“Stem cells beat kidney rejection,” says BBC News. The broadcaster says that an injection of stem cells given alongside a kidney transplant could remove the need for a lifetime of treatment to suppress the immune system.
The news is based on research detailing the outcomes of eight experimental kidney transplants where the organ came from a living donor. In addition to having their kidney removed, the donor also donated blood stem cells, which can develop into any type of blood cell, including immune system cells. After the recipient patient had received chemotherapy and radiotherapy to suppress their own immune system, the donor kidney and stem cells were transplanted. The aim was to help prevent the organ from being rejected by altering the recipient’s immune system to match that of the donor kidney. Five of the eight patients were able to have their immunosuppressant drugs reduced within one year. Furthermore, there was no evidence that the donor’s transplanted immune cells had started to attack the recipient’s healthy tissue, a possible complication of this type of treatment.
Although this is only early-stage research, the results of this small case series are promising and could have implications for the future of organ transplants, particularly in those cases where the donor and recipient are not an immunological match to each other.
Where did the story come from?
The study was carried out by researchers from Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago and other institutions in the US. Funding was provided by the US National Institute of Health; the Department of the Army, Office of Army Research; the National Foundation to Support Cell Transplant Research; the WM Keck Foundation; and the American Society of Transplant Surgeons Collaborative Scientist Award. The study was published in the peer-reviewed journal Science Translational Medicine.
The BBC News website provides good coverage of this research.
What kind of research was this?
This was a case series reporting on the results of eight patients receiving kidney transplants alongside haematopoietic stem cells (HSCs – cells that can develop into any type of blood cell . These were taken from “mismatched” donors (either related or unrelated to the recipient . If they are “mismatched”, the donor and recipient do not share the same human leukocyte antigens (HLAs , which are proteins located on the surface of immune cells and other cells in the body. The immune system recognises “foreign” HLAs and will attack cells that carry them, potentially leading to rejection. If donor cells carry the same HLAs there is less chance that the host’s immune cells would recognise the transplant tissue as foreign. This is why the ideal situation is to find a suitable HLA-matched donor for individuals awaiting a transplant, although this is often not possible.
The research investigates a theory known as “chimerism” (named after a mythical creature made up of parts of different animals , where the transplant recipient has both their own immune cells and those that come from the donor. The hope is that this will prevent the body from rejecting the transplant. However, there is a chance that this could increase the risk of what is known as graft versus host disease (GVHD , which is where the donor’s immune cells instead attack the healthy tissue of the host. HSC transplant also carries a risk of what is known as “engraftment syndrome”, which is characterised by a fever, skin rash and other symptoms.
What did the research involve?
This case series reported the outcomes of eight adults (age range 29-56 years who were receiving a kidney transplant from a living, unmatched donor. A special technique was used to retrieve relevant cells from the donor’s blood, including both HSCs and “graft facilitating cells” (FCs – which are a type of immune cell derived from HSCs .
Prior to transplant of the donor kidney and HSCs/FCs, the recipients were first treated with chemotherapy and radiotherapy to suppress their own immune system and reduce the chance of rejection. After the transplant they received continued treatment with two drugs to suppress their immune system and reduce the chance that their bodies would reject the transplant. They were discharged from hospital two days after the transplant and managed as outpatients.
The researchers monitored the patients to look at how the procedure was tolerated and whether GVHD or engraftment syndrome occurred.
What were the basic results?
By one month after transplant the level of chimerism in the recipients’ blood (where they demonstrated cell lines coming from both their own stem cells and the donor’s stem cells was reported to vary between 6 and 100%.
One patient developed a viral blood infection and blood clot in one of their kidney arteries two months after transplant. Two patients demonstrated only slight chimerism and were maintained on low-dose immunosuppressive treatment. However, five patients demonstrated “durable chimerism” and were able to be weaned from immunosuppressive treatment by one year. None of the recipients developed GVHD or engraftment syndrome.
How did the researchers interpret the results?
The researchers conclude that transplant of HSCs is a “safe, practical, and reproducible means of inducing durable chimerism”. It also appeared to be tolerated with no signs of GVHD or engraftment syndrome.
If confirmed in larger studies, the researchers say that this approach to transplantation could free some patients from the need for immunosuppressive treatment within one year of transplantation.
Conclusion
This research reported on the cases of eight patients who were receiving a kidney from an unmatched living donor. Alongside the kidney transplant, to the recipients were also given a transplant of the donor’s haematopoietic stem cells, which have the ability to transform into a range of blood cell types. The aim was that slightly altering the recipient’s immune system to produce cells that “matched” those of the donor kidney would help prevent the organ from being rejected. Five of the eight patients were able to have their immunosuppressant drugs reduced within one year. Furthermore, no patients developed a serious condition called graft versus host disease (where the donor’s transplanted immune cells start to attack the recipient’s healthy tissue , and no patients developed another complication of HSC transplant, known as engraftment syndrome, which includes fever, skin rash and other symptoms.
Importantly, this is only early-stage research, reporting the results of treatment in only eight people. Further follow-up in these patients will be needed, in addition to study in much wider groups of patients. However, the results are promising and could have implications for the future of kidney transplant and the transplant of other organs, particularly in people for whom it has not been possible to find a suitable matched donor.
Analysis by Bazian
Links To The Headlines
Stem cells beat kidney rejection. BBC news, March 9 2012
Breakthrough in kidney transplant 'could cut waiting list'. The Daily Telegraph, March 9 2012
Links To Science
Krebs TS Johansen PO. Lysergic acid diethylamide (LSD for alcoholism: meta-analysis of randomized controlled trials. Journal of Psychopharmacology, published online before print March 8 2012
LSD “helps alcoholics to give up drinking”, BBC News has today reported.
This unusual claim is based on a review examining research into the powerful hallucinogenic and its potential to treat alcoholism. The review analysed the results of six medical trials performed between 1966 and 1971, a time when LSD was still used for the treatment of some psychiatric conditions. Although it seems unthinkable now, the drug was prescribed to some patients until evidence began to suggest that it could cause long-term harm, leading it to be withdrawn.
Although the review suggested that LSD could help dependent people to stop drinking, the limitations of the quality, methods and age of the research gathered mean that the researchers cannot support using the drug to treat alcohol misuse or dependency. Since the research was conducted, social and medical perceptions of drug harms have changed considerably, and it is highly unlikely the benefits - if any - would outweigh the risks, particularly as there are now many options for helping people with alcohol problems.
LSD is a class A drug that is illegal to possess or sell. The effects of taking LSD are highly unpredictable, and while some individuals may experience enjoyable hallucinations it carries high risk of considerable personal and psychological harm, both at the time of taking the drug and in the longer-term.
Where did the story come from?
This study was carried out by researchers from the Norwegian University of Science and Technology (NTNU and Harvard Medical School. It was funded by the Research Council of Norway and published in the peer-reviewed Journal of Psychopharmacology.
The Daily Mail gives slightly overinflated coverage of this story, which doesn’t take into account the review’s numerous and significant limitations. BBC News does make it clear that the review looked at trials from the 1960s and 1970s.
What kind of research was this?
LSD (lysergic acid diethylamide was first created in a lab in the 1930s, and in the decades that followed there was great interest in whether the psychedelic chemical could have medical uses. As the drug significantly alters how people think and perceive their surroundings, there was some speculation that it could open patients’ minds to psychotherapy.
This speculation centred on whether the substance could help people with severe mental health problems, although it was also considered as a potential treatment for more minor conditions, such as anxiety and phobias. Given its perceived benefits, LSD was administered to psychiatric patients for several years; but as it became associated with recreational use and negative effects for patients, it was withdrawn from medical use.
According to the authors of this new research, numerous clinical investigators have claimed that treating alcoholics with individual doses of LSD in combination with psychosocial interventions may help prevent further alcohol misuse. They suggested this could work by allowing patients to understand better their behavioural patterns and therefore become motivated to build and maintain a sober lifestyle.
This was a systematic review and meta-analysis, which aimed to combine the results of all relevant trials that have used LSD (lysergic acid diethylamide to treat alcoholism. A systematic review of randomised controlled trials (RCTs is the best way of reviewing the available evidence on the health effects of a particular intervention. Systematic reviews are, however, often inherently limited by the different methods of the individual trials that they combine, including the populations they studied, how the intervention is given (such as frequency, dose and duration and outcomes measured.
What did the research involve?
The researchers searched PubMed and PsycINFO databases to identify any published trials that included key terms relating to LSD, alcohol and dependence. They included any RCTs of LSD treatment for alcoholism. In RCTs, an intervention such as LSD-use is compared with a “control treatment”, such as standard treatment or no specific treatment. The researchers described that the control treatments in eligible trials could involve any type of other treatment, including using “low doses” of LSD (up to 50 micrograms, which was lower than the intervention doses . Two reviewers analysed the studies and extracted data.
Primary outcomes of interest were alcohol misuse, which was defined as “alcohol use or consequences of alcohol use, as systematically measured by interview or self-report at the first reported follow-up”. Secondary outcomes of interest were alcohol misuse in the short-term (approximately three months , medium-term (approximately six months and longer-term (approximately 12 months . They also looked at reports of abstinence and adverse events. Where possible, they pooled the results of individual studies. If any trials had included people with psychiatric conditions such as schizophrenia or psychosis, the researchers excluded these from their analyses.
The researchers identified six eligible trials, all of which were dated between 1966 and 1971. Five trials were conducted in the USA and one in Canada. The trials included 536 individuals (general age range 30s-50s; all male except two females , of whom 61% were randomly assigned to receive “full-dose” LSD and 39% a control treatment or no intervention. The trials all gave a single oral dose of LSD as the intervention, with doses ranging between 210 and 800 micrograms (average 500 . Control conditions included “low-dose” LSD (25 or 50 micrograms , amphetamines, ephedrine sulphate (a stimulant drug or no drug treatment. All participants were said to be seeking treatment for alcoholism and had been admitted to alcohol-focused treatment programmes before being recruited to the trials.
The researchers said that the individual trials varied in their preparation for the LSD treatment session, with most studies providing only brief participant information, with often little or no description of the possible effects of LSD. During treatment, the most common procedure was described to be “simple observation with brief reassurance by clinical staff”. In only three studies did the treatment groups also receive clinical interviews, psychotherapy or active guidance. After the experimental drug session, only one study included multiple review sessions that reviewed the experiences during the drug session. The other five studies provided either only one brief review session or no review session at all.
All of the trials defined their methods for assessing the effects of the drug on alcohol use, but these varied between trials (such as using rating scales on alcohol use, assessing abstinence or using social adjustment rating scales .
What were the basic results?
Five trials gave “categorical” data (for example, whether a patient was improved or unimproved , and in these five trials 59% of those taking LSD (185 of 315 and 38% of controls (73 of 191 had improvements in their alcohol use at first follow-up. The pooled results of all six trials demonstrated increased odds of improvement in alcohol misuse, with LSD treatment compared to control ( odds ratio 1.96, 95% confidence interval 1.36 to 2.84 . This, they calculated, meant six people would need to be treated with LSD for one person to gain benefit at the time of first follow-up.
When the researchers divided the trials up into those assessing short-term (two to three months , medium-term (six months and longer-term effects (12 months , significant improvements were only seen at short- and medium-term follow-up.
Three trials reported on abstinence rates but only found a benefit of LSD at short-term follow-up.
In total the trials reported eight adverse reactions at the time of taking the drug. These included becoming agitated, acting “bizarrely” and having a seizure.
How did the researchers interpret the results?
The researchers concluded that “a single dose of LSD, in the context of various alcoholism treatment programmes, is associated with a decrease in alcohol misuse”.
Conclusion
Fifty years ago, researchers and doctors considered LSD to be a possible treatment for patients with mental health problems, until evidence showed that it could cause long-term psychological problems in some people. This review of six previous trials cannot be considered to provide evidence that LSD could be beneficial for people with alcohol problems. This is in no small part due to the questionable methods of the reviewed trials, the most recent of which was carried out 41 years ago.
Although LSD may have been considered suitable for testing in a trial at a time when its recreational use was quite common, it is highly unlikely that it would be considered now, given how considerably social and medical perceptions of drug harms have changed since then. This is notable by the attitudes displayed in the previous trials, which reportedly gave the participants very little information ahead of their LSD treatment session: most studies provided only brief participant information with often little or no description of the possible effects and risks of taking LSD. This would be considered unethical and unacceptable in trials today.
There was also very little follow-up of patients to see the long-term effects of taking LSD. Only one study included multiple review sessions assessing the individual’s experiences of taking the drug; the other five studies provided either only one brief review session or no review session at all. Therefore, how individuals are affected by taking LSD – regardless of its effects on their subsequent alcohol use - are unknown. At the time of taking the drug, there were eight reports of participants being agitated, acting “bizarrely”, having a seizure or having other “unspecified” adverse reactions.
LSD is a class A drug that is illegal to possess or sell. The effects of taking LSD are highly unpredictable, and while some individuals may experience “pleasant” hallucinations, the individual is putting themselves, and potentially others, at high risk of considerable personal and psychological harm, both at the time of taking the drug and in the long term.
Given the potential danger, it seems unlikely that LSD would be considered for future testing in people with alcohol dependence. It’s particularly important to note that we now have a range of medicines and psychological interventions for treating alcoholism that weren’t available at the time of this previous research.
Links To The Headlines
LSD 'helps alcoholics to give up drinking'. BBC News, March 9 2012
LSD could treat alcoholism because 'trips' make you reassess addiction. The Daily Telegraph, March 9 2012
Can LSD cure alcoholism? Trials show 59 per cent of problem drinkers improve after a single dose of powerful hallucinogen. Daily Mail, March 9 2012
Links To Science
Krebs TS, Johansen PO. Lysergic acid diethylamide (LSD for alcoholism: meta-analysis of randomized controlled trials. Journal of Psychopharmacology. Published online March 8 2012
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