Our Current Research
We wish to detect renal transplant recipients in our programme who are tolerant to their transplant. This means that they have another immune response that neutralizes their ability to reject their transplant. This study has been made possible by the detection of genes that are associated with tolerance or non-responsiveness. (14) Our recipients will also have assays of their rejecting cells, tolerizing cells and antibodies mediating rejection (functional assays). By combining the results of the gene analyses with the functional assays we will be able to define which recipients are tolerant to their transplant and therefore can safely have their immunosuppressive drugs reduced. A second study following from these findings will be to cease immunosuppressive drugs in tolerant recipients if reduction in immunosuppression is safe (the first study). All these recipients will be fully informed of the risks, benefits and alternatives of these studies and those participating will be carefully monitored. Immunosuppressive drugs will be reintroduced if this proves to be necessary. This work is being done in collaboration with Professor Sarwal at Stanford University USA.
- Immunosuppressive drugs carry significant risks of cancer, infection, bone disease and nephrotoxicity. Reduction in their doses will decrease these adverse events: cessation of these drugs will eliminate these adverse events but there may be residual morbidity from their previous use.
- Achieving these objectives is the “holy grail” of transplantation. For the first time we have this opportunity because a group of genes associated with tolerance can be detected. We should take this opportunity.
2. Antibody Mediated Rejection
Chronic rejection is the commonest cause of transplant failure although death with a functioning graft is the commonest cause of transplant loss (15) in Australia. Antibodies from the recipient directed against the transplant play the major role in rejecting the transplant. With our pathology colleagues we are evaluating a technique to improve the accuracy of diagnosing antibody mediated rejection in the kidney by detecting a complement derivative bound to the antibody when it lodges in the kidney. We have found that its deposition in the glomerulus (or filter) carries a poor prognosis for the transplant and heralds the need to treat the rejection vigorously.
We think that this technique carries the promise of detecting antibody mediated rejection (both acute and chronic forms) in its early stage enabling the use of early treatment.
- Reversal of acute antibody rejection is possible if detected early. This work will help achieve this.
- It also carries the promise of early detection of chronic rejection and will facilitate the development of effective treatments which have not been achieved to date.
3. Information Technology – Transnet
We have constructed a point of clinical care software programme, Transnet, for transplantation, dialysis, vascular access and renal medicine. It is web based and liked to pathology and radiology databases. We are now constructing a business intelligence “back end” to analyse data in Transnet with respect to standard outcome measures of performance (key performance indicators) and our own clinical research questions. We are working with the IT division within HNELHD and Ascribe Computer Software Limited.
- These analyses will strengthen our clinical performance and provide answers to clinical questions that we and others ask. Scientific papers will flow from these activities and the training of surgeons and physicians in transplantation will be enhanced.
4. Studies about Ischaemia Reperfusion Injury in Transplantation
Each transplant is injured in the donor, when transiting between donor and recipient and then during implantation and reperfusion. So called Ischaemia Reperfusion Injury (IRI) remains an unsolved problem leading to delayed transplant function, acute rejection and occasionally transplant loss. No satisfactory treatment exists for IRI.
From our previous published research (5, 6, 7) we are measuring the extent of injury using the integrin molecule αvβ6 and studying the effect of Castanospermine upon IRI. The reasons for proposing that Castanospermine may be beneficial are that it is a powerful anti-inflammatory molecule and may stop the entry of damaging cells into the organ after IRI. Hence delayed graft function may be curtailed and fibrosis stalled.
- If these results are favourable in animal models these strategies will be applied to clinical renal transplantation. Castanospermine could be infused with cold preservation solutions at the time of organ procurement after measuring the extent of damage; a randomized controlled trial would be constructed to examine its impact scientifically in this context.
5. Thompson JF, McCosker CJ, Hibberd AD, Chapman JF, MacDonald GJ, O’Connell DL, Mohacsi PJ, Spratt PM, Mahoney J. Identification of the cadaveric potential organ donors in New South Wales. Anaesthesia and Intensive Care. 1995; 23: 75-80.
6. Trevillian PR, Paul H, Millar E, Hibberd AD, Agrez MV αv β6 integrin expression in diseased and transplanted kidneys. Kidney international 2004; 66:1423-33.
7. Grochowicz PM, Hibberd AD, Bowen KM, Clark DA, Cowden WB, Willenborg DO. Castanospermine an oligosaccharide processing inhibitor reduces membrane expression of adhesion molecules and prolongs heart allograft survival in rats. Transplant Immunology 1996; 4: 275-285.
14. Vilayur E, Trevillian P, Nanra R, Gillies A, Heer M, Hibberd AD. A systematic study of linear C4D deposition in glomerular capillary loops in renal transplant biopsies. The Transplantation Society August 2008 Transplantation 2008 (abstract).
15. Hibberd AD, Trevillian PR, Roger S D, Wlodarczyk JH, Stein AM, Bohringer EG, Milson Hawke SM Assessment of the bioequivalence of a generic derivative of cyclosporin A by a randomized controlled trial in stable renal transplant recipients. Transplantation 2006; 81 (5); 711- 7.