'Research on to ensure graft survival'

Interview with Dr Hiroshi Toma and Dr. Kazunari Tanabe.

Dr. Hiroshi Toma, Director of the Tokyo Women's Medical University, and Dr. Kazunari Tanabe Assistant Professor in the Department of Urology, Kidney Centre and Head of the section of Kidney Transplantation and Renovascular Surgery at the university, form one of the leading kidney transplant teams in Japan. Since 1971, they have performed over 2,000 transplants, more than 200 of them across blood groups. According to Tanabe, in the past decade the donor pool increased by over 20 per cent in Japan because of cross-blood group transplantation.

The two doctors were in Chennai on an invitation from the Madras Institute of Nephrology, which is celebrating its 15th anniversary, and the Balaji Medical and Educational Trust, which is celebrating five years of its existence. They spoke to nephrologists about their experiences in cross-blood group transplantation. Excerpts from an interview they gave Asha Krishnakumar:

What are the main causes of the increase in the number of patients with chronic renal failure the world over?

Tanabe. About 20-30 years ago, chronic glomerular nephritis (an inflammatory disease of the glomerula, the filter in the kidney that removes uric toxins) was the main cause of chronic renal failure. But today, diabetes and hypertension, which are increasing rapidly throughout the world, seem to be the major reasons. I think diabetes is the single most important factor for the increased incidence of chronic renal failure.

In Japan, the number of patients needing dialysis has increased three times, from 10,000 ten years ago. Some 10 per cent of the Japanese people are diabetic and 40 per cent of them end up with chronic renal failure.

What is the incidence of chronic renal failure?

Toma. Though we do not have the exact figures, I believe the incidence varies with industrialisation. For instance, in India, it seems to occur in 100 per million people every year, while in Japan, it may occur in 200 per million people. In Japan, we do 700-800 transplants a year. Our hospital does 20-25 per cent of all transplantations done in our country. Since 1971, we have done 2,000 transplantations in our hospital.

How does the incidence vary with industrialisation?

Toma. With industrialisation people's lifestyles change, food habits change. People become sedentary, they do not exercise, and so on. Of course, genetics has an important role in getting diabetes, but lifestyle change is a very important reason for increase in the incidence of the disease.

Does the incidence of ESRD (end-stage renal disease) vary with sex, age, ethnicity and geographic location?

Tanabe. Not with sex. But age seems to be important, as Type II diabetes, whose incidence increases with age, is the major cause of the ESRD. In Japan and the United States, the average age of a person undergoing dialysis is 63. I have not seen any study on the incidence of the disease across ethnic groups. But I do know that in the U.S., African-Americans are more prone to the disease compared to Caucasians.

What are the treatment options for chronic renal failure?

Tanabe. There are only two options - dialysis or transplantation. There are two types of dialysis - haemodialysis and CAPD (continuous ambulatory peretoneal dialysis). But neither is sufficient to remove all the uric toxins. Normally, haemodialysis is done thrice a week, each session lasting four hours. That is 12 hours a week of haemodialysis, or less than 10 per cent of the hours in a week. In such a situation, only 7-8 per cent of uric toxins can be removed, with close to 90 per cent remaining in the body. This leads to chronic uremia, which may cause athelosclerosis (heart disease) and bone diseases that shortens the life span.

But renal transplantation completely resolves these kinds of problems. Of course, the recipient has to be on immuno-suppresant medicines, which can cause side-effects. Earlier there used to be tremendous side-effects such as steroid-induced osteoporosis, athelosclerosis and so on. But now we sometimes take patients off steroids, prescribe low dosages of steroids and cyclosporin, or put patients on Tactrotimus (IL-2 inhibitor) and so on, and thereby minimise the side-effects.

So, are the protocols of treatment changing?

Tanabe. Yes, treatment protocols or drug combinations are changing to minimise the side-effects. Pharmacology has improved so much that transplant patients have practically little or no side-effects. Twenty years ago, one could easily identify a transplant patient, with bloated face, increased weight and so on due to the intake of steroids. But, now, it is very difficult to make them out from normal people.

What kind of research - pharmacological, treatment methods and diagnosis - is going on?

Tanabe. A lot of work is going on to ensure graft survival. Short-term graft survival is not a major problem. A five-year graft survival with cyclosporin and tacrotimus is over 90 per cent. But our concern is primarily on increasing long-term graft survival rates - 10 to 20 years. In Japan, the graft survival rate 16 years after transplantation is 50 per cent. To better that and to be able to prevent non-immunological injury to the kidneys, we need more effective immuno-suppresants.

Non-immunology injury that reduces the graft survival rate depends largely on the age of the transplanted kidney (the older the kidney, the lower the survival rate). But conditions such as diabetes and hypertension that damage the kidneys, as also obesity, lower the graft survival rate. These are things a transplant patient should be very careful about. Thus, a lot of work is going on to study the effects of immunological and non-immunological kidney injury on the graft survival rate.

Also, after transfusion or the first transplantation, patients may have anti-HIV (human immunodeficiency virus) antibodies. This is very harmful to the kidneys. Over 20 per cent of the people have these antibodies and they are high-risk sensitive recipients. They pose a big problem during transplantation. A lot of work is on to improve graft survival rates, especially in the long term.

For non-immunological factors we need to use effective hypertension drugs that protect kidney functioning. Work is on in this area as well. Apart from choosing the appropriate drugs, it is important to focus on the diet to prevent hypertension and so on. A lot of work is on in the management and treatment with a view to increasing long-term graft survival rates.

We have to accept high-risk patients, we cannot refuse anybody. We accept older patients, AB incompatible patients, and those with high complications such as vascular and heart diseases owing to diabetes. A lot of clinical research work is on to improve the management and increase the long-term graft survival of such high-risk patients.

At the basic level, we are concerned about strengthening the immune systems or tolerance levels to accept the donor organs and, at the same time, keep up the defence mechanisms against bacteria, viruses and other such germs. Achieving this has been the main struggle since the beginning of the organ transplantation programme. But we have not been very successful in this till now. One of the most interesting research works in this area is doing bone marrow transplantation on the recipient from the donor so that the immunology of the donor also gets transferred to the recipient. Then the donor's kidney is transplanted onto the recipient. In such a case there is no need to use immuno-suppresant drugs and there is no immunological injury to the kidney. There would be no reason for the donor kidney to be rejected in this case as the immuno-competant cells of the recipient become compatible with that of the donor's. In this process, the recipients may have some infections. That is what we need to overcome.

This is very interesting. How does one do this?

Tanabe. There is no established technique as yet. The Harvard Medical School tried doing this, but there are still some problems. We are also trying to do this at our centre. We are now working on monkeys and mice. Monkeys are difficult as they are very similar to humans, with a very complicated immuno-system. We hope to complete this research work in the next five years.

Throughout the world, there is a big gap between donors and the number of people waiting for a kidney. What is the situation in Japan?

Toma. It is very difficult to get donor organs. We also face a lot of problems as the Japanese are reluctant to donate organs as they cannot accept brain death. There are over 10,000 ESRD patients waiting for a kidney and, we get only about 100 cadaver organs in a year. Several patients die just waiting for a kidney. So, we have no choice but to expand our live kidney donation programme. Live unrelated donation is not allowed in Japan; it is illegal.

How do you increase your donor pool?

Tanabe. We are focussing a lot of work to increase our donor pool. For instance, in 1989, we started the cross-blood transplantation programme. Fifteen years ago, 15-20 per cent of the recipients who had relatives to donate were found to be AB incompatible and hence could not get a transplant done. But after we started this programme, those 20 per cent of patients who have relatives willing to donate but do not have matching blood group have benefited. This has led to a big increase - at least by 20 per cent - in the number of transplantations in Japan. In our hospital, we have done over 200 transplantations across blood groups. In Japan over 10 hospitals do across-blood group transplantations against only two or three centres in the U.S.

In the U.S., the laparoscopic or keyhole surgery to remove the donor kidney for transplantation has increased the number of relatives coming forward to donate as it means no blood, less pain, and shorter hospital stay. This has enhanced the donor pool. Thus in the U.S. live donation increased from 10 per cent to 60 per cent last year.

So, we hope cross-blood transplantation and laparoscopic harvesting of kidneys will increase the donor pool significantly. It may not be dramatic or happen overnight, but it will certainly improve gradually.

What is the procedure for doing across blood group transplantation?

Tanabe. The antibodies of blood groups A and B are removed from the patients before surgery by a procedure called Double Filtration Plasma Pheresis (DFPP). This is done several times till the antibodies against the blood group disappear from the patient. Then the transplantation is performed. The plasma removed from the patient is again separated into albumin and globulin and the former is returned to the patients. This minimises risk as only the antibodies are removed.

Does the graft survival rate vary with the same blood group and across blood group transplantations?

Tanabe. When we started the cross-blood group transplantation in 1989, there was a difference in the graft survival rate within five years after transplantation and was the same after that. But, now, with the use of newer and better drugs, the graft survival rates are the same for both - over 95 per cent for three years - and the rejection rates are also similar. The rejection rates are higher and the graft survival rates are poorer for the anti-HIV antibody positive or hyper-sensitive patients. Thus, the immunological barrier for the highly sensitised recipients is much higher than the AB incompatible transplantations. This is because the anti-HIV antibody is much more difficult to remove and recurs easily; it destroys the kidney easily. So, we desensitise the recipients who are anti-HIV antibody positive and then perform the transplantation.

Do patients undergoing cross-blood group transplantation need to use more immuno-suppresants than in the case of same-blood group transplantation?

Toma. There is no difference in the use of immuno-suppresants. Only, the antibodies need to be removed from the donor blood before transplantation in the case of cross-blood group graft.

We also do laparoscopic springectomy (removing the spring; a two-hour procedure) on the recipients before the transplantation, as spring - the oasis in the bonemarrow - is a very important organ for immuno-response. The spring has a lot of B-cells that help in producing every kind of antibodies. That is why we remove the spring to remove the antibodies. In the early 1980s, without springectomy, cross-blood group transplantation was not successful. But now, with newer and more powerful immuno-suppresants, the Mayo Clinic in the U.S. does cross-blood group transplantations successfully, even without springectomy. But nobody knows the long-term results. Just to be on the safe side, we do springectomy before cross-blood group transplantations.

What ways do you adopt to save the kidney?

Tanabe. When there was a tumour in the kidney, we used to remove the whole organ. This resulted in the loss of functioning of kidney tissues, leading to a rapid progression of kidney failure. But now many patients have diabetes, hypertension, glomerular nephritis and so on. If we remove the whole kidney in case of tumours in all these patients, then they will be left with only one kidney, thereby increasing the risk of ESRD. Hence we prefer to spare the kidney tissues and remove only the tumour, without disturbing normal kidney functions. But we have to pay attention to the recurrence of the tumour. So, we also remove the region around the tumour to reduce the risk of recurrence. This procedure was started in the U.S. in the 1980s.

As the kidney has a lot of blood vessels, does it require some special technique to remove the tumour?

Tanabe. Yes. It is a difficult surgery. Small tumours are all right. It just needs to be cut and stitched up. But the real problem is with the bigger ones. We study the area carefully for the arteries and veins, cool the kidney, cut out the tumour and then close the blood vessels. But if the tumour is too big, we remove the kidney from the body, cool it, take out the tumour, close the blood vessels, and then put it back into the body. This takes a long time. This is a new technique but we now do it routinely in our hospital.

What is your view on kidney commerce?

Toma. The International Society of Transplantation and the Japanese Society of Transplantation are strongly against the buying and selling of organs. We are for totally doing away with trade in kidney. The only long-term solution for any country is to focus on preventive measures, concentrating on diabetes, glomerular nephritis, hypertension and so on, the main causes of renal failure, and at the same time step up research work to decrease rejection and increase graft survival rates, which include the development of better immuno-suppresant drugs.

As one gets older, regular check-up is a must as early detection can make a lot of difference to managing the kidney without going in for dialysis or transplantation. To detect problems in children, it is important to educate paediatricians to detect kidney problems early.