related complications that fall below targets established for nontransplant CKD patients. They are at increased risk of graft loss. More attention needs to be paid to managing these complications and preparing these patients for a return to dialysis and/or retransplantation.

Variation between centres in access to renal transplantation in UK: longitudinal cohort study

Objective To assess whether equity exists in access to renal transplantation in the UK after adjustment for case mix in incident patients with end stage renal disease. Design Longitudinal cohort study. Setting UK Renal Registry and UK Transplant Registry. Participants All incident renal replacement treatment patients (n=16 202) from 65 renal centres submitting data to the UK Renal Registry between 1 January 2003 and 31 December 2005, followed until 31 December 2008 (or until transplantation or death, whichever was earliest). Outcome measures Proportion of incident dialysis patients at each renal centre who were registered on the national transplant list; time taken to achieve registration; and proportion of patients subsequently transplanted. Results We found that recipients’ age, ethnicity, and primary renal diagnosis were associated with the likelihood of accessing the waiting list or receiving a transplant. After adjustment for case mix, significant inter-centre variability existed in access to the transplant list (change in −2LogL=89.9, df=1, P<0.001), in the time taken to register patients on the waiting list (change in −2LogL=247.4, df=64, P<0.001), in receipt of a renal transplant from a donor after brain stem death (change in −2LogL=15.1, df=1, P=0.001), and in receipt of a renal transplant from a living donor or a donor after cardiac death (change in −2LogL=46.1, df=1, P<0.001). Conclusions Significant variation in access to renal transplantation exists between centres within the UK that cannot be explained by differences in case mix.

Effect of Pamidronate on Bone Loss After Kidney Transplantation: A Randomized Trial

BACKGROUND Kidney transplantation is associated with an increased risk of bone fracture and rapid loss of bone mineral density after kidney transplantation. STUDY DESIGN Randomized controlled trial. SETTING & PARTICIPANTS Patients were randomly assigned to treatment (n = 46) or control (no treatment; n = 47) groups. Patients were stratified according to parathyroid hormone level and sex. Those with parathyroid hormone level less than 150 pg/mL were excluded. INTERVENTION The treatment and control groups received pamidronate, 1 mg/kg, perioperatively and then at 1, 4, 8, and 12 months or no treatment, respectively. All received calcium (500 mg) and vitamin D (400 units) daily. Immunosuppression was cyclosporine and prednisolone, with no difference in dosing between the 2 groups. OUTCOMES & MEASUREMENTS Bone mineral density was evaluated by means of dual-energy x-ray absorptiometry of the lumbar spine and hip at baseline and 3, 6, 12, and 24 months, with the primary end point at 1 year of percentage of change in bone mineral density from baseline. Clinical fractures were recorded and also evaluated by means of spinal radiographs at baseline and 1 and 2 years. RESULTS Pamidronate protected bone mineral density at the lumbar spine; bone mineral density increased by 2.1% in the treatment group and decreased by 5.7% in the control group at 12 months (P = 0.001). Protection was also seen in Wards area of the hip (P = 0.002) and the total hip (P = 0.004). There was no difference in femoral neck bone mineral density loss between the 2 groups. Fracture rates in the treatment and control groups were 3.3% and 6.4% per annum, respectively. LIMITATIONS This study was not powered to detect differences in fracture rates. CONCLUSION Pamidronate protects against posttransplantation bone loss at the lumbar spine and Wards area of the hip.

Access to Transplantation and Transplant Outcome Measures (ATTOM): study protocol of a UK wide, in-depth, prospective cohort analysis

Introduction There is significant intercentre variability in access to renal transplantation in the UK due to poorly understood factors. The overarching aims of this study are to improve equity of access to kidney and kidney–pancreas transplantation across the UK and to optimise organ allocation to maximise the benefit and cost-effectiveness of transplantation. Methods and analysis 6844 patients aged 18–75 years starting dialysis and/or receiving a transplant together with matched patients active on the transplant list from all 72 UK renal units were recruited between November 2011 and March 2013 and will be followed for at least 3 years. The outcomes of interest include patient survival, access to the transplant list, receipt of a transplant, patient-reported outcome measures (PROMs) including quality of life, treatment satisfaction, well-being and health status on different forms of renal replacement therapy. Sociodemographic and clinical data were prospectively collected from case notes and from interviews with patients and local clinical teams. Qualitative process exploration with clinical staff will help identify unit-specific factors that influence access to renal transplantation. A health economic analysis will explore costs and outcomes associated with alternative approaches to organ allocation. The study will deliver: (1) an understanding of patient and unit-specific factors influencing access to renal transplantation in the UK, informing potential changes to practices and policies to optimise outcomes and reduce intercentre variability; (2) a patient-survival probability model to standardise access to the renal transplant list and (3) an understanding of PROMs and health economic impact of kidney and kidney–pancreas transplantation to inform the development of a more sophisticated and fairer organ allocation algorithm. Ethics and dissemination The protocol has been independently peer reviewed by National Institute for Health Research (NIHR) and approved by the East of England Research Ethics Committee. The results will be published in peer-reviewed journals and presented at conferences.

Maximizing renal preservation in acute renal failure

Several critical questions about the optimum management of patients with the systemic inflammatory response syndrome (SIRS), prerenal ARF and ATN have been recently addressed in clinical studies. For example, does early goal-directed therapy in sepsis and severe shock lead to a lower mortality? What is the preferred choice of intravenous fluid for volume replacement in ARF? Can ARF be avoided in certain circumstances? Can the risk of aminoglycoside-induced nephrotoxicity be reduced? What are the roles of low-dose dopamine and frusemide infusions in ARF? In patients with established ARF, does any particular method of renal replacement therapy (RRT) have advantages over others? Are there any treatments that can ameliorate ATN? This article aims to answer these questions by reviewing the recent developments in these important areas.

Chronic kidney disease in kidney transplant recipients-is it different from chronic native kidney disease?

Background. The rate of change in estimated glomerular filtration rate (&Dgr;eGFR), factors influencing &Dgr;eGFR, and its association with mortality has not been well studied in renal transplant recipients. Methods. Adult kidney-only recipients between January 2001 and December 2004, with surviving grafts 1 year after transplantation, from England and Wales were followed up till 31 December 2006, graft failure or death. The four variable modification of diet in renal disease equation was used to estimate GFR and &Dgr;eGFR assessed using linear least square regression. &Dgr;eGFR of −1 mL/min/1.73m2 per year and above was considered to be stable or improving function. Linear regression and Cox regression analyses were used to examine factors influencing &Dgr;eGFR and its association with mortality, respectively. Results. Of the 2, 927 patients included, &Dgr;eGFR was −1.3±6.0 mL/min/1.73 m2 per year and eGFR remained stable or improved in the majority (54.8%). Baseline graft function at 1 year or live donor status did not influence &Dgr;eGFR. Male donor to female recipient transplantation, younger recipients, diabetes, white race, and human leukocyte antigen mismatch were associated with faster decline in eGFR. &Dgr;eGFR was not associated with mortality when censored for graft failure. Conclusions. Majority of renal transplant recipients experienced stable or improved graft function. Specific donor and recipient characteristics influenced the rate of decline in eGFR. The lack of association of &Dgr;eGFR with mortality, the stability of eGFR in the majority, and influence of donor characteristics on &Dgr;eGFR suggest caution when applying prognosis knowledge from the native kidney disease to the kidney transplant population.

Understanding cost of care for patients on renal replacement therapy: looking beyond fixed tariffs

BACKGROUND In a number of countries, reimbursement to hospitals providing renal dialysis services is set according to a fixed tariff. While the cost of maintenance dialysis and transplant surgery are amenable to a system of fixed tariffs, patients with established renal failure commonly present with comorbid conditions that can lead to variations in the need for hospitalization beyond the provision of renal replacement therapy. METHODS Patient-level cost data for incident renal replacement therapy patients in England were obtained as a result of linkage of the Hospital Episodes Statistics dataset to UK Renal Registry data. Regression models were developed to explore variations in hospital costs in relation to treatment modality, number of years on treatment and factors such as age and comorbidities. The final models were then used to predict annual costs for patients with different sets of characteristics. RESULTS Excluding the cost of renal replacement therapy itself, inpatient costs generally decreased with number of years on treatment for haemodialysis and transplant patients, whereas costs for patients receiving peritoneal dialysis remained constant. Diabetes was associated with higher mean annual costs for all patients irrespective of treatment modality and hospital setting. Age did not have a consistent effect on costs. CONCLUSIONS Combining predicted hospital costs with the fixed costs of renal replacement therapy showed that the total cost differential for a patient continuing on dialysis rather than receiving a transplant is considerable following the first year of renal replacement therapy, thus reinforcing the longer-term economic advantage of transplantation over dialysis for the health service.

Renal after cardiothoracic transplant: the effect of repeat mismatches on outcome.

Background. Histocompatibility matching is not considered important in nonrenal solid organ transplants (NRSOT). There is no evidence to base guidance on whether mismatched human leukocyte antigen (HLA) antigens should be avoided in subsequent renal transplantation. Methods. This study examines the effect of repeat HLA mismatches on renal allograft survival and function in all renal after cardiothoracic transplants undertaken in the United Kingdom between 1997 and 2003 using the UK Transplant data. Results. A repeat HLA-A, -B, or -DR mismatch occurred in 16 of 53 (30%) cases. Recipients without a repeat mismatch were more likely to be male, but recipient age, donor age, recipient-donor age difference, donor gender, donor type, or cold ischemia time were comparable. Immunosuppressive therapy was similar in both groups. No differences were observed in renal allograft function at 1 or 5 years between the repeat mismatch group (estimated glomerular filtration rate [mean±standard deviation] 41.6±16.6 and 37.5±12.8 mL/min/1.73 m2) and the no repeat mismatch group (47.2±15.7 and 48.0±15.9 mL/min/1.73 m2). Renal allograft survival was also similar in the two groups at 1 and 5 years. Conclusions. In this limited, heterogeneous, observational cohort of cardiothoracic transplant patients who went on to receive a sequential kidney transplant, a repeated HLA antigen mismatch was not associated with a detrimental effect on kidney transplant outcome.