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Although the first immonosuppressant, the corticosteroid cortisone, was introduced in 1951, it was hindered by a lack of efficacy and side effects. Consequently it was not until 1959 when azathioprine became available that transplantation really became a realistic option. Azathioprine was more effective and better tolerated, and it is still in use today.
Azathioprine works by inhibiting cell division. However, it has relatively wide- ranging effects and this can mean that transplant patients immunosuppressed with this drug may be at risk of skin malignancies. In addition, when given at the same time as certain other drugs, including the gout treatment allopurinol, azathioprine can produce dangerous side effects, affecting the white blood cells and bone marrow. Consequently if you are taking this drug you must make sure you tell your doctor who will probably reduce the amount of azathioprine you are taking.
Other side effects associated with azathioprine include: nausea, which can be reduced if tablets are taken after food; unexpected bruising; and temporary hair loss.
By the time azathioprine was introduced, other corticosteroids had long been identified as immunosuppressive agents and were found to be better than cortisone. This meant that the gold standard in the evolving field of transplantation became the combination of azathioprine and prednisolone. Initially, the very large doses of prednisolone that were then thought necessary caused major steroid side effects including Cushings disorder, loss of bone density, salt and water retention and obesity. However, subsequent work showed that lower doses of steroids could be used as effectively and were much better tolerated by patients.
Until the late Seventies, the combined use of azathioprine and prednisolone was the mainstay of immunosuppression. In one year graft survival rates the percentage of patients who did not experience rejection within a year of the transplant reached around 60 per cent.
The real breakthrough came with the discovery of cyclosporin A in 1976. Cyclosporin A prevents the division of the cells that are uniquely involved in rejection, namely the white cells of lymphocytes called T cells. Early multicentre trials showed that it was capable of reducing acute allograft rejection, resulting in one year graft survival rates that were between 16 and 20 per cent higher than in groups immunosupppressed with azathioprine and steroids alone.
Cyclosporin quickly became accepted as the new standard in renal transplant immunosuppression. Similar results were reported for its use in heart, liver and pancreas transplantation. Nevertheless Cyclosporin A has some limitation. The main problem is that it is associated with kidney toxicity. Other possible side effects include nausea, diarrhoea, headache, tiredness, hand tremor, swollen gums, raised blood pressure and increased growth of facial and body hair.
More recently in 1994, cyclosporin was released in a new formula, Neoral Cyclosporin, which in trials has been shown to give better immunosuppression than the older formulation called Sandimmune. Most renal patients in the UK have been transferred to this new agent.
Although the introduction of cyclosporin in the UK in the early 1980s increased one year graft survival rates from 64 to 78 per cent, long-term kidney graft survival rates did not change dramatically.
This continued loss of transplanted kidneys many years after the initial transplant, along with the unpleasant and in some cases dangerous side effects of cyclosporin, prompted the development of other immunosuppressant drugs.
(CellCept) Mycophenolate mofetil was introduced in the UK in early 1996 and is one of a new generation of immunosuppressant drugs. CellCept prevents cell division of T and B lymphocytes in a similar way to azathioprine but is much more selective. As a consequence, it has a much better side effect profile, with less anaemia and netropenia. It can also be used with allopurinol. Whilst some patients can experience diarrhoea with CellCept, this can be ameliorated by taking the tablets with food or taking it three or four times a day as opposed to twice a day.
Three large studies of CellCept in renal transplantation have been published. Broadly speaking, they showed that this drug reduces the incidence of rejection by around 50 per cent; and reduces the need for more powerful second-line immunosuppressant agents such as ATG/OKT3 to treat steroid-resistant rejection.
In addition, the drug is licensed for use in heart transplantation, where a large three-year study has shown survival benefits in patients treated with CellCept. Maybe the potential advantage of the drug is that it may allow the reduction of other immunosuppressive medication and thus further reduce side-effects and improve long term survival.
Tacrolimus (Prograf) is another of the newer immunosuppressive agents that has a licence for clinical use in this country. It has a similar mechanism of action to cyclosporin, but is up to 100 times more powerful. Trials suggested that compared to the old formulation of cyclosporin, Prograf leads to a significant reduction in episodes of acute rejection and use of antilymphocyte therapy to treat acute rejection. However, more patients appear to develop diabetes post transplant. This represents a major risk that must be balanced with the potential benefits.
In 1995 reports suggested a significant improvement in long term renal graft survival for recipients of Prograf-based immunosuppression. However, more recent studies have failed to confirm this. Long term trials versus Neoral Cyclosporin are still underway.
Many other compounds are already in clinical trials, some of which have already been tested in quite large numbers of patients, and which may in the future offer advantages over existing therapies, both in terms of their effectiveness and their tolerability. Results of these clinical trials are awaited with interest.
The immunosuppressive medications and their doses will be carefully worked out for you. Take your medicine only as prescribed by your doctor and do not change anything without checking with them first.
Even though these medications may cause side-effects, remember that these medications are required to treat your condition. In studies, up to 20 per cent of late kidney graft failure resulted from patients failing to take their immunosuppressants.
Although it's important to find out what the potential side effects of your medications are, be aware that side effects of medication are different for every person. Moreover, many go away as your body adjusts to the medicine. But if side effects do occur they may need medical attention - so check with your doctor if any continue or are bothersome to you.
If in Any Doubt Seek Advice from your Doctor!
This Article copied with permission from the
National Kidney
Federation's Kidney Life; Issue Winter 1999. Many
Thanks.