Patients with end-stage renal failure may be overjoyed to receive a donor kidney - but it is only the start of the battle to prevent rejection and keep the patient well. Jenny Bryan looks at drug treatments that can help

The number of people requiring treatment for end-stage renal failure is growing. Renal replacement therapy accounts for nearly 2 per cent of the NHS budget - or£25,000 per patient a year.

At any time, about a quarter of the 25,000 people in Britain undergoing RRT are on the list as suitable for a kidney transplant. During 1998, more than 1,500 transplants were carried out in the UK.

The average cost of a kidney transplant is£10,000-£15,000, plus£3,000 a year for follow-up treatment and immunosuppression. This compares with£23,000 a year for hospital-based dialysis and£20,000 a year for continuous ambulatory dialysis at home.

Live donor transplants make up 5-10 per cent of total kidney transplants in the UK compared with 30 per cent in the US and 45 per cent in Norway.

British surgeons have been reluctant to use live donors in the past because of the risks of major surgery to the donor rather than the recipient. But reassuring results from abroad, coupled with waiting list pressures, are behind a recent increase in live donor operations.

Though a transplant can give recipients back a normal, active life, the drugs needed to prevent rejection of the new organ can make them ill, reduce their immunity to infection and, in the long term, destroy the kidney.

In an effort to prolong the life of transplanted kidneys and their recipients, a number of new drugs have been introduced to replace or combine with conventional anti-rejection treatments.

Drugs for immunosuppression Immunosuppressive drugs are used to suppress the rejection of kidney transplants by preventing T and Blymphocytes from mounting their normal immune reactions to foreign tissue (see box, top right). The disadvantage is that if people taking immunosuppressive agents catch certain infections, such as chickenpox, they can become very ill; they are also prone to certain types of cancer.

Patients usually take a mixture of anti-rejection agents after their operation, with the dose increased or decreased according to the individual's response. The most commonly used cocktail consists of azathioprine, a corticosteroid and cyclosporin.

Azathioprine inhibits DNA synthesis and therefore limits lymphocyte proliferation and graft rejection. The snag is that as it has a blanket effect on blood cells it also inhibits protective immune responses and can cause other blood disorders.

Corticosteroids reduce formation of antibodies and production of immune cells such as macrophages and monocytes. They reduce the risk of rejection but, in high doses, disturb normal adrenal gland function, with extensive adverse effects including bone destruction, weight gain, lipid abnormalities and arterial damage.

Steroids may be used in the postoperative period to prevent rejection but every effort is made to reduce the dose.

Cyclosporin has revolutionised transplant surgery since its introduction in the early 1980s. It selectively inhibits T-cell activation and expression of immune mediators, notably interleukin 2 (IL-2). Although it has been extremely effective in reducing transplant rejection, longterm treatment can damage the kidneys and raise blood pressure.

The new anti-rejection drugs New immunosuppressant agents, introduced in the past five years, are unlikely to replace traditional agents such as cyclosporin and have their own side-effects. But they give transplant physicians a greater choice of treatment and the opportunity to juggle drug doses if problems arise.

Tacrolimus (previously called FK506) is marketed by Fujisawa as Prograf. Originally isolated from a soil sample taken at the foot of Mount Tsukuba in Japan, tacrolimus inhibits T-cell activation, differentiation and proliferation. Several studies suggest that tacrolimus-based anti-rejection cocktails are more effective at reducing acute rejection than those containing cyclosporin, though side-effect warnings are similar. In a 12-month multicentre European clinical trial, there was a 26 per cent acute rejection rate with tacrolimus compared with a 46 per cent rate with cyclosporin.

3Graft and patient survival rates were not significantly different.

A recent meta analysis of results of four comparative trials involving 1,037 patients confirmed a significant reduction in acute rejection with tacrolimus after a minimum of 12 months post-transplant.

4Risk of acute rejection was halved and need for rescue treatment with antilymphocyte antibodies reduced by over 60 per cent with tacrolimus compared to cyclosporin.

However, there was a five-fold increase in prevalence of diabetes - a complication of tacrolimus which usually occurs soon after transplantation and may necessitate dosage reduction of steroid and tacrolimus.

Although comparative data on the effects of the two drugs on chronic rejection is still awaited, laboratory evidence suggests that, unlike cyclosporin, tacrolimus does not boost levels of transforming growth factor-b (TGF-b) - a substance which has been implicated in cell proliferation and fibrosis seen in chronic rejection.

Mycophenolatemofetil (MMF), marketed by Roche as CellCept, reduces the risk of acute rejection by inhibiting T and B lymphocyte proliferation, preventing antibody formation. Clinical trials have demonstrated that, used in combination with cyclosporin and corticosteroids, mycophenolate reduces acute rejection, compared with azathioprine. It is relatively well tolerated, though it does cause gastrointestinal upset, but it is not associated with the kidney and lipid problems linked with some antirejection agents.

MMF is therefore being positioned by Roche for use: post-operatively in combination with cyclosporin and steroids (as an alternative to azathioprine);

subsequently, as an alternative to cyclosporin or tacrolimus in patients at high risk of developing renal damage or who have had rejection episodes, or as a way of reducing the need for steroids in patients prone to steroid side-effects.

Like tacrolimus, MMF has theoretical benefits for preventing chronic rejection since it appears to reduce smooth muscle proliferation in the kidney.

Monoclonal antibody therapy is being used increasingly in the first few days after transplantation to prevent acute rejection. Already licensed is basilimaxab (Simulect) from Novartis, while Roche's daclizumab (Zenapax) is scheduled for European launch this summer. These monoclonal antibodies target the CD25 antigen on T-cells, thus preventing IL-2 from binding to them and triggering proliferation. They are not intended to replace current combination regimens; instead, they are likely to be useful in preventing rejection in high-risk grafts.

Polyclonal antibody therapy with OKT3 is sometimes used to treat bouts of acute rejection, as is antithymocyte globulin (ATG).

In the US, antibody therapy is often used before transplantation to reduce lymphoycte levels and hence the risk of acute rejection. But evidence of survival benefit is lacking.

Cost-effectiveness Mycophenolate versus azathioprine.

The daily cost of MMF is greater than that of azathioprine, but analyses suggest the extra cost is offset by the reduction in morbidity conferred by more effective treatment. In a large US study, the acute rejection rate with MMF in the first post-transplant year was 27.9 per cent, compared with 47 per cent with azathioprine.

Results of a cost-effectiveness analysis are summarised in the table (above), but overall, the MMF-treated patients had slightly lower first-year costs than those treated with a regimen containing azathioprine ($27,807 as against $29,158).

Tacrolimus versus cyclosporin. A number of unpublished analyses have been carried out suggesting a cost advantage in favour of tacrolimus in kidney transplantation, owing to reduced hospitalisation and dialysis costs associated with the lower acute rejection rates. The only easily traceable published comparison refers to the use of tacrolimus and cyclosporin as immunosuppressive therapy in liver transplantation in German centres.

This demonstrated a cost-effectiveness ratio for tacrolimus that is about 15.5 per cent better than for cyclosporin.

The operation

The key to success is careful matching of the donor and recipient tissue types. This involves ensuring first that their blood groups and human leucocyte antigens - protein fingerprints - on the surface of human cells are as closely matched as possible.

Finally, cross-matching tests mix blood cells from the two in the laboratory to ensure they do not react badly. The suitable organ should be transplanted as soon as possible, up to a maximum of 30 hours after removal, to minimise its time without a blood supply. The operation takes two to four hours. The old, failed kidney is usually left in place and the new one inserted through an incision in the front of the abdomen and attached to the recipient's blood supply and ureter.

Patients are up and about within a day or two and can usually go home within five to seven days. In live donor operations the donor kidney is removed through the donor's back, sometimes requiring removal of the bottom rib. Donors can usually go home within four to five days.

What can go wrong?

Forty years after the first successful kidney transplant operations, the main challenge remains preventing the donated organ from being rejected.

According to data from the Renal Transplant Audit for 1984-93, 84 per cent of kidney transplants are still functioning after a year, 70 per cent at five years and 58 per cent at 10 years. The rejection process begins when T lymphocytes in the blood recognise foreign proteins (antigens) on the surface of the cells of the new kidney.

Helper T cells (also called CD4 cells), alert killer T (CD8) cells to attack. They also stimulate B lymphocytes to produce antibodies to destroy the foreign tissue. There are three types of reject ion:

Hyperacute rejection occurs if there are big differences between blood or other cell types between donor and recipient.

Antibodies already present in the blood will mount an immediate, destructive immune attack, within minutes of surgery. This was a serious problem with early transplants when donor and recipient tissues were not well matched, but it is rarely an issue today. However, hyperacute rejection is a key obstacle to be overcome when using organs from other species (xenotransplants).

Acute rejection usually arises in the first six months after transplantation and results in loss of function of the new organ. It occurs in up to half of the people who have a kidney transplant and, although it can be treated so that most patients do not lose their graft, it increases the risk of chronic rejection and, ultimately, kidney failure.

Chronic rejection is the long-term rejection of the donated kidney months or years after surgery. Function deteriorates until the patient has to go back on dialysis and await a further transplant.

REFERENCES

1 UK Renal Registry, 1998.

2 Nicholson ML, Bradley JA. Renal transplantation from living donors. Br Med J 1999; 318 (7181): 409-410.

3 Mayer A, Dmitrewski J, Squifflet J et al .

Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection. Transplantation 1997; 64 (3): 436-443.

4Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. Br Med J 1999; 318: 1104-1107.

5Sullivan S, Garrison L, Best J et al . The cost-effectiveness of mycophenolate mofetil in the first year after primary cadaveric transplant. J Am Soc Nephrol 1997; 8: 1592-1598.

6 Bachinger A, Kirchoff D, Rychlik R. Immunosuppression with tacrolimus (FK 506) and cyclosporin A for preventing graft rejection after liver transplantation.

Retrospective evaluation of medical costs based on FG-0157 study in 224 patients (Germany). Chirurg 1998; 69(9): 957-962.

Jenny Byran is a clinical journalist