: 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.
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.
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.
Tacrolimus reduced TGF-β 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.
These findings suggest that pirfenidone can attenuate the limited fibrotic potential of tacrolimus.
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.
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)‐l, transforming growth factor (TGF)‐β 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.
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.
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.
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.
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.
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 postoperative 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.
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