Biomedical subjects
John L R Forsythe
Publications and source records attributed to John L R Forsythe.
The assembly line approach in kidney transplantation--back to the future?
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"Dirty little secrets"--endotoxin contamination of recombinant proteins.
The identification of Toll-like receptors has revolutionised our understanding of innate immunity. TLR4 transduces the LPS signal and that of a number of structurally and functionally unrelated agonists. However, recent evidence adds to longstanding concerns that endotoxin contamination of bacterially derived recombinant TLR4 agonists is responsible for effects attributed to these molecules. We highlight key factors in differentiating specific agonist effects from those of endotoxin and emphasize why conventional methods of detecting and eliminating LPS may lead to erroneous results. We propose that considerable caution is needed in the investigation of TLR4 agonists, particularly when using proteins produced in a bacterium that also houses the most ideal TLR4 agonist, LPS.
Which index is optimal for assessment of baseline comorbidities in kidney transplant recipients?
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Impact of cadaveric renal transplantation on survival in patients listed for transplantation.
The aim of this study was to assess the magnitude of the survival benefit of renal transplantation compared with dialysis in patients selected for transplantation in Scotland. Longitudinal study of survival and mortality risk in all adult patients (1732) listed for a first transplant between January 1, 1989, and December 31, 1989, in Scotland. A time-dependent Cox regression analysis adjusted for comorbidity, sociodemographic and geographic factors, primary renal disease, time on dialysis, and year of listing compared the risk of death for patients receiving a first cadaveric transplant versus all patients on dialysis listed for transplantation. After adjustment for the covariates, the relative risk (RR) of death during the first 30 days after transplantation was 1.35 (95% confidence interval [CI], 0.63 to 2.86) compared with patients on dialysis (RR = 1). The long-term RR (at 18 mo) for the transplant recipients was 0.18 (95% CI, 0.08 to 0.42) when compared with patients on dialysis (RR = 1). This lower long-term risk of death was present in all patients undergoing transplantation, irrespective of their age group or primary renal disease. Similar results were seen when survival with a transplant was censored for graft failure. The projected life expectancy with a transplant was 17.19 yr compared with only 5.84 yr on dialysis. Despite an initial higher risk of death, long-term survival for patients who undergo transplantation is significantly better compared with patients who are listed but remain on dialysis. A successful transplant triples the life expectancy of a listed renal failure patient.
Higher quality of life in living donor kidney transplantation: prospective cohort study.
This prospective, longitudinal cohort study investigated the effect of donating or receiving a kidney on quality of life and relationship dynamics. Forty donors and 35 recipients from two UK transplantation centres completed the World Health Organisation quality of life questionnaire (WHOQOL) with additional questionnaires before, 6 weeks and one year after operation. Before donation the donor mean quality of life score in the physical domain was 18.8. This was significantly higher than the UK value for a healthy person of 16.4 (P < 0.001). Six weeks after operation, donor score reduced to UK normative levels however improved again at one year (17.7). Recipient mean physical domain score before was 11.4, significantly lower than the UK norm (P < 0.01), increasing to 16.0 one year after. Both donor (P < 0.009) and recipient (P < 0.05) experienced a significant improvement in their mutual relationship. Recipients expressed anxiety about the donor before operation. Donors were not concerned about living with one kidney. We concluded that living kidney donation has no detrimental effect on the physical or psychological well being of donors one year after donation. Transplantation results in a major improvement in quality of life for the recipient. Most donors would donate again, if this were possible.
The incidence and importance of bacterial contaminants of cadaveric renal perfusion fluid.
Infections represent a significant risk in the postoperative transplant recipient. The perfusion fluid used to perfuse and preserve the kidneys prior to transplantation represents a potential medium in which organisms can grow. The aim of this study was to determine the incidence and clinical relevance of bacterial contamination of perfusion fluid. A total of 4 centres participated in the study and 269 perfusion fluid samples were taken for microbiological analysis. Organisms were isolated from 38 out of 218 (17.4%) perfusion fluid samples taken prior to allograft implantation and 23 out of 51 (45%) samples taken at procurement. Low virulence organisms predominated although Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli were also isolated. Although infective complications were not seen in the allograft recipients, given the frequency with which contamination occurs and the variation in unit antibiotic protocols, we recommend the routine culturing of perfusion fluid to ensure that any potentially significant organisms are identified and treated appropriately.
Human leukocyte antigen and the allocation of kidneys from cadaver donors in the United Kingdom.
The national scheme currently used for the allocation of cadaver kidneys in the United Kingdom includes factors demonstrated to improve transplant outcome and promote equity in organ allocation. Introduced in 1998, the scheme is based on human leukocyte antigen matching, gives priority to children and highly sensitized patients, and incorporates features to assist transplantation in patients who are difficult to match. The scheme is open and transparent and subject to continuous audit and review to address any inequities in access to transplant that become apparent.
Incentives to promote organ donation.
The worldwide shortage of organs has led to the development of incentives to promote organ donation. These incentives vary widely in nature ranging from financial remuneration to preferential access to conditional donation. Such strategies to increase organ donation present a variety of ethical dilemmas challenging traditional concepts of justice and equity of access. In addition, there are legal and logistic considerations that must be discussed. The case is made that schemes using incentives to promote organ donation must meet the requirements of society for justice, equity of access, and avoidance of racial or other bias.
How great is the survival advantage of transplantation over dialysis in elderly patients?
BACKGROUND: Patients >60 years old represent 66% of all new patients starting renal replacement therapy in Scotland. The aim of this study was to investigate whether or not transplantation provides any survival benefit in this group of patients. METHODS: 325 patients >60 years old listed for transplantation in Scotland between 1 January 1989 and 31 December 1999 were followed up until 31 December 2000. Sociodemographic, comorbidity, listing and transplant data were obtained from the national renal and transplant databases and case-notes review. Survival was compared between those who received a transplant and those who were listed but did not receive a transplant by the end of the follow-up period. Mann-Whitney, chi(2), Fisher's exact and log-rank tests were used where appropriate. RESULTS: Of the 325 patients listed, 128 (39.4%) received a first transplant within the study period and the remaining 197 (60.6%) continued to undergo dialysis. The transplant recipients were younger at listing (P<0.0001), lived closer to the transplant centre (P = 0.043) and spent less time on the active waiting list (P<0.0001) than patients who remained on dialysis. They had less ischaemic heart disease (P = 0.024), cerebrovascular disease (P = 0.03) and arrhythmias (P = 0.016). The overall mortality rate was 0.16 per patient-year for dialysis and 0.10 for transplantation. There was a significantly lower risk of death (RR = 0.35, 95% CI 0.22--0.54; P<0.0001, log-rank) and a longer life expectancy after listing with a transplant (8.17 vs 4.32 years). CONCLUSIONS: Renal transplantation offers a significant survival advantage over dialysis in elderly patients with end-stage renal failure who are considered suitable for transplantation.
The role of vascular endothelial growth factor in the kidney in health and disease.
Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen, angiogenic factor and enhancer of vascular permeability. Expressed in the epithelial cells of the developing glomerulus and tubular epithelium, VEGF plays an important role in the development and maintenance of the early vasculature of the kidney. Here, we review the available literature regarding the expression and function of VEGF both in the developing and healthy adult kidney. Furthermore, we highlight how VEGF expression is altered in the diseased kidney and how this modulated expression may impact on and reflect underlying functional changes occurring during the disease process. As discussed, many controversial issues remain, particularly concerning the role of VEGF in the diseased kidney. That VEGF has been proposed as a potential future therapeutic target for the management of some renal diseases requires first that the precise role of VEGF in the normal kidney and various renal pathologies be further and more clearly defined.
Equity of access to renal transplant waiting list and renal transplantation in Scotland: cohort study.
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.
To biopsy or not to biopsy.
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Insurance issues in living kidney donation.
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Establishing a transplant coordinator-led living kidney donor follow-up clinic.
BACKGROUND: The long-term risks of renal failure and hypertension are statistically low for living kidney donors as a group, but can have serious consequences for the individual. OBJECTIVES: To describe the experience with a transplant coordinator-led living donor follow-up clinic. METHOD: Living kidney donors are reviewed on an annual basis by a designated coordinator (registered nurse). A 24-hour urine collection estimates renal function. Blood pressure and blood chemistry are measured and urinalysis performed. Current health status and wound discomfort are assessed. Any medical problems identified are referred to a specialist hospital department or to the donor's family practitioner. RESULTS: Fifty-nine appointments were booked and 12 (20%) donors did not attend. Renal function was within acceptable limits for all attending donors. Three donors had raised blood glucose levels and 8 donors were hypertensive; all were referred to family practitioners. Forty-seven donors (35 new, 12 return) completed a questionnaire on the follow-up provided. Thirty-eight (81%) were satisfied with the follow-up, and 47 (100%) agreed this clinic provided adequate follow-up. Thirty-three (70%) donors stated they preferred that the transplant coordinator performed the follow-up, 3 (6%) preferred the family practitioner, and 11 (23%) had no preference. CONCLUSIONS: There are many possible solutions to the provision of lifelong care of living kidney donors. The model of a transplant coordinator-led clinic appears to have a high degree of patient acceptance, perhaps because of the continuity of care provided by a known member of the transplant team. Further work is required to identify reasons for nonattendance.
Ethical market in organs. Defending the indefensible?
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Does a kidney-sharing alliance have to sacrifice cold ischemic time for better HLA matching?
BACKGROUND: The Scotland-Northern Ireland Kidney Allocation Alliance was created in August 1998. The purpose was to optimize the transplant service through increased regional exchange, higher quality matched kidneys, and better organ distribution. METHODS: An analysis was performed on prospectively collected data regarding retrieval and transplant activity. The degree of HLA matching, the cold ischemic time (CIT), the balance of exchange, and graft survival were analyzed for a 2-year period after the introduction of the new alliance and compared with the last year before alliance. RESULTS: There was a 17.7% increase in the number of transplants performed. In the 2-year period, 78% of kidneys were exported from the retrieving center compared with 55% in the prealliance year, (P<0.05, chi2). The proportion of 000 mismatched transplants and other favorable matches increased from 9.5 to 21% and from 52.5 to 61%, respectively. There was no significant difference between the CIT for the three study periods, nor between the CIT for locally used kidneys versus those exchanged within the Alliance (P>0.05, Student's t test). The largest center was a net importer of kidneys, whereas small and medium-sized centers balanced their exchange within the 2-year period. The 1-year transplant survival rate improved from 81.5% in the prealliance year to 88.4% at the end of the second year. CONCLUSIONS: The introduction of a regional kidney allocation alliance has improved the degree of HLA matching and increased the exchange of organs, without a significant increase in the CIT and any detrimental effect on graft survival.