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M L Nicholson

Publications and source records attributed to M L Nicholson.

At least 37 records · Page 2Linked to original sources
PubMed2004

A comparison of traditional open, minimal-incision donor nephrectomy and laparoscopic donor nephrectomy.

Laparoscopic donor nephrectomy (LDN) and minimal-incision donor nephrectomy (MILD) are less invasive procedures than the traditional open donor nephrectomy approach (ODN). This study compares donor and recipient outcome following those three different procedures. Sixty consecutive donor nephrectomies were studied (n = 20 in each group). Intra-operative variables, analgesic requirements, donor recovery, donor/recipient complications and allograft function were recorded prospectively. Operating and first warm ischaemia times were longer for LDN than for ODN and MILD (232+/-35 vs 121+/-24 vs 147+/-27 min, P < 0.001; 4+/-1 vs 2+/-2 vs 2+/-1 min, P < 0.01). Postoperative morphine requirements were significantly higher after ODN than after MILD and LDN (182+/-113 vs 86+/-48 vs 71+/-45 mg; P < 0.0001). There was no episode of delayed graft function in this study. Donors returned to work quicker after LDN than after ODN and MILD (6+/-2 vs 11+/-5 vs 10+/-7; P = 0.055). Donor and recipient complication rates and recipient allograft function were comparable. We concluded that MILD and LDN reduce postoperative pain and allow a faster recovery without compromising recipient outcome.

Adult↗
PubMed2004

Interleukin 6 production during abdominal aortic aneurysm repair arises from the gastrointestinal tract and not the legs.

BACKGROUND: Abdominal aortic aneurysm (AAA) repair is associated with a systemic inflammatory response. This inflammatory response probably arises as a result of an ischaemia-reperfusion injury to the legs and gastrointestinal tract. In this study the relative contributions of these areas to the inflammatory response were assessed during elective AAA repair. METHODS: Blood was sampled from the femoral vein, portal vein and radial artery of 14 patients undergoing elective AAA repair at five time points during the procedure. Plasma was snap-frozen for subsequent batch analysis of interleukin (IL) 6. RESULTS: The plasma IL-6 concentration rose steadily throughout the procedure at all three locations. The increase in plasma IL-6 was significantly greater in the portal vein than in the radial artery during ischaemia (P = 0.020). The plasma IL-6 concentration was also significantly higher in the portal vein than in the femoral vein (P < 0.001) and radial artery (P < 0.001) during reperfusion. There were no significant differences between radial artery and femoral vein IL-6 levels at any time point. CONCLUSION: Ischaemia and reperfusion during AAA repair were associated with a marked increase in IL-6 concentration in the portal vein, suggesting that IL-6 was produced by the gastrointestinal tract.

Analysis of Variance↗
PubMed2004

The post-operative mortality of ruptured abdominal aortic aneurysm repair.

INTRODUCTION: Late peri-operative death after ruptured abdominal aortic aneurysm (RAAA) repair is usually due to multiple-organ failure. The aim of this study was to identify any factors that are associated with mortality in this group of patients. METHODS: A retrospective case-note review of a single decade's operative experience of RAAA repair in a single centre. Only those patients with confirmed rupture at laparotomy were included. Sixty-three pre- intra- and post-operative variables were recorded where possible for each patient who survived surgery and the initial 24-hours post-operatively. Multi-variate analysis was performed using stepwise logistic regression. The P-POSSUM, RAAA-POSSUM, RAAA-POSSUM (physiology only), V-POSSUM, and V-POSSUM (physiology only) models were all compared to determine how each performed in these patients. RESULTS: Two hundred and twenty-three cases of confirmed RAAA were identified, of whom 139 survived the operation and initial 24-hours post-operatively. In-hospital mortality in this group of patients was 32.4%. Variables significantly associated with mortality after multi-variate analysis, were low intra-operative systolic blood pressure, the presence of a consultant anaesthetist at the initial operation and the development of cardiac, renal or gastro-intestinal complications. All POSSUM models except the V-POSSUM and P-POSSUM (physiology only) models demonstrated no significant lack of fit in this dataset. DISCUSSION: Factors associated with delayed peri-operative death after RAAA are not the same as those previously found to be associated with overall peri-operative mortality after RAAA repair.

Aged↗
PubMed2004

Cytokines, their genetic polymorphisms, and outcome after abdominal aortic aneurysm repair.

BACKGROUND: Excessive cytokine production has been implicated in the development of organ failure. Polymorphic sites in cytokine genes have been shown to affect levels of production in vitro and may influence cytokine production in vivo. The aims of this study were to determine if cytokines or their genetic polymorphisms were related to outcome after abdominal aortic aneurysm (AAA) repair. METHODS: A prospective study of 135 patients undergoing open AAA repair. Plasma levels of TNF-alpha, IL-1beta, IL-6 and IL-10 were measured 24 h post-operatively and genotypes for the TNF-alpha -308, IL-1beta+3953, IL-6 -174, IL-10 -1082 and IL-10 -592 polymorphisms were determined for each patient. RESULTS: After elective AAA high levels of IL-10 were associated with both prolonged critical care (P<0.001) and hospital stay (P=0.001). The presence of a G allele at the IL-6 -174 locus was associated with a higher incidence of organ failure (P=0.04) and an A allele at TNF-alpha -308 with prolonged critical care stay (P=0.03). After ruptured AAA the development of multi-organ failure was associated with high levels of IL-6 (P=0.01) and TNF-alpha (P=0.04). High TNF-alpha levels were also associated with mortality (P=0.01). CONCLUSION: Post-operative cytokine levels are related to outcome after AAA repair. Cytokine gene polymorphisms may provide a method for determining which patients are at high risk of complications.

Aged↗
PubMed2004

An audit over 2 years' practice of open and laparoscopic live-donor nephrectomy at renal transplant centres in the UK and Ireland.

OBJECTIVE: To collate information on the practice of live-donor nephrectomy and compare this with the published British Transplantation Society (BTS) guidelines for best practice, using two questionnaires sent to all renal transplant centres in the UK and Ireland to cover practice for the years 2000 and 2002. METHODS: A postal questionnaire was sent to all surgical kidney transplant consultants in the UK and Ireland, including questions on the practice of live-donor nephrectomy in the year 2000 (the questionnaire was sent in 2001) and 2002 (questionnaire sent in 2003). RESULTS: All 28 centres responded fully for both years; 27 centres used live kidney donation in 2000, decreasing to 24 in 2002. Consultants reported 356 operations in 2000, representing 19% of all kidney transplants, and 403 in 2002, representing 23% of all kidney transplants. Three centres offered laparoscopic donor nephrectomy in 2000, and five did so in 2002. Most centres organize donor and recipient operations synchronously, and most have a consultant anaesthetist present for the donor procedure. There were variations in the use of analgesia and thromboprophylaxis, and in donor follow-up. CONCLUSIONS: There is widespread application of live-donor nephrectomy in the UK but BTS guidelines are not closely followed. Minimal access donor nephrectomy is offered at a few centres but many have plans to introduce this into their practice.

Analgesics↗
PubMed2004

Obtaining explicit consent for the use of archival tissue samples: practical issues.

BACKGROUND: Over the past few years, research ethics committees have increasingly demanded explicit consent before archival tissue samples can be used in research projects. Current UK guidance in this area requires an assessment of whether it is "practical" to obtain explicit consent. Ethics committees have little experience or evidence to help them to judge what is "practical" in this context. METHODS: We attempted to obtain general consent for research use of surplus tissue from renal transplant biopsies from the entire patient population of the renal transplant unit in Leicester. The nature of this patient population would be expected to facilitate this task. RESULTS: A total of 495 letters were sent. Attempts were made to contact non-responders when they attended the outpatient clinic. One year after the initiation of the project, the opinions of 26% of the patients had still not been ascertained. CONCLUSIONS: The results confirm that the vast majority of patients are happy for "surplus" biopsy material to be used for research; the situation does not parallel the use of autopsy tissue. A requirement to obtain explicit consent for the study of archival tissue is likely, however, to block or at least seriously delay research, which is contrary to the public interest and specifically may harm the interests of the patients concerned. In the UK, the problem of tissue being used against the wishes of the donor has now been largely replaced by the problem of prohibition of tissue use against the wishes of the donor.

Biopsy↗
PubMed2004

Prospective randomised trial of the use of Daclizumab in renal transplantation using kidneys from non heart beating donors.

OBJECTIVES: Transplantation using non-heart beating donors (NHBD) is one way of reducing the global kidney shortage. Unfortunately the large warm ischaemic insult sustained by the graft leads to a high rate of delayed graft function (DGF). We have investigated the use of a regimen utilising an II-2r blocker (DZB) in place of Tacrolimus for the initial post-operative immunosupression with the aim of reducing the incidence of DGF. METHODS: Prospective randomised controlled trial based in two NHBD UK centres (Leicester and Newcastle). 51 patients were enrolled over two years and randomised into two treatment arms: 1. DZB/MMF/Steroids (Tacrolimus started when creatinine dropped below 350 micromol/l) 2. Tacro/MMF/Steroids. RESULTS: There was one death, during the study period, in a patient who had had a non-functioning graft removed. The overall incidence of immediate function (IF) was higher than expected (28%), no significant difference was found in the incidence of immediate graft function between the two groups (35% group 1 and 22% group 2). Sub-group analysis however has shown a significant advantage for the delayed introduction of Tacrolimus for machine perfused grafts (IF: 53% vs 13%, chi2 p=0.015). There was no difference in the rate of rejection. CONCLUSIONS: The delayed introduction of Tacrolimus reduces the incidence of DGF in machine-perfused NHBD kidney transplantation.

Antibodies, Monoclonal↗
PubMed2003

The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy.

BACKGROUND: Overexposure to cyclosporine is a risk factor for chronic allograft nephropathy (CAN) and dose reduction has been advocated. The purpose of this study was to determine the impact of adding the non-nephrotoxic immunosuppressant, rapamycin, after cyclosporine dose reduction in renal-allograft recipients with CAN. METHODS: Thirty-one patients with biopsy-confirmed CAN were prospectively randomized to receive a 40% cyclosporine dose reduction with (rapamycin, n=16) or without (control, n=15) the addition of rapamycin 2 mg/day. Renal function and side-effect parameters were assessed. Patients had renal allograft biopsies taken at recruitment and after 6 months. Glomeruli were isolated from these and underwent total mRNA extraction followed by RT-PCR-ELISA to assess transforming growth factor-beta1, collagen III, TIMP-1, TIMP-2, and matrix metalloproteinase-2 expression. Samples were also stained with Sirius red and the percentage interstitial volume fraction quantified by computerized histomorphometric analysis. Data are presented as mean (+/-SD). RESULTS: Patient characteristics and cyclosporine trough levels after dose reduction (rapamycin 68 [+/-21] vs. control 56 [+/-19] ng/mL, P=NS) were similar in both groups. Rapamycin patients had a significant fall in Cr-51 radioisotope glomerular filtration rate (31.6 [+/-8.9] to 27.3 [+/-8.6] mL/min, P<0.01) that was not significant in controls (29.5 [+/-10.4] to 27.0 [+/-8.0] mL/min, P=NS). Transforming growth factor-beta1 expression fell over time in control but remained constant in rapamycin patients. Conversely collagen III expression increased over the 6-month follow-up in rapamycin patients but not in controls. Both had comparable increases in TIMP-1 and matrix metalloproteinase-2 but only rapamycin patients developed a significant increase in TIMP-2. Sirius red-stained interstitial volume fraction fell over the study in controls (15.3-11.2%, P=0.06) but not in rapamycin patients (16.2-16.3%, P=NS). CONCLUSION: Rapamycin (2 mg/day) did not improve functional, molecular, or histological outcome in patients with CAN after cyclosporine dose reduction. Further studies involving larger numbers of patients are necessary to confirm these findings.

Adult↗
PubMed2003

Fibrosis-associated gene expression in renal transplant glomeruli after acute renal allograft rejection.

BACKGROUND: Acute allograft rejection is thought to be a risk factor for chronic allograft nephropathy, the cardinal features of which are vasculopathy, interstitial fibrosis and glomerulosclerosis. Fibrosis-associated genes might act as ad interim surrogate markers for chronic allograft nephropathy. The aim of this study was to determine mRNA expression of fibrosis-associated genes in glomeruli plucked from protocol renal transplant biopsies, in patients with or without a history of acute rejection. METHODS: A consecutive series of 52 patients (31 male, 21 female) was assessed. Donor categories were cadaveric, living related or asystolic. Transplant recipients received either cyclosporin- or tacrolimus-based immunosuppression. Patients routinely underwent percutaneous needle-core renal transplant biopsy at 1 week, and 3 and 6 months. Acute rejection episodes were confirmed histologically and treated with intravenous methylprednisolone, or antithymocyte globulin if steroid resistant. Individual glomeruli were plucked and total mRNA was extracted. Fibrosis-associated genes were amplified by reverse transcriptase-polymerase chain reaction (PCR) and quantified by enzyme-linked immunosorbent assay. RESULTS: The expression of both collagen type III (mean 0.42 versus 0.31 arbitrary units of PCR products corrected for a housekeeping gene) and collagen IV (mean 0.46 versus 0.42 arbitrary units) at 6 months did not differ between recipients who experienced acute rejection episodes and those who were free from rejection. There was also no significant difference between groups in terms of mRNA expression of collagen IValpha2, matrix metalloproteinase 2, tissue inhibitor of matrix metalloproteinases 1 and 2, transforming growth factor beta or tenascin. CONCLUSION: These results suggest that acute rejection episodes do not increase the expression of fibrosis-associated genes in glomeruli from renal transplant biopsies.

Acute Disease↗
PubMed2003

Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis.

BACKGROUND: The aim of this study was to compare the effect of Neoral cyclosporin- and tacrolimus-based therapy on the development of renal allograft fibrosis (chronic allograft nephropathy; CAN) in a prospective randomized trial. METHODS: A total of 102 patients undergoing renal transplantation were randomized to immunosuppression with either microemulsion cyclosporin (Neoral; 15 mg per kg per day adjusted to whole-blood trough concentrations of 200-300 ng/ml) or tacrolimus (0.2 mg per kg per day adjusted to whole-blood trough levels of 8-15 ng/ml) in conjunction with steroids, or at a lower dose (7 mg per kg per day and 0.1 mg per kg per day respectively) with the addition of azathioprine for non-heart-beating renal transplant recipients. Renal transplant interstitial fibrosis was quantified using computerized histomorphometric measurement of picrosirius red-stained 1-year protocol renal transplant biopsies. Levels of interstitial fibrosis were compared in relation to observed efficacy and toxicity profiles of the two drugs. RESULTS: There was a significant increase in allograft interstitial fibrosis in the patients treated with Neoral compared with those given tacrolimus. There was no significant difference in the demographic characteristics between the patient groups or in the incidence of acute rejection (Neoral 36 per cent versus tacrolimus 35 per cent) or steroid-resistant rejection (both 10 per cent) between the two drugs. There was a higher incidence of insulin resistance in the tacrolimus group (post-transplant diabetes mellitus, glucose tolerance testing) but this was not statistically significant. Neoral was associated with a significant increase in total cholesterol (P = 0.030) and low-density lipoprotein (P = 0.021) levels, which persisted throughout the study period. CONCLUSION: Despite equivalent efficacy and pretransplantation risk factors for CAN, Neoral was associated with increased allograft fibrosis and significantly higher serum low-density lipoprotein cholesterol levels compared with tacrolimus.

Adult↗
PubMed2003

Cytokine gene polymorphisms and the inflammatory response to abdominal aortic aneurysm repair.

BACKGROUND: Cytokines are key mediators of the inflammatory response to surgery and polymorphic sites in their genes have been shown to affect cytokine production in vitro. The aim of this study was to determine whether cytokine gene polymorphisms affect cytokine production in vivo in patients undergoing abdominal aortic aneurysm (AAA) repair. METHODS: One hundred patients admitted for elective AAA repair had plasma levels of interleukin (IL) 1beta, IL-6, IL-10 and tumour necrosis factor (TNF) alpha measured at induction of anaesthesia and 24 h after operation. Genotypes for each patient were determined using induced heteroduplex genotyping for the following loci: IL-1beta + 3953, IL-6 - 174, IL-10 - 1082/-592 and TNF-alpha - 308. RESULTS: Patients with an IL-10 - 1082 A allele had a significantly higher IL-10 response to surgery than those without an A allele (P = 0.030) and there was also a significant difference in IL-10 response between patients with IL-10 - 1082 AA genotypes and those with GG genotypes (P = 0.030). CONCLUSION: Elective AAA repair results in a measurable cytokine response. In this study the magnitude of this response was not affected by the individual patient's cytokine gene polymorphisms.

Aged↗
PubMed2003

Rapamycin inhibits vascular remodeling in an experimental model of allograft vasculopathy and attenuates associated changes in fibrosis-associated gene expression.

BACKGROUND: Rapamycin inhibits extracellular matrix (ECM) accumulation (fibrosis) and vascular remodeling in experimental models of chronic allograft dysfunction (CAD) by poorly understood mechanisms. The aim of this study was to assess the effect of rapamycin on the expression of fibrosis-associated genes and correlate this with observed changes in ECM remodeling in an experimental of model allograft vasculopathy. METHODS: Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerized histomorphometry of F344-to-Lewis rat aortic allograft sections harvested at serial timepoints. Expression of fibrosis associated genes was studied by means of semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Rapamycin (0.5 mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intragraft gelatinase, collagen III and tissue inhibitor of metalloproteinase 1 (TIMP 1) mRNA levels. At a lower dosage (0.25 mg/kg/day), rapamycin inhibited intimal hyperplasia and medial ECM accumulation, but there was a lesser effect on vascular remodeling. Lower dose allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intragraft matrix metalloproteinase 9 (MMP 9) mRNA than those treated with the higher dose. CONCLUSIONS: These data suggest that, in addition to the tissue response to injury, the alloimmune injury itself may contribute directly to the vascular remodeling that occurs in allograft vasculopathy. Rapamycin at higher but not lower doses inhibited both of these pathologic processes.

Animals↗
PubMed2003

Kidney transplantation from non heart-beating donors.

The use of non heart-beating donor (NHBD) kidneys to expand transplant programmes offers an answer to the problem of donor shortage. This source of kidneys is utilised by very few renal transplant units despite longstanding and growing evidence of equivalent graft function and survival, compared with cadaveric donor organs. This article reviews the selection criteria, technical approaches and logistical organisation involved in NHBD kidney retrieval and transplantation and outlines the evidence for graft function and survival, and patient outcome. The ethical and legal implications of running a NHBD programme are discussed, and some areas of current and likely future research are covered.

Graft Rejection↗
PubMed2003

The role of cytokine gene polymorphisms in the pathogenesis of abdominal aortic aneurysms: a case-control study.

BACKGROUND: Cytokines are the primary mediators of inflammation and also influence matrix metalloproteinase expression, both of which are important in development of abdominal aortic aneurysm (AAA). A significant, but as yet unknown, familial factor contributes to the pathogenesis of AAA. Many cytokine genes contain polymorphic sites, some of which affect cytokine production in vitro. Cytokine gene polymorphisms may therefore influence the pathogenesis of AAA. The purpose of this study was to determine whether there is any association between cytokine gene polymorphisms and AAA. METHODS AND RESULTS: This case-control study comprised 100 patients with AAA and 100 age-matched and sex-matched control subjects. For each case and control subject in the study, genotypes at the following cytokine gene polymorphic loci were determined: interleukin (IL)-1beta +3953, IL-6 -174, IL-10 -1082, IL-10 -592, and tumor necrosis factors-alpha -308. Allele and genotype frequencies were compared between AAA and control groups, and odds ratios (OR) were calculated for the presence of AAA with each allele at each locus examined as risk factors. The IL-10 -1082 A allele was significantly more common in the AAA group than the control group (P =.03). The OR for the IL-10 -1082 A allele as a risk factor for AAA was 1.8 (95% confidence interval, 0.9-3.6). DISCUSSION: These associations suggest a significant role for IL-10 in the pathogenesis of AAA. This association of AAA with the IL-10 -1082 A allele is also biologically plausible; the IL-10 -1082 A allele is associated with low IL-10 secretion, and it may be that AAA develops in patients who are unable to mount the same anti-inflammatory response as those who do not have AAA.

Aged↗
PubMed2003

The systemic inflammatory response syndrome, organ failure, and mortality after abdominal aortic aneurysm repair.

BACKGROUND: Organ failure is a major cause of morbidity and mortality after abdominal aortic aneurysm (AAA) repair. The aim of this study was to determine the relationships between the systemic inflammatory response syndrome (SIRS), organ failure, and mortality after AAA repair and to determine whether the clinical monitoring of SIRS was a useful adjunct to clinical method. METHODS: One hundred consecutive patients undergoing open AAA repair were prospectively studied. Patients were divided into three groups: those undergoing elective AAA repair, those with symptomatic but nonruptured AAA, and those with ruptured AAA. The presence of SIRS and organ failure was recorded on a daily basis for each patient until discharge or death. RESULTS: Most patients had SIRS develop during the postoperative period: 89% of the elective group, 92% of the emergency nonruptured (urgent) group, and 100% of the ruptured group. Multiorgan failure occurred in 3.8% of the elective group, 38% of the urgent group, and 64% of the ruptured AAA group. After ruptured AAA repair, the concurrent absence of both SIRS and any organ failure for 48 hours had a sensitivity of 93% and a specificity of 91% as a predictive indicator of subsequent survival to hospital discharge. Patients in whom multiorgan failure developed after ruptured AAA repair had a significantly higher mortality rate (69%) than those who did not (0%; P =.001; 95% CI for the difference, 30.2% to 85.8%). CONCLUSION: The differences in the incidence rate of multiorgan failure between the patient groups compared with the high incidence rate of SIRS in all patient groups supports the two-hit hypothesis of multiorgan failure. The presence of multiorgan failure after ruptured AAA repair is associated with poor outcome. The absence of SIRS and organ failure in these patients is a good predictive indicator of survival.

Aged↗