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Managing Chronic Rejection

One of the most important challenges that continues to taco transplant surgeons, physicians and patients today is chronic rejection. While the incidence of acute rejection has tallen sharply over the past two decades - largely as a result ot the introduction ot etfective immunosuppressive agents such as cyclosporin A - rates ot chronic rejection have stuhhornly remained the same. Chronic rejection now represents a major cause of gratt tailure in transplant recipients, further increasing the demand heing placed on waiting lists.

Although the causes and mechanisms of chronic rejection are still tar from fully understood, there are perhaps two working hypotheses to explain the aetiology and pathophysiology of this poorly understood phenomenon.

" Immunosuppressive treatment with NeoralŪ

should ultimately have an impact on the

incidence of chronic relection "  


1. Chronic rejection is primarily antigen-dependent, influenced hy early as well as late immunological injury.

2. Alloanfigen-independent events may contrihute suhstantially to the progressive changes.

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Perhaps most interesting is the evidence for the role of alloantigen-independent factors gained from observations of the function of kidney grafts from living unrelated donors as compared to the less optimal results of cadaver grafts. Living unrelated donors tend to he younger and healthier than cadaver donors. lschaemic reperfusion injury may adversely affect late outcome and clinical evidence suggests that this factor combined with early rejection episodes gives a worse outcome than that produced by either injury alone. Much discussion continues around the subject and some controversy. While there is no question that acute rejection is certainly a risk factor for the emergence of chronic rejection, there is debate as to whether it is a direct cause.

In a paper presented by Dr Arthur Matas it was suggested that there appears to be a sub-group of acute rejection patients at particularly high risk of chronic rejection. This includes patients who experience a late acute rejection more than three months post transplant); those who have more than one episode ot acute rejection; and those acute rejection patients whose creatinine levels tail to return to haseline. Hence, any intervention that has a tavourable impact on these three risk tactors, should also reduce the likelihood of chronic rejection. A second major tactor predisposing to chronic rejection may he pharmocokinetic variability. I presented research showing that a major factor in chronic rejection is the degree of variability of the average concentration ot cyclosporin A, as presented in the old tormulation, in the bloodstream known as the coetficient of variation.
The lower a patient's coetficient of variation the lower the chances of chronic rejection (Figure 1). I identitied those patients with a coefficient ot variation of average cyclosporin A concentration less than or egual to 28.4 per cent as those at significantly reduced risk of chronic retection. This suggests that immunosuppressive treatment with Neoral - the oral tormulation of cyclosporin A which provides more consistent and predictive drug exposure than Sandimmun - should ultimately have an impact on the incidence ot chronic rejection.

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