M. L. Nicholson

Human islet cell transplantation--future prospects.

Summary

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 (3°–8°C) 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).

Arteriovenous Fistula Formation using Transposed Basilic Vein : Extensive Single Centre Experience

OBJECTIVESnThe expanding haemodialysis population has lead to increased requirement for more complex vascular access. The aim of this study is to present the results of an extensive series of brachiobasilic arteriovenous fistulae.nnnMETHODSnBBAVF were performed using single-stage vein transposition. A retrospective review of case notes was performed.nnnRESULTSnOne hundred and sixty eight BBAVF were created in 144 patients. This was the first access procedure in only 30 cases and the fourth or fifth in 30. At 24h, 165 fistulas (98%) were patent. One hundred and eleven fistulas (66%) were used for haemodialysis and 57 (34%) were never used, of which 39 (23%) were due to fistula failure. The cumulative secondary patency at 1, 2 and 3 years was 66%, 50% and 41% respectively. There were 201 complications in 119 patients (71%), including thrombosis (29%), arm oedema (17%), infection (13%) and arterial steal syndrome (11%). Ten angioplasties and 48 operative procedures were performed for complications. Pre-operative ipsilateral subclavian catheter had been placed in 62 cases (37%) and was associated with poor patency.nnnCONCLUSIONSnBBAVF represents an important option for vascular access with acceptable patency rates, although complication rates remain significant.

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

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.

Application of nitric oxide and carbon monoxide in a model of renal preservation.

Nitric oxide and carbon monoxide exert vasodilatory effects that minimize ischaemia–reperfusion injury. An isolated porcine kidney model was used to assess the effects of administering the nitric oxide donor sodium nitroprusside (SNP) and carbon monoxide‐releasing molecule (CORM) 3 during a period of warm preservation followed by reperfusion.

A paired study comparing the efficacy of renal preservation by normothermic autologous blood perfusion and hypothermic pulsatile perfusion

THE REDUCTION in metabolic rate effected by hypothermia constitutes the central tenet of traditional organ preservation. The antithesis of this approach is to provide for metabolic demand during normothermic preservation. This latter strategy has two potential benefits. First, if metabolic requirements are met during preservation, then longer preservation with better posttransplant function may be achieved than for an organ suffering prolonged cold ischemia. Second, normothermic perfusion may allow ex vivo organ function to be restored and therefore assessed prior to transplantation. This may provide a basis for viability assessment, thus reducing the risks of primary nonfunction of allografts. POPS (pulsatile organ perfusion system) (Transmedics, Boston, Mass, USA) is a new warm perfusion system for organs, using blood as the principle component of the perfusate. The aim of this study was to compare the efficacy of preservation of porcine kidneys by normothermic autologous blood perfusion and hypothermic machine perfusion (RM3 system, Waters, Mass, USA.)

Vascularized pancreas allotransplantation--clinical indications and outcome.

Aims This review examines the status of vascularized pancreas transplantation as a treatment for Type 1 diabetes mellitus (DM).

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

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.

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

Abstract 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.

A neural network approach to the diagnosis of early acute allograft rejection.

THE DEVELOPMENT of the Banff classification of renal allograft pathology is intended to improve the reproducibility and the accuracy of the diagnosis of acute renal allograft rejection. These are two separate concepts. A recent trial involving most of the renal transplant pathologists in the United Kingdom found that using the Banff classification improved reproducibility, but accuracy of diagnosis was unchanged from a conventional approach. We argued that this could arise because the Banff classification concentrates on the tight definition of a small number of features (tubulitis, intimal arteritis) but ignores “softer” evidence of transplant rejection such as edema, lymphocyte size, eosinophilic infiltration, and so forth. We have previously reported using a Bayesian Belief inference network to integrate the histopathologic data. When tested using 21 selected difficult transplant biopsies, all of which had clear retrospective clinical diagnoses of acute rejection or not, a trainee pathologist obtained 19 of 21 correct diagnoses. When the same “test” cases were seen by 31 consultant renal transplant pathologists, the best individual performance was 18 of 21. However, the Bayesian network has limitations in its flexibility, which led us to develop a single layer neural network, using the MATLAB neural network toolbox. This network was initially trained with observations from 100 randomly selected renal transplant biopsies, all with clear retrospective diagnoses, using gradings of 12 morphologic features: tubulitis, intimal arteritis, interstitial lymphocytic infiltrates, interstitial edema, interstitial haemorrhage, acute glomeralitis maximal numbers of large “activated” lymphocytes, plasma cells, and eosinophils, venulitis, arterial endothelial activation, and venous activation. When tested using the 21 selected “difficult” biopsies used in the earlier study, the initial performance of the network was disappointing; all but three were graded as negative for rejection. We therefore added a further 25 cases to the training set; these were all selected to have caused diagnostic difficulty at the time of biopsy, but the subsequent clinical course provided a clear diagnosis of rejection or no rejection. After training with this set the network performance improved dramatically, with 19 of 21 correct diagnoses. Conventional logistic regression produced inferior results; only 8 of 21 correct diagnoses, even when including all 125 “training” cases. It appeared that unlike the neural network, logistic regression was “misled” by the inclusion of “obvious” cases in the 100 training set. These results show that logical, reproducible integration of multiple morphologic variables can be achieved by a computer-based neural network approach in a way that can out perform the informal data integration capabilities of the pathologist and that is better than conventional logistic regression. It is likely that the power of this approach can be improved by the inclusion of other types of information, such as clinical and biochemical features. The network currently devised is not in a “user-friendly” format, but there is no technical reason why a program using this approach could not be produced in a way that continues to “learn,” if retrospective validated diagnoses are included. If applied in different centres, such training would automatically make the network adapt to local clinical and pathologic practice, making interobserver variation much less important than at present.