transplant research

ScienceDaily (Feb. 26, 2009) — Platelets, tiny and relatively uncharted tenants of the bloodstream known mostly for their role in blood clotting, turn out to also rally sustained immune system inflammatory responses that play a critical role in organ transplant rejection, according to a new report from Johns Hopkins scientists.

“Platelets potentially hold sway over many aspects of transplant biology,” says Craig Morrell, D.V.M., Ph.D., an assistant professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine. “Our data, as well as others’, show a surprising interplay of platelets and the immune system, so it’s time for the transplant world at large to have platelets on its radar.”

A self-described “platelet guy” transfixed by the unexplored biology of these circulating bodies, Morrell collaborated with clinicians in the fields of transplant to write a comprehensive review of platelets and transplant biology, published in the January issue of the American Journal of Transplantation.

“It all began with the observation that when transplant tissue is rejected, platelets line up in the interior of blood vessels feeding the tissue,” Morrell says. “It turns out they are not just bystanders, but have a role in driving that rejection.”

As one of the most abundant cell types in the blood — second only to the oxygen-carrying red variety — platelets are ubiquitous but relatively unexplored, Morrell says. “It’s crazy how many potentially active molecules are jam-packed in these small cells and that we’re only just beginning to appreciate their pro-inflammatory qualities.”

In fact, mounting evidence from Morrell and others shows that platelets are part of a sustained and general immune response that can trigger or exacerbate organ rejection. Not only do they rush to the scene of a wound and adhere to local blood vessels, preventing fatal bleeding, they also dump out granules that “talk to” immune system white blood cells, Morrell says, recruiting them from far and wide to stave off potential infections.

These are on the whole very good things for platelets to do, Morrell says, but in the context of organ transplants, their pro-inflammatory function gets out of control, and they do more bad than good after contributing to initial wound healing.

Strategies using drugs or other means to keep platelets quiet and non-inflammatory might benefit transplant patients in the long run because chronic rejection — as contrasted with acute or immediate organ rejection — is a major complication for which there is little current treatment, according to Hamid Rabb, M.D., medical director of kidney transplantation and a professor of medicine at the Johns Hopkins University School of Medicine.

In prior research using mice with skin transplants, Morrell and his team noted that increased platelet interactions led to increased and prolonged white cell interactions with the inner lining of the blood vessels and worsened transplant vessel damage.

“We watched platelets flowing through the blood vessels of transplanted skin in mice with and without platelets and determined tissue-platelet interactions by comparing the speeds of those flows,” says Morrell, whose team ultimately demonstrated that antibodies made in reaction to the transplanted tissue sparked platelet activation and white cell recruitment.

Studies on tissue from platelet-depleted mice helped confirm the importance of platelets in white cell activation and recruitment, strongly suggesting that limiting the inflammatory response might improve transplanted tissue survival.

Mounting evidence suggesting that platelets are activated not only post-transplant, but also during organ harvest, presents new opportunities for attacking organ injury and rejection head-on, says Rabb. The traditional target of current anti-rejection medicine is the so-called T lymphocyte — a white blood cell believed to be the major orchestrator of the immune response against any foreign tissues, including transplants.

“The thought was that if we hit the general that initiates acute rejection, it would put the troops in disarray,” says Rabb. “Traditional therapies therefore inhibit or deplete T lymphocytes and other white blood cell components of the immune system. The newest kid on the block is the platelet and it represents an opportunity to target the effectors of organ injury rather than only the general.”

The authors of the review, who were supported by National Institutes of Health grants, are A.D. Kirk, Emory Transplant Center, Emory University; W.M. Baldwin III, formerly of Johns Hopkins and now at the Lerner Research Institute; and Morrell, of Johns Hopkins.

Transplant Surgery – A Delicate Balance

From HealthNewsDigest.com

Plastic Surgery
Transplant Surgery – A Delicate Balance
By
Feb 8, 2009 – 12:51:34 PM

(HealthNewsDigest.com) – In an incredibly complex 22-hour procedure, the Cleveland Clinic’s microsurgical-research team performed the United States’ first almost-total face transplant last December. The procedure gave a disfigured woman a chance at a normal life, a life that began today when she left the hospital. It’s also another demonstration of the astonishing progress the medical community has made in transplant surgery. For most of us, the awe-inspiring story ends there. But for a transplant patient, finding a donor and then surviving surgery is only half the battle. Next comes a lifelong fight to keep the human body from doing what it is exquisitely designed to do: reject foreign bodies and tissue.

And in this arena, researchers are still struggling with a complex problem. The immunosuppressive drugs that patients need to take to prevent organ rejection are toxic, and the side effects can be debilitating or even deadly in the long term. Medication dosage or quantity can be reduced to limit toxicity, but that also increases the risk of rejection. Alternately, the immune system may be suppressed too much, and infection may overwhelm the body. Finding the right balance is a delicate, sometimes impossible task.

The balancing act can be rough on patients. Laura Ellsworth, 33, of Vancouver, Wash., underwent a living donor kidney transplant 10 years ago with a kidney donated by her father. She takes 17 different pills every day, a mixture of immunosuppressive drugs and medications to control her blood pressure. The regimen increases her risk for heart disease, infection, skin cancer and osteoporosis. She visits a dermatologist regularly for skin-cancer checks, and even though she’s only in her early 30s, she has undergone several bone scans to check for osteopenia, a precursor of osteoporosis.

Despite the challenges for patients, it’s clear that transplant medicine is making advances. Doctors are able to keep transplanted organs functioning for longer lengths of time, and most of the approximately 250,000 people living with transplants in the United States, like Ellsworth, are living full, productive lives. Still, a majority of transplanted organs do eventually fail. And patients have to be vigilant about protecting their fragile immune systems to give themselves a fighting chance.

One sign of hope lies in a promising new experimental procedure developed by Dr. David Sachs, head of the Transplant Biology Research Center at Massachusetts General Hospital and a professor of surgery at Harvard Medical School. In a small trial, Sachs was able to achieve immune-system tolerance in several transplant patients completely without using immunosuppressive drugs.

Though the immune system is elegant—distinguishing between the organs, blood, tissues and cells that are part of the “self” and outside invaders such as splinters, dust or germs—it isn’t perfect. Splinters become infected, dust can trigger allergies and germs can get through immune-system defenses. When it comes to organ transplants, the challenge is that the immune system is not making a mistake. Except in the case of identical twins, a transplanted organ is “non-self,” and the immune response to the transplanted organ is all-out war. “What the immune system wants to do is destroy that organ,” says Dr. Sang-Mo Kang, associate professor of surgery at the University of California San Francisco and surgical director of the Intestinal Rehabilitation and Transplantation Program. “Evolution or nature never envisioned the transplant. And therefore, the immune response is absolutely incredible.”

Jennifer Searl, one of Sachs’s patients, knows all about that powerful immune-system response, and how devastating it can be when the immunosuppressive drugs aren’t able to fight it properly. She had her first kidney transplant when she was 13 years old (as in Ellsworth’s case, a kidney donated by her father). Her 10-year stint on the immunosuppressive drugs she needed to keep that kidney functioning was horrific. She was taking 20 pills a day and developed cataracts, high-blood pressure, osteopenia, and painful viral warts on the sole of her right foot.

“It was absolutely the worst time of my life,” says Searl, now 29 and a research librarian in Peabody, Mass. “It was like trading one disease, my kidney disease, for a bunch of other horrible problems caused by these drugs. I hated them.”

Her immune system eventually overcame the drugs and her body rejected the kidney. Things looked bleak, but then she met Sachs. Thanks to the Massachusetts General doctor, Searl is thought to be the first person in the world in whom immune-system tolerance was achieved in a non-matched kidney transplant (where the donor organ is different from the recipient’s tissue type, as is the case in all transplants except those involving identical twins). She has been off immunosuppressive medications for more than six years, an extraordinary accomplishment.

Although there has been some success in weaning patients off immunosuppressive drugs when a donor is closely matched, transplant recipients in Sachs’s protocol received kidneys that were mismatched, like Searl’s. These types of transplants are the most common and, unfortunately, are the most likely to fail, even with an onslaught of anti-rejection drugs: 10 percent will fail within one year, 30 percent within by five years and 45 percent within 10 years.

Sachs’s procedure involves partially destroying the patient’s bone marrow before the transplant to reduce the number of cells involved in organ rejection. Searl went through the protocol in 2002 with a kidney donated by her mother. During transplant surgery, her mother’s bone marrow was injected into one of Searl’s blood vessels, in the hope that Searl’s immune system would achieve “mixed chimerism,” essentially a state in which a patient’s immune system takes on some of the characteristics of the donor’s.

“The results were outstanding,” Sachs says of the procedure, which was successful in 4 of the 5 patients he has used the protocol on. (The results of the trial were published in The New England Journal of Medicine in January 2008.) “We were ecstatic, but everyone has to realize this is just one step.” The next step, according to Sachs, is to see if the regimen works in a larger group of patients. “We need much more patient experience, but the ultimate goal is to help transplant patients live longer and live more normal lives,” he says. If all goes well, Sachs hopes the protocol will eventually be extended to all transplanted organs.

Dr. Maria Siemionow, who heads the microsurgical research team that performed the face-transplant procedure at the Cleveland Clinic, is pursuing another research track. In her animal lab, she’s begun a series of rat experiments designed to trick a host immune system to recognize transplanted tissue as self. She has identified an antibody—a type of protein that links to an invader and repels it—that allows the host immune system to tolerate transplanted tissues without the need for long-term immunosuppression. So far, these rats have achieved immune tolerance for as long as two years.

Siemionow acknowledges that the treatment is not yet ready for human subjects. “We can do a lot with rats and immune tolerance, but humans are so much more complex,” she says. Still, she is hopeful the approach will move forward in human clinical trials in about a year.

Progress is invariably slow in this type of research, and Sachs is feeling the pressure, with the number of patients waiting for organ transplants far exceeding the number of available organs. The hope, he believes, lies in xenotransplantation, essentially a process of growing organs from animals that are compatible with a recipient’s immune system. But that prospect, Sachs says, “is a longer way off,” and would, of course, benefit from just the kinds of advances in preventing organ rejection he’s working on.

For now, even when experimental treatments are successful, as they have been so far for Jennifer Searl, there are still no easy fixes. The procedure she underwent was grueling. The initial effect of having her bone marrow partially destroyed prior to surgery—with low-dose chemotherapy, medication and radiation—was very hard on her, as was spending several weeks in isolation after surgery while her immune system was rebooting. It was “an incredibly lonely time,” Searl says.

But now that time has been supplanted by what she calls “a completely full, normal life.” Searl is a marathon runner and swims on a masters’ team. She likes to read, and admits to a penchant for the television show “Gossip Girl.” “I just feel so normal,” she says. “I don’t know what the future will bring. But today, I can say I’m finally free.”

And if Sachs’s treatment proves to be successful in a larger trial, there’s a good chance that more transplant patients may one day be able to say the same thing.

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The recent disclosure of a kidney sale in Chennai raises fears that there is a widespread racket in Tamil Nadu.

The recent disclosure of a kidney sale in Chennai raises fears that there is a widespread racket in Tamil Nadu.

DOES the kidney trade continue to thrive in Tamil Nadu despite the implementation of the Transplantation of Human Organs Act (THOA), 1994? Has the government taken adequate steps to narrow the gap between the demand and supply of kidneys to help patients with end-stage renal disease (ESRD)? Are the steps initiated by the government to promote cadaver donation yielding results? Is it true that the authorities are trying to find a narrow technical solution to a very complex problem? These and several other questions relating to kidney transplantation have come to the fore again with a resident of Chennai alleging that he sold his kidney to a person who was not related to him. Transplantation of a kidney from an unrelated donor is against the law except when done with an altruistic motive.

M. Sekar, 33, lives in Bharathi Nagar in Villivakkam, which has for long been in the news for kidney trade. The residents here are mostly construction workers, hawkers, vendors or others taking up low-paying jobs and fall in the below poverty line (BPL) category. As pointed out by Dr Sunil Shroff, managing trustee of the Multi Organ Harvesting Aid Network (MOHAN), it seems every other household in the area has a donor.

Sekar’s case appeared in the local media in the end of December 2008 after a non-governmental organisation (NGO), Manitha Urimai Makkal Iyakkam, brought it to light. A kolamaavu (rangoli powder) vendor, Sekar claimed that a kingpin of the illegal trade contacted him a few months earlier and he agreed to part with his kidney for a price the man quoted. The surgery was done in a hospital in the city in October 2008, and he was given only a part of the promised sum, he alleged. Just as most live unrelated donations of kidneys in the past were for monetary considerations, Sekar also said that he had “sold” his kidney to save his family from the debt trap. A major portion of the money was used to repay a loan his father had raised in order to marry off his two sisters. Sekar said the middleman had tutored him to tell the Authorisation Committee – constituted under the THOA – that he was related to the recipient.

T. Santhakumar, president of the Iyakkam, alleged that people who were desperately in need of money in Villivakkam and certain other areas including Ennore and Thiruvottiyur in North Chennai were lured into selling their kidneys. Describing Sekar’s case as the tip of the iceberg, he said the full magnitude of the issue would come to light only if a thorough investigation was done in the areas. The organisation also called for urgent measures to break the hospital-broker nexus and help the hundreds of poor people who had donated kidneys to unrelated recipients.

Official denial

Official sources deny the existence of any fresh racket involving illegal kidney transplantations in the State. According to Secretary (Health) V.K. Subburaj and Director of Medical Education Dr S. Vinayagam, investigations following the media reports of the kidney donation by the Villivakkam resident have revealed that the allegation is baseless. Records available with the Authorisation Committee and the hospital where the surgery was performed also showed that the donor was related to the recipient, Subburaj said.

Dr Vinayagam said the committee had interviewed the donor and the entire proceedings had been videographed. There was no need for any suo motu probe into the commercial dealings in organs in the absence of any evidence, Subburaj said. Officials in the government say that kidney trade in the State is a thing of the past. According to them, things began to change significantly after the government took a string of measures to tighten the procedures relating to organ donation.

However, there are some experts who feel that the racket may be operating at the subterranean level though major hospitals are wary of performing illegal transplantations in view of the law. “This problem arises out of poverty and it takes place in many Third World countries. Law-breakers breach laws and the THOA is not an exception. It is unfortunate that we are trying to find a narrow technical solution to a very complex sociological problem,” said a senior medical expert.

Data provided by the Directorate of Medical Education in Tamil Nadu show that around 75 per cent of the kidneys available for transplants in the State have come from live unrelated donors “by reason of affection or attachment towards the recipient”, as per Clause 9 of Chapter II of the THOA. About 27 per cent of the recipients have been foreigners. Moreover, the Authorisation Committees have rejected only a microscopic percentage of the applications; of 682 cases that appeared before it during 2007 and 2008, only 18 were rejected. Still, official sources claim that the government has taken vigorous steps to curtail the number of live unrelated donations of kidneys. Highlighting the State government’s initiatives, Subburaj said that after illegal kidney transplant cases were reported in 2007, a series of measures were taken to tighten the procedures relating to organ transplantation by issuing seven Government Orders (G.O.s) from January 8 to September 5, 2008. According to him, the government had authorised 58 hospitals in the State to conduct kidney transplantation.

“A system is in place to ensure regular monitoring. Approvals are given only for cases with genuine and correct documents. The Authorisation Committees constituted in Chennai, Madurai and Coimbatore meet every Friday to scrutinise the applications and give their approval,” he said.

Steps have also been taken to strengthen the office of the Director of Medical and Rural Health Service, who is the appropriate authority to deal with any irregularity. A police team has been placed under his/her control exclusively to help him/her in the investigation process if any case of irregularity is reported. Besides, each Authorisation Committee has a police officer as its member. “After taking these steps, we have never come across any case of irregularity,” Subburaj said.

However, even while saying that the Villivakkam incident does not indicate a fresh kidney racket in the State, some experts assert that this kind of kidney sale has been going on all the time. “It ebbs a little when the government brings in some strict measures as a result of a scam, and when things cool down, it becomes normal again. This is primarily because it is a life-and-death issue for the recipient, and the well-off can afford any amount of money to save their lives. On the other side, the very poor and the deeply indebted are in need of money very badly. This is a strong combination and any kind of regulatory framework gets subverted fairly easily,” said C.E. Karunakaran, trustee of the National Network for Organ Sharing (NNOS).

Though the government’s initiatives have curbed to some extent the transactions that take place on the basis of the altruistic clause (Clause 9 of Chapter II) of the THOA, the sale of kidneys using the near-relative clause goes on. The hospitals also play ball in this because they need the business, he said. He said the government had the power to take action against erring hospitals or individuals involved in the racket and such action would act as a deterrent. Karunakaran also said that though any regulatory measure could be strictly enforced if there was a will, the rich and the powerful and those with political contacts generally got round these measures.

Will the government come forward to rehabilitate live unrelated donors as most of them belong to the BPL category and suffer from tremendous psychological pressure? Dr Shroff referred to a cross-sectional survey conducted among 305 individuals in Chennai in February 2001; the respondents had sold a kidney each around six years before the survey. The study conducted by four experts, including Madhav Goyal, showed that in India, selling a kidney did not lead to a long-term economic benefit for the donor and sometimes it caused a decline in his/her health.

Subburaj said the government had not thought about rehabilitation so far but could extend financial assistance by dovetailing it with existing programmes. He said the donors were being given medical assistance. As a follow-up, the donors were periodically examined even after the surgery and they would not be left high and dry, he added.

But some experts are sceptical about this. “That is unlikely to happen as the rehabilitation of these hapless donors by the government would amount to admitting that the regulation has been subverted,” said Karunakaran.

Referring to a consultation on “Organ Transplant in Tamil Nadu – The Future” held by the State Health Department in association with the NNOS in March 2007, Karunakaran expressed the hope that the government’s cadaver transplantation programme would get off the ground in the next few months and “we can see sustained activity [in this area]”.

It is estimated that around 50 per cent of the nearly 5,000 kidneys transplanted in a year in the country are donated by genuine live relatives, while the remaining 50 per cent are “commercial kidneys”. In Tamil Nadu, Karunakaran said, around 1,000 transplants were performed annually.

Government officials and experts admit that in the prevailing situation, there is no quick-fix solution to the problems arising out of the yawning gap between the demand and supply of human organs in general and kidneys in particular, in view of the ever increasing number of ESRD patients. As many as 1.5 lakh people in the country require dialysis or a kidney transplant every year. According to official sources, one in every 1,000 persons suffers from chronic kidney disease.

Cadaver transplant

Against this backdrop, the government, in consultation with experts, has taken a series of steps to encourage and streamline cadaver transplant. “One of the reasons for the commercialisation of organ transplants was the lack of coordination with regard to cadaver transplantation. Close on the heels of the launching of the cadaver transplant programme, major hospitals in the State have expressed their willingness to be part of the network,” said Dr J. Amalorpavanathan, convener of the Cadaver Transplant Programme. He said the formation of an autonomous organ harvesting and distributing body at the State level was in a nascent stage.

Recalling the role of the MOHAN Foundation in the area, Dr Shroff said that there had been more than 20 cadaver donations in the State in the last three months of 2008 compared with 22 donations in the past three years. He said cadaver donation was catching up with the people after a doctor-couple donated their son’s organs last September; the boy was declared brain dead following an accident.

If the prevailing low rate of cadaver donation in the country – 0.07 per million population – were increased to one per million population, there would be adequate organs available for transplantation and there would be no need for live donations, he said.

Another issue that has been debated is the suggestion of a section of medical personnel and ethicists to declare organ donation by live unrelated donors as “regulated sale” or “rewarded gift”. A regulated market will ensure transparency in the commercial dealing, they feel. But Karunakaran said the experience in Iran where the system is in vogue “shows that those who have sold their kidneys through an open mechanism feel at the end of the day that they are worse off and they would not recommend anybody else to sell their kidneys”.

A discussion on the issue at a meet of experts in Istanbul, Turkey, in the middle of last year concluded that rewarded gifting of organs from live persons should not be allowed. The State government also rejected such an idea because of the THOA and other factors, Karunakaran said.

Experts including Dr Amalorpavanathan and the authorities concerned suggest that the focus should shift to preventive health care as the recipient has to spend Rs.10,000 to Rs.25,000 a month on medicines for the rest of his life to prevent the transplanted organ from getting rejected, and this is not viable for the poor. “The solution lies more in preventive nephrology. The two major causes of renal diseases in adults are diabetes and hypertension. This calls for radical alteration of our lifestyle,” he said. “If you reduce the incidence of these two diseases, the requirement for kidney transplants will come down and the demand can be taken care of by related donors and cadavers.

Tackle organ trafficking by promoting donation

The best way to tackle organ theft and trafficking for organs is by promoting voluntary donation and voluntary sale. The role of government should be to prevent crime, and not to enter into a contract between two parties. Crime includes cheating, trading others organs, and making profit out of it. A person who is willing to offer kidney or organs voluntarily for a price should be allowed to do so, and government should ensure that the contract is honoured. this will thwart the organ traffickers and gory crimes for organs.