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Biomedical subjects

Michael L Nicholson

Publications and source records attributed to Michael L Nicholson.

At least 19 recordsLinked to original sources
PubMed2007

Static normothermic preservation of renal allografts using a novel nonphosphate buffered preservation solution.

The aim of this study was to assess the viability and function of renal allografts under normothermic conditions using a novel nonphosphate buffered preservation solution AQIXRS-I. Porcine kidneys were flushed at 30 degrees C with AQIXRS-I at 100 mmHg pressure after 5-10 min warm ischaemic time and stored statically at either 4 degrees C or 30 degrees C for 2 h (n = 6 per group). Assessment of renal function by physiological and biochemical parameters was performed by perfusing the organs with autologous blood at 37 degrees C, with an initial circulating serum creatinine concentration of 1000 mumol/l on an isolated organ perfusion system for 6 h. Although the hypothermic group demonstrated overall superior renal function, the normothermic stored kidneys displayed a statistically comparable acid-base balance (7.37 +/- 0.15 vs. 7.3 +/- 0.09, P = 0.24). Furthermore, renal function was still evident after 6 h perfusion with increasing oxygen consumption, renal blood flow and reduced renal vascular resistance. The effectiveness and versatility of AQIXRS-I as a preservation solution under both normothermic and hypothermic conditions has been demonstrated. Renal viability was maintained after 2 h static normothermic storage. This study provides a foundation for further analysis utilizing normothermic preservation.

Adenosine Diphosphate↗
PubMed2006

Apoptosis and caspase-3 in long-term renal ischemia/reperfusion injury in rats and divergent effects of immunosuppressants.

BACKGROUND: Caspase-3 plays a key role in apoptosis, but the involvement of apoptosis and caspase-3 in mediating long-term ischemia/reperfusion (I/R) and immunosuppressive injury are not fully defined. The present study was undertaken to investigate apoptosis and caspase-3 in a renal I/R injury rat model with or without immunosuppression. METHODS: The right renal pedicle was clamped for 45 minutes and left nephrectomy was induced. Cyclosporin A (CsA), tacrolimus (Tac), rapamycin (Rap), or mycophenolate mofetil (MMF) were administered daily. Animals were killed at 16 weeks, and the levels of apoptosis (with in situ end-labeling fragmented DNA), caspase-3 protein (with immunohistochemistry, Western blotting, and activity assay), and messenger RNA (mRNA; with quantitative reverse-transcriptase polymerase chain reaction) were evaluated. RESULTS: Kidneys with I/R injury showed increased apoptosis in tubular and interstitial areas compared with control kidneys. Tacrolimus, Rap, and MMF significantly reduced apoptosis, but CsA did not. Distribution of full-length caspase-3 widened in I/R-injured kidneys from normal distal tubules and collecting ducts to dilated proximal tubules and expanded interstitium, whereas active caspase-3 was mainly scattered in damaged tubules and interstitium. Active caspase-3 staining and 24-kDa active caspase-3 protein was enhanced in I/R-injured and CsA-treated kidneys, but decreased by Tac, Rap, and MMF. These results were also consistent with changes in caspase-3 activity. Although caspase-3 mRNA levels were significantly increased in uninephrectomy and I/R-injured kidneys, they were not significantly affected by the immunosuppressants. In addition, all changes detected were positively correlated with renal structure and function. CONCLUSION: Apoptosis and caspase-3 are not only involved in the long-term renal I/R injury, but also mediate the divergent effects of immunosuppression in this model.

Animals↗
PubMed2006

Biomarkers of oxidative damage to predict ischaemia-reperfusion injury in an isolated organ perfusion model of the transplanted kidney.

Ischaemia-reperfusion (IR) injury is known to be a risk factor influencing both short and long-term graft function following transplantation. The pathophysiology of IR injury is suggested to involve elevated reactive oxygen species production resulting in oxidative damaged cellular macromolecules. The objective of this study was to evaluate oxidative damage following IR using an isolated organ perfusion model of the transplanted kidney, in order to determine a simple, preferably non-invasive biomarker for IR injury. Porcine kidneys were retrieved with 10 or 40 min warm ischaemic (WI) time and haemoperfused for 6 h on an isolated organ perfusion machine. ELISA was used to detect carbonyls, 8-isporostane and 8-hydroxy-2'-deoxyguanosine, representing protein, lipid and DNA damage respectively in pre and post reperfusion samples of plasma, urine and biopsy material. Plasma carbonyl and 8-isporostane and were significantly increased in the 40 min group compared to pre-perfusion (0.96 +/- 0.10 vs. 0.62 +/- 0.06, P < 0.001 and 1.57(1.28-4.9) vs. 0.36(0.09-0.59), P < 0.05). The levels also correlated with creatinine clearance used to determine renal function (r = - 0.6150, P < 0.01 and r = - 0.7727, P < 0.01). The results of this study suggest both plasma carbonyl and 8-isporostane to be reliable biomarkers to predict the level IR injury.

Animals↗
PubMed2006

Comparison of right and left laparoscopic live donor nephrectomy.

OBJECTIVE: To compare the anatomy and function of right and left kidneys retrieved by laparoscopic live donor nephrectomy (LDN). PATIENTS AND METHODS: In all, 84 transperitoneal LDNs were performed, 66 left and 18 right. Two different right-sided LDN techniques were used: initially, the inferior vena cava (IVC) was controlled with a Satinsky clamp introduced through a 6-8 cm right upper quadrant incision, through which the kidney was also removed (six patients). Subsequently, the IVC was completely mobilized by laparoscopic retrocaval dissection (in 12 patients), allowing the use of a linear stapler-cutter, including the caval ostium with the renal vein. The kidney was then removed through a short Pfannenstiel incision. RESULTS: Left kidneys had longer renal veins (38 vs 27 mm; P < 0.05), but there were no differences in arterial length (32 vs 31 mm). Three right kidneys required back-table renal vein lengthening. The operative duration was shorter for right-sided LDNs (132 vs 182 min; P < 0.05). The serum creatinine level at 3 months was 131 vs 134 mmol/L for right and left kidneys, respectively. CONCLUSIONS: Despite faster surgery suggesting that the right LDN is technically easier, there is a greater need for back-table reconstruction of the renal vein. The functional results of right and left kidneys are equivalent.

Humans↗
PubMed2005

The experimental agent pirfenidone reduces pro-fibrotic gene expression in a model of tacrolimus-induced nephrotoxicity.

BACKGROUND: Tacrolimus nephrotoxicity is thought to contribute to renal allograft dysfunction and subsequent failure, a process that is underpinned by alterations in mRNA expression of genes involved in matrix metabolism. The new anti-fibrotic pirfenidone was tested for its potential to reverse markers of renal dysfunction. MATERIALS AND METHODS: Rats were salt-depleted before tacrolimus and pirfenidone treatment. Serum creatinine, urinary protein/creatinine ratio, extracellular matrix deposition (ECM), and mRNA expression of genes involved in matrix turnover were assessed. RESULTS: Tacrolimus reduced TGF-beta mRNA expression below control levels and treatment with pirfenidone at all doses did not alter this effect. Likewise, TIMP-1 mRNA expression was depressed by the addition of tacrolimus and pirfenidone caused a further decrease in expression. Collagen III, MMP-2, and MMP-9 expression was unchanged by tacrolimus, but pirfenidone reduced collagen III below control levels. ECM was slight (1-4%) and not significantly different between groups. CONCLUSIONS: These findings suggest that pirfenidone can attenuate the limited fibrotic potential of tacrolimus.

Animals↗
PubMed2005

Current practices of donor pancreas allocation in the UK: future implications for pancreas and islet transplantation.

Recent refinements in technique mean islet cell transplantation offers the chance of a cure to an increasing patient cohort with diabetes. Such developments put pressure upon the scarce resource of donor organs, with potential competition between the modalities of cellular and solid organ transplantation. This questionnaire based study examines current patterns of donor pancreas procurement and use. Reasons for non procurement are studied together with the attitudes of transplant professionals to pancreas allocation. The minority of potentially useful pancreata are currently made available to either whole pancreas or islet transplant programs. Whilst professionals appreciate the role of each modality, there is a need to define criteria for pancreas allocation to avoid under use of donor organs.

Adolescent↗
PubMed2005

Inflammation and caspase activation in long-term renal ischemia/reperfusion injury and immunosuppression in rats.

BACKGROUND: We have previously shown the long-term influence of renal ischemia/reperfusion (I/R) injury and immunosuppression on fibrotic genes and apoptosis in a rat model. For the first time, we have now investigated the effects of I/R and immunosuppression on inflammation and caspase activation. METHODS: I/R injury was induced in the right kidney and the left was removed. Cyclosporin (CsA) (10 mg/kg), tacrolimus (0.2 mg/kg), rapamycin (1 mg/kg), or mycophenolate mofetil (MMF) (10 mg/kg) was then administered for 16 weeks. The effects of I/R and immunosuppressants on interstitial inflammation, interleukin (IL)-1beta expression, caspase-1 and caspase-3 activation, tubulointerstitial damage, and fibrosis were evaluated. RESULTS: ED-1+ (a specific rat monocyte/macrophage marker) cells were mainly localized in the tubulointerstitium and periglomerular areas and increased in I/R group compared to controls (P < 0.01). This was further increased by CsA, but decreased by tacrolimus, rapamycin, or MMF (P < 0.05). The 17 kD active IL-1beta remained unchanged, but 35 kD IL-1beta precursor was decreased by rapamycin in comparison with I/R group (P < 0.05). The 45 kD or 20 kD caspase-1 was increased by I/R or CsA, respectively, and decreased by rapamycin (P < 0.05). The 24 kD caspase-3, which proved to be an active caspase-3 subunit, was increased in I/R and CsA groups and deceased by tacrolimus, rapamycin, or MMF (P < 0.05), but not 32 kD precursor or 17 kD active caspase-3. The activity data of caspase-1 and caspase-3 exhibited the same trend as Western blotting data. The staining of active caspase-3 was scattered in kidneys, mainly in tubular and interstitial areas, which was consistent with that of ED-1+ cells. There was a strong positive correlation between interstitial inflammation and 24 kD caspase-3 expression or caspase-3 activity (r = 0.814 or 0.484), all of which were also closely related with urinary protein (r = 0.537, 0.529, or 0.517), serum creatinine (r = 0.463, 0.573, or 0.539), tubulointerstitial damage (r = 0.794, 0.618, or 0.712) and fibrosis (r = 0.651, 0.567, or 0.469), all P < 0.01. CONCLUSION: This study shows that the mechanisms of long-term I/R injury and immunosuppressants treatment include interstitial inflammation and caspase activation, most clearly demonstrated by the 24 kD active caspase-3.

Animals↗
PubMed2005

Minimally invasive surgery for live kidney donors: techniques and challenges.

Live kidney donation is assuming an increasingly prominent role in kidney transplantation programs. The traditional operative approach has been through an incision in the upper quadrant of the abdomen or in the loin, with the attendant potential postoperative complications associated with a large surgical wound. These problems may act as disincentives to prospective donors. The introduction of laparoscopic donor surgery in 1995 heralded a new era offering reduced post-operative pain and improved cosmetic result. It is hoped that these benefits may counter some disincentives and thereby increase donation rates. Three minimal-access approaches and their advantages and disadvantages are described: classical laparoscopic, hand-assisted laparoscopic, and retroperitoneoscopic surgery. Published reports indicate extensive experience with the first 2 of these approaches and less experience with the latter. All 3 approaches present technical, physiological, and anatomical challenges in the context of retrieving an organ that is fit for transplantation. For minimal-access surgery to be accepted as the procedure of choice for live kidney donors, it must be demonstrated that morbidity is not transferred from donor to recipient when these techniques are used. Some concerns about these procedures are addressed. High-level evidence in the form of randomized controlled trials is generally lacking, but experiences of surgeons and patients suggest that, with appropriate modifications, these techniques are safe for both donors and allografts and also benefit donors' recovery.

Clinical Competence↗
PubMed2004

A comparison of renal preservation by cold storage and machine perfusion using a porcine autotransplant model.

BACKGROUND: Pulsatile machine perfusion offers theoretical advantages as a method of preserving kidneys before transplantation. This may be particularly the case for organs taken from non-heart-beating donors (NHBD), but there is still a lack of data to support this view. The aim of this study was to compare the effectiveness of static cold storage in ice (CS) and hypothermic pulsatile machine perfusion (MP) as methods of renal transplant preservation. METHODS: Groups of large white pigs (n=5) underwent left nephrectomy after warm ischemic times (WIT) of 0 or 30 min. Kidneys were preserved by CS or by cold (3degrees-8degreesC) MP for 24 hr. The left kidney was then autotransplanted into the right iliac fossa and an immediate right nephrectomy was performed. Renal function was assessed daily for 14 days. RESULTS: Fourteen-day animal survival rates for 0 and 30 min WIT were four of five and one of five after both CS and MP. In the zero WIT groups, there was improved recovery of renal function after MP (area under the creatinine curve, 4,722+/-2,496 [MP] vs. 8,849+/-2,379 [CS]; P<0.05). MP did not improve renal function after 30 min of WIT (mean daily area under the creatinine curve, 1,077+/-145 [MP] vs. 1,049+/-265 [CS]). CONCLUSIONS: In this model, MP improved 24-hr preservation of kidneys not subjected to warm ischemia (heart-beating donor model), but there was no evidence that MP was a better method of preservation than CS for kidneys exposed to 30 min of WIT (NHBD model).

Animals↗
PubMed2004

A report on the activity and clinical outcomes of renal non-heart beating donor transplantation in the United Kingdom.

The use of kidneys from non-heart beating donors (NHBDs) presents a paradox; whilst they provide more organs for transplantation, there is an increased risk of poor graft outcome, particularly in the short term. This study has highlighted the difference in early graft function and late graft survival between NHBD kidneys with short (controlled) and long (uncontrolled) warm ischaemic times. Whilst it would seem that it is preferable to use controlled donors only, their numbers are small. By employing a rational approach to the use of each of these types of kidney, such as structured viability assessment and risk analysis, it may be that the results of uncontrolled NHBD can be improved.

Adolescent↗
PubMed2004

A prospective study of the predictive power of spiral computed tomographic angiography for defining renal vascular anatomy before live-donor nephrectomy.

OBJECTIVE: To determine the accuracy of spiral computed tomography (CT) imaging of donor venous anatomy by comparing CT angiography (CTA) and operative findings, for both laparoscopic (LDN) and open donor nephrectomy. PATIENTS AND METHODS: LDN presents unique surgical challenges, particularly with complex venous or arterial anatomy. The limitations of surgical access, poor visibility of the superior and posterior borders of the renal vein during LDN, and the variability of venous anatomy in this region, contribute to the difficulty of LDN, underlining the importance of imaging beforehand. Forty live donors (mean age 46 years, sd 11; 65% female) were assessed by CTA before donation. Scans were reported by the same radiologist. The number and diameter of 'predicted' renal arteries, veins and renal vein tributaries were documented. The donor kidney was removed by two consultant surgeons, and after back-table perfusion the same details were recorded and taken as the 'reference' findings. Tributaries of <1 mm diameter were not recorded. The right kidney was retrieved in seven patients; 25 of the 40 kidneys were retrieved by LDN and the other 15 by open surgery. RESULTS: In all, 48 actual renal arteries were identified at nephrectomy; of these, 47 were predicted by CTA. Likewise, 41 actual renal veins were found at nephrectomy, 40 of which were predicted. The overall accuracy of spiral CTA in predicting the presence or absence of renal vein tributaries was 83% for gonadal and adrenal veins, and 75% for lumbar veins. There were seven false-negative lumbar veins found at nephrectomy; in these cases the CTA films were retrospectively examined, and five of these seven veins were identified. The predicted renal vein tributary diameter correlated poorly with the measured diameter at nephrectomy. CONCLUSIONS: Assessing potential renal donors before surgery with spiral CTA provides an accurate prediction of the presence or absence of the gonadal and adrenal vein, but is less accurate for predicting lumbar veins. This is especially pertinent as the posterior lumbar tributaries have the most intra-individual variation, and are the most difficult to display and control at LDN. This highlights the need for meticulous dissection of the renal vein, particularly along its posterior wall.

Female↗
PubMed2004

The surgical management of peritoneal dialysis catheters.

Peritoneal dialysis is a safe and effective form of renal-replacement therapy. Its use is increasing as the gap widens between the number of patients waiting for renal transplants and the number of available organs. This article reviews the surgical considerations and complications of peritoneal dialysis that may present to general surgeons.

Catheterization↗
PubMed2003

Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia.

Modern immunosuppressive agents such as tacrolimus and rapamycin are claimed to be associated with a reduction in vascular narrowing, a central feature of chronic rejection. This study assesses the effect of cyclosporine, tacrolimus and rapamycin on the development of intimal thickening, fibrosis-associated genes and deposition of extracellular matrix (ECM) proteins in a model of intimal hyperplasia. Male Sprague-Dawley rats received either no treatment or 5 mg/kg cyclosporine, 0.1 mg/kg tacrolimus or 0.05 mg/kg rapamycin. Animals underwent left common carotid balloon angioplasty, and intima medial ratios, pro-fibrotic gene expression and ECM accumulation were calculated at 14 and 28 days. Cyclosporine was associated with increased intimal thickening compared to controls ( P < 0.004). Tacrolimus had no effect on intimal thickening, whilst rapamycin significantly inhibited intimal thickening at both 14 and 28 days ( P < 0.004 and P < 0.026, respectively). All groups significantly inhibited matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-beta and collagen III expression at 14 days ( P < 0.001), but increased ECM deposition. However, rapamycin marginally reduced ECM deposition compared to cyclosporine ( P < 0.06). Treatment with cyclosporine was associated with worsening of vascular narrowing, whilst rapamycin showed a beneficial reduction in intimal thickening. Treatment with all immunosuppressive agents resulted in increased ECM deposition. Rapamycin may halt the progression of vascular narrowing compared to both cyclosporine and tacrolimus.

Angioplasty, Balloon↗
PubMed2003

Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates.

BACKGROUND: Clinical trials in renal transplantation must use surrogate markers of long-term graft survival if conclusions are to be drawn at acceptable speed and cost. Morphologic changes in transplant biopsies provide the earliest available evidence of damage, and "protocol" biopsies from stable grafts can be used to reduce the number of patients needed in clinical trials. This approach has been inhibited by concerns over safety, but the risk of biopsy of a stable kidney, with no active inflammation or acute functional impairment, has never been formally estimated. METHODS: In accordance with a predefined set of questions, a retrospective audit of a sequential series of protocol biopsies was performed in four major transplant centers. RESULTS: A total of 2,127 biopsy events were assessed for major complications, and 1,486 were assessed for minor ones. There were no deaths. One graft was lost, under circumstances indicating that the loss should have been prevented. Three episodes of hemorrhage required direct intervention. Three further patients required transfusion. There were two episodes of peritonitis, but one was arguably an unrelated event. All serious complications presented within 4 hr of biopsy. CONCLUSIONS: The incidence of clinically significant complications after protocol biopsy of a stable renal transplant is low. Direct benefits to the patients concerned (irrespective of the benefit that may accrue in clinical trials) were not formally assessed but seem likely to outweigh the risk of the procedure. We believe that it is ethically justifiable to ask renal transplant recipients to undergo protocol biopsies in clinical trials and routine care.

Biopsy↗
PubMed2003

Cardiac allograft vasculopathy: current concepts and treatment.

Cardiac allograft vasculopathy (CAV) remains the leading limiting factor of patient and graft survival after the first post-operative year. The pathogenesis involves both immunological and non-immunological factors. Here, we present recent advances and discuss potential preventative and treatment regimens. A review of the current literature of heart transplantation, detailing molecular mechanisms, pharmacological risk factors and novel immunosuppression regimens was performed. Recent findings demonstrate the pivotal role of the endothelium, resulting in release of pro-fibrotic cytokines, recruitment of circulating leucocytes, proliferation of vascular smooth muscle cells, and deposition of extracellular matrix proteins (ECMs). The role of HMG-CoA reductase inhibitors and anti-hypertensives remains controversial, but there is increasing evidence advocating their prophylactic use. We can conclude that novel immunosuppressive agents such as rapamycin, mycophenolate mofetil and FTY-720 are experimental immunosuppressive agents that are undergoing evaluation in clinical trials. The prophylactic use of statins and anti-hypertensive drugs needs to be defined but needs to suggest potential strategies to prolong cardiac allograft survival.

Heart Transplantation↗
PubMed2003

The effect of combined rapamycin/cyclosporine on the changes in pro-fibrotic gene expression that occur during the development of allograft vasculopathy in rats, compared with cyclosporine or rapamycin in isolation.

Chronic allograft dysfunction, the leading cause of solid-organ transplant failure, is characterised by histological evidence of extracellular matrix (ECM) accumulation (fibrosis). The aim of this study was to compare the effect of combined rapamycin and cyclosporine therapy on fibrosis-associated gene expression and ECM turnover during the development of allograft vasculopathy, compared with either agent alone. Lewis recipients of F344 rat thoracic-to-abdominal aorta transplants were administered rapamycin, cyclosporine, combined rapamycin and cyclosporine or no treatment. F344-to-F344 isografts served as controls. Six grafts in each group were harvested at 16 weeks. Vascular remodelling and ECM accumulation (Sirius red) were measured by computerised histomorphometry of aortic sections. Messenger RNA was extracted from frozen tissue, and expression of fibrosis-associated genes was studied by means of semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Rapamycin (0.5 mg/kg per day) or cyclosporine (5 mg/kg per day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodelling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intra-graft gelatinase, collagen III and tissue inhibitor of metalloproteinase (TIMP)-1 mRNA levels. Combined rapamycin and cyclosporine inhibited intimal hyperplasia; however, there was a lesser effect on vascular remodelling and medial ECM accumulation. Combined-treatment aortic allografts were also seen to have a more-severe inflammatory infiltrate and larger amounts of intra-graft matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)-beta and TIMP-1 mRNA than those treated with monotherapy. Rapamycin and cyclosporine act synergistically to inhibit intimal hyperplasia but not the inflammatory infiltrate, allograft fibrosis or vessel remodelling. In the high-responder F344-to-Lewis rat model, effective immunosuppression is required to reduce graft fibrosis.

Animals↗
PubMed2003

Rapamycin has no effect on fibrosis-associated gene expression or extracellular matrix accumulation when administered to animals with established or early allograft vasculopathy.

BACKGROUND: Most patients with functioning heart transplants have established and progressive chronic allograft vasculopathy, a fibroproliferative process for which there is no effective treatment. Coronary artery disease is characterized by histologic evidence of extracellular matrix accumulation (fibrosis). This study compares the effect of rapamycin administered to rats with established allograft vasculopathy on histologic indices of disease progression, extracellular matrix accumulation (fibrosis), and the expression of genes known to regulate extracellular matrix turnover in this model. METHODS: Lewis recipients of Fisher 344 rat thoracic to abdominal aorta transplants were administered rapamycin starting at 8, 12, and 16 weeks posttransplant or no treatment. Six grafts in each group were harvested at 24 weeks. Vascular remodeling and collagen accumulation (Sirius red) were measured by computerized histomorphometry of aortic sections. mRNA was extracted from frozen tissue, and the expression of fibrosis-associated genes was studied by means of semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: Rapamycin had no effect on the progression of early or established allograft vasculopathy with regard to intimal thickening, remodeling, extracellular matrix accumulation, or profibrotic gene expression, regardless of the time commenced. CONCLUSION: The attenuation of the fibroproliferative response in rodents by rapamycin is not seen if the onset of rapamycin therapy is delayed.

Animals↗