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Drug May Reduce Cancer Legacy of Kidney Transplants

Posted on: Friday, 15 April 2005, 03:00 CDT

After 30 years of immunosuppression the risk of acquiring a cancer is 80%. Wendy Laursen reports on a promising new drug for recipients of kidney transplants.

The kidneys remove wastes from the blood and maintain the fluid balance of the body. Blood is passed through small filtering tubes called nephrons, and then returned to the circulatory system by the renal artery. Wastes and excess water are passed to the bladder via the ureter.

Kidney disease is one of the leading causes of death in many countries. In Australia, kidney disease causes or contributes to an estimated 9.5% of all deaths. High blood pressure, bladder reflux, cysts and poorly controlled diabetes are among the causes of kidney disease. Smoking has also been associated with reduced kidney function.

Kidney function can be reduced by 90% before a person feels sick, and people with advanced kidney disease may die from associated complications, such as cardiovascular disease, before the problem is recognised.

Dialysis or a transplant is required when damage to the nephrons is severe enough to prevent the organs from functioning. Approximately 14,200 Australians receive dialysis and 10% of these are waiting for a kidney transplant. The average waiting time is 4 years with approximately one person per week dying before a kidney becomes available.

For a new kidney to be accepted by the body, transplant recipients are prescribed immunosuppressive drugs and must stay on them for the rest of their life. Immunosuppressive drugs alter the production of T-cells that fight infection or foreign substances in the body. They reduce the likelihood of the organ being rejected but also increase the risk of cancer, most commonly skin cancer in Australia. After 30 years of immunosuppression the risk of acquiring a cancer is 80%.

Australian researchers are making a major contribution to transplant medicine and working to improve the management of kidney disease around the world. Dr Timothy Mathew, Medical Director of Kidney Health Australia, is helping to reduce the cancer risk for kidney recipients. "It is a really big issue," he said. "The number of people dying after a kidney transplant from cancer is soon going to exceed the number dying from cardiovascular causes. We are getting better and better at reducing the cardiovascular risk but we are not getting better at reducing the cancer risk."

Cyclosporine is the most common drug prescribed in Australia for immunosuppression after a kidney transplant. It is a compound derived from a Norwegian fungus that inhibits the signalling process that activates T-cells.

"Cyclosporine was a revolutionary drug in the mid-1980s and was responsible for helping the graft survival rate improve substantially at that time. It remains the most popular main agent for immunosuppression in Australia and elsewhere, but against all that positive information has come the realisation that when it is used in the very long term it has a harmful effect by slowly, but progressively, scarring the kidney."

Mathew was part of a team of researchers that set out to determine if a new immunosuppressive drug, sirolimus, was a suitable replacement for Cyclosporine. Sirolimus is an antibiotic derived from a species of bacteria found on Easter Island. It inhibits the proliferation of T-cells via a different biochemical mechanism to cyclosporine. Sirolimus has the potential to dramatically reduce the cancer rate of transplant recipients, and an earlier 4-year trial had shown that it did not cause kidney scarring.

In trials conducted throughout Australia, Canada, the USA and Europe, the researchers compared sirolimus or a placebo in combination with cyclosporine, sirolimus without cyclosporine, and switching to sirolimus 3 months after a transplant. A total of 1981 patients participated in the trials.

After 2 years, patients receiving both sirolimus and cyclosporine had a slightly lower cancer rate than those just on cyclosporine. None of the 81 patients receiving sirolimus without cyclosporine developed cancer, and those who switched to sirolimus after 3 months had a significantly lower rate of cancer than those who didn't.

Mathew is optimistic about the results but he believes it is too soon to be advising people to be switching to sirolimus. "That is what I would call soft observation. It is controlled data and it is good data, but the numbers are still small and the length of time is short," he said.

The results are unlikely to be incorporated into clinical guidelines for doctors until a larger-scale study is conducted. Sirolimus has side-effects such as increasing blood cholesterol levels and decreasing platelet counts, and further studies are required to assess its long-term effects. "The guideline process is really the gold standard, addressing the really good evidence that we can be confident about. It is the platform on which all the good policies and best practices are made," Mathew said.

A global initiative called Kidney Disease: Improving Global Outcomes (KDIGO) was formally established in December 2003 to improve the care of people with kidney disease worldwide. KDIGO is an independent organisation founded under the leadership of US renal specialist Dr Garabed Eknoyan. Many specialists from around the world have now committed themselves to the project, which aims to integrate research findings, develop guidelines and assist countries with their implementation.

"The guidelines will be developed from the perspective of what is best for a patient with kidney disease. Obviously local resources will dictate what may ultimately be affordable in any one region. This is a choice that each country which elects to adopt the guidelines will have to make," Eknoyan said.

Eknoyan believes that countries with guidelines already in place, such as Australia, Canada and the USA, will benefit from the pooling of resources and achieve more uniform recommendations. Their expertise will help countries without guidelines with the implementation process. "Ultimately it is governments and organisations that apply the guidelines and translate them into clinical practice," he said.

Professors Gavin Becker and Rowan Walker of Royal Melbourne Hospital will be representing Australia in KDIGO. These doctors have a major role in the development of Australian kidney management guidelines through Caring for Australians with Renal Impairment (CARI), which commenced in 1999 and is funded by the pharmaceutical industry. A recent survey of Australian renal specialists showed that most believed the CARI guidelines were of practical benefit.

The KDIGO leaders are targeting all aspects of kidney health, not just end-stage renal failure. They refer to an analysis by Dr Scott Weingarten, Professor of Medicine at the University of California, Los Angeles, who found that states guidelines for preventative care can be more effective than some new technologies because 70% of disease is preventable.

The need for early management of kidney disease is also emphasised by Mathew. More than one-quarter of Australians with kidney failure have had their first consultation with a kidney specialist less than 3 months prior to commencing treatment even though it has been shown that early detection can slow the progression to kidney failure in 20-50% of cases. About half of the people with a high risk of kidney disease, such as those with diabetes, do not have the correct tests done to check for early kidney damage.

Mathew believes that Australian medical practitioners are striving to use the best world evidence in their management of kidney disease. As part of Kidney Health Australia he is committed to educating all Australians to help prevent kidney disease. Kidney Health Australia helps to raise public awareness with initiatives such as Wee Week and Kidney Watch Australia.

"More than one-quarter of Australians with kidney failure have had their first consultation with a kidney specialist less than 3 months prior to commencing treatment..."

Wendy Laursen is a freelance science journalist.

Copyright Control Publications Pty Ltd Apr 2005

Source: Australasian Science

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