Non-directed live kidney donation.
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ABO Blood-Group System↗
Biomedical subjects
Nicholas R Brook
Publications and source records attributed to Nicholas R Brook.
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Non-heart beating donor kidneys with delayed graft function have superior graft survival compared with conventional heart-beating donor kidneys that develop delayed graft function.
Delayed graft function may have an association with reduced graft survival, and nonheart-beating donor (NHBD) kidneys have higher rates of delayed graft function (DGF) than heart-beating donor (HBD) kidneys. This study compared outcome of renal transplants from HBDs who developed DGF, with NHBDs who developed DGF. All recipients of HBD and NHBD kidneys who developed DGF were identified during a 10-year period. All patients with graft primary nonfunction were excluded from analysis. Four hundred and fifty-six functioning transplants were performed. Delayed graft function occurred in 69 (17%) HBD and 55 (93%) NHBD kidneys. The grafts developing DGF were well matched for donor and recipient age. The rate of acute rejection was similar; [n = 16/69 (23%) HBD vs. n = 13/55 (24%) NHBD]. Cold ischaemia was 21 h in the HBD group and 17 h in NHBD group (p > 0.05). Serum creatinine was similar for both groups at 1.3 and 6 years (p > 0.05 for all time points). Graft survival in the NHBD recipients with DGF was significantly better at 3 years (84%) compared with recipients of a HBD renal transplant that developed DGF (73%) (p < 0.05), and at 6 years (62% survival for HBDs and 84% survival for NHBDs). This study shows that graft survival was better for NHBD kidneys up to 6 years after transplantation.
Adult↗
Nonheart-beating kidney donation: current practice and future developments.
BACKGROUND: Nonheart-beating kidney donation (NHBD) is gaining acceptance as a method of donor pool expansion. However, a number of practitioners have concerns over rates of delayed graft function, acute rejection, and long-term graft survival. The ethical issues associated with NHBD are complex and may be a further disincentive. Tailored strategies for preservation, viability prediction, and immunosuppression for kidneys from this source have the potential to maximize the number of available organs. This review article presents the current practice of NHBD kidney transplantation, examines the results and draws comparisons with cadaveric kidneys, and explores some areas of potential development. METHODS: A review of the current literature on NHBD kidney donation was performed. RESULTS: The renewed interest in NHBD kidneys is driven by a continuing shortfall in available organs. Those centers involved in NHBD report an increase in kidney transplants of the order of 16% to 40% and there is no evidence that the financial costs are higher with NHBDs. The majority of experience comes from Maastricht category 2 NHBDs, where an estimation of warm time is possible. This is generally limited to 40 minutes. There are variations in the technique for kidney preservation prior to retrieval, but most centers use an aortic balloon catheter. Much work has looked at the ideal technique for kidney preservation prior to implantation. Evidence suggests that machine perfusion produces the best initial function rates, decreased use of adjuvant immunotherapy and fewer haemodialysis sessions than static cold storage. CONCLUSION: Despite being associated with poorer initial graft function, the long-term allograft survival of NHBD kidneys does not differ from the results of transplantation from cadaveric kidneys. Further, serum creatinine levels are generally equivalent. Constant reassessment of the ethical issues is required for donation to be increased while respecting public concerns. Use of viability assessment and tailoring of immune suppression for NHBD kidneys may allow a further increase in donation from this source.
Heart Arrest↗
Intra-renal resistance reflects warm ischaemic damage, and is further increased by static cold storage: a model of non-heart-beating donor kidneys.
BACKGROUND: Non-heart beating donor kidneys increase transplant activity, but their use is associated with a higher rate of both primary non-function and delayed graft function than cadaveric kidneys, due to a period of cold ischaemic damage superimposed on a period of warm ischaemia. We aimed to measure intra-renal resistance in machine perfused porcine kidneys subjected to different periods of warm ischaemic injury, with additional, varying, cold ischaemic times, in an attempt to mimic the injury suffered by NHBD kidneys and test the predictive power of viability testing. MATERIAL/METHODS: Landrace pigs were killed by lethal injection, and the kidneys were subjected to varying WITs of 10-90 minutes prior to explantation. Kidneys were subsequently stored for varying cold times of 2 to 48 hours. IRR (pressure/flow) was calculated during 6 hours cold pulsatile machine perfusion. RESULTS: For all WITs, IRR was higher at the start than at the end of machine perfusion (P<0.001). There was a strong correlation between IRR on MP, and WIT, but no correlation after 6 hours MP. Intra-renal resistance increased as kidneys were exposed to longer CITs; this effect was most marked for the longer WITs (P<0.004), However, the slope gradient was similar for the different WITs. CONCLUSIONS: Early IRR accurately reflects kidney in-situ WIT, and machine perfusion reduces IRR whilst cold ischaemia imposed on periods of warm ischaemia increases IRR and attenuates the beneficial effect of MP. Machine perfusion may partially ameliorate the effects of WIT in terms of IRR, and may prove useful in pre-transplant viability assessment of NHBD kidneys.
Animals↗