Showing posts with label Transplants. Show all posts
Showing posts with label Transplants. Show all posts

Sunday, May 14, 2017

Can we genetically modify animals to procure organs for humans?


Why the need to use animal organs for human transplants? Is there even such a need? No, rather it's a technological solution proposed for an urgent but non-scientific supply and demand problem, namely, shortage of organs. More people die on waiting lists than receive transplants. This fait accompli is apparently all that's necessary to breathe life into the need for Xenotransplantation - Wikipedia, i.e., animal organ transplant into humans. However, accepting this fait accompli at face value is not only dangerous but also quite disingenuous for the following reasons.

Why Xenotransplantation Isn't An Appropriate Response To The Organ Crisis: It Doesn't Address The Underlying Issue
Transplant waiting lists keep growing. Not too few donors. Rather too many potential recipients. While donations and transplants remain steady, numbers waiting for transplants grow year-on-year (1) in developed countries. Scenario is palpably ghastlier in poorer countries, where forget transplants, even dialysis is usually beyond reach for many organ failure patients.

Why is the need for transplants increasing though? This is typically swept under the carpet as increasing morbidity rates. But why are morbidity rates increasing in the first place, especially in developed countries? Somehow this, the very crux of the matter, gets short shrift in both the biomedical literature and popular media.

~80% of those on waiting lists need kidneys due to ESRD (end-stage renal disease, Chronic kidney disease - Wikipedia). Increasing numbers of organ failure patients have ESLD (end-stage liver disease) (2). Most common predisposing factors are alcoholic liver cirrhosis (3), diabetes (4) and obesity (5). Clearly lifestyle issues drive need for more transplants. That is not to imply all transplants are for lifestyle-mediated chronic diseases but rather that much of the annual increase is driven by such preventable increases in morbidity.

Bad diets and sedentary lifestyles are apparently impossible to change as are the underlying socioeconomic structure and accompanying culture that increasingly make these the norm the world over. In other words, preventable, consumption-driven practices that predispose to transplant-requiring chronic health conditions have been allowed to seed and settle into society, no questions asked. Let's state the obvious. Where's the profit in prevention? Changing the culture, especially diet and lifestyle, is hard work, and even less appetizing for those habituated to feeding on the profits to be made from chronic diseases.

Thus, once such preventable diseases have taken root, capital intensive high-tech solutions to treat them including even xenotransplants become all the rage. Few mention that the organ crisis is nothing new, having existed since at least the 1980s (6). Evidently a case of the tail wagging the dog, the prevailing hegemony is thus to hardly ever allude in the first place to why need for organs is increasing and how to reduce it but rather to bemoan the organ crisis and contrive ever more creative and ethically challenging ways to increase the organ pool.

These creative though ethically challenging solutions started with expanding the definition of appropriate transplant sources. Originally, only deceased donations were allowed. Then definition of death expanded to include the legal fiction of two types of death, circulatory death (traditionally used) and brain death (7) so organs could be harvested from more bodies. Obviously brain death 'decriminalizes the harvesting of beating hearts' (8). Then donations from the living got the nod. Any surprise organ trafficking and global black market in organs followed suit (9), especially among the multitude too poor to feed themselves or their children (10, 11, 12)? After all their bodies are all they can offer the market.

Some European countries such as Greece and Spain have even taken the creative urge to extremes, embracing the currently fashionable Nudge theory - Wikipedia by introducing opt-out consent (13), where people are automatically presumed to have given consent to post-death organ donations unless they specifically take the trouble to opt-out while they're still alive. Supposed rationale is we humans are well-intentioned but lazy. Well-intentioned as in of course, we intend to choose to donate our organs after death but somehow we're too lazy to ever get around to giving the necessary legal heft, i.e., consent, to our good intentions.

And of course, desperation increasingly permeates the medico-legal culture which now explores using even infected (14) and mismatched kidney transplants (15). Meantime, the ongoing US drug overdose epidemic provides a ghastly book-end to the organ crisis by increasing organ availability (16).

Why Xenotransplantation Isn't A Solution To The Organ Crisis: Immunological Rejection & Infectious Disease Risk
And so we arrive at xenotransplantations, a path to unlimited supply of donors and their organs at least in theory. After all, what other purpose for this planet and its various denizens but to serve the human's needs. Unfortunately for the human, in this instance biology has turned out to be a more intractable partner.
In other words, technocracy encourages solutionism rather than trying to understand the fundamental crux of the problem, which in this case is spiraling rates of lifestyle-driven chronic diseases. Reducing them would automatically reduce the need for transplants in the first place (see below from 20, emphasis mine).
'Medical strategies to prevent end-stage organ failure
The prevention or delay of end-stage organ failure must be accomplished to reduce the need for organ transplantation and to achieve national self-sufficiency. This approach is especially relevant to low-income countries, where resources can be better used for other pressing medical needs. Thus, education programmes about organ donation for the public and the media should also address the maintenance of a healthy lifestyle. Early detection and prevention of diseases leading to end stage organ failure, such as diabetes, cardiovascular disease, and kidney disease, is necessary.'
Bibliography
1. Organ Procurement and Transplantation Network
2. Williams, Roger, et al. "Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis." The Lancet 384.9958 (2014): 1953-1997.
3. Williams, Roger, et al. "Implementation of the Lancet Standing Commission on Liver Disease in the UK." The Lancet 386.10008 (2015): 2098-2111. https://www.researchgate.net/pro...
4. Wild, Sarah H., et al. "Type 2 diabetes and risk of hospital admission or death for chronic liver diseases." Journal of hepatology 64.6 (2016): 1358-1364.
5. Williams, Bronwen, Michelle Clayton, and Joanne Bosanquet. "Obesity: a growing threat to liver health." Gastrointestinal Nursing 13.Sup10 (2015): S16-S19.
6. Miller, Melanie. "A proposed solution to the present organ donation crisis based on a hard look at the past." Circulation 75.1 (1987): 20-28. http://circ.ahajournals.org/cont...
7. Truog, Robert D., and Franklin G. Miller. "Changing the conversation about brain death." The American Journal of Bioethics 14.8 (2014): 9-14.
8. Epstein, Miran. "Constructing the Legal Concept of Death: The Counterhegemonic Option." The American Journal of Bioethics 14.8 (2014): 45-47.
9. Scroll, Sanjay Nagral, August 3, 2016. Better buy than die? The unfortunate enduring saga of organ sales in India
10. Epstein, Miran. "The ethics of poverty and the poverty of ethics: the case of Palestinian prisoners in Israel seeking to sell their kidneys in order to feed their children." Journal of medical ethics 33.8 (2007): 473-474. https://www.researchgate.net/pro...
11. Budiani‐Saberi, Debra A., and Francis L. Delmonico. "Organ trafficking and transplant tourism: a commentary on the global realities." American Journal of Transplantation 8.5 (2008): 925-929. https://www.researchgate.net/pro...
12. Danovitch, Gabriel M., et al. "Organ trafficking and transplant tourism: The role of global professional ethical standards—The 2008 Declaration of Istanbul." Transplantation 95.11 (2013): 1306-1312. https://www.researchgate.net/pro...
13. The Economist, Nov 20, 2008. Opting out of opting out
14. Stat, Elie Dolgin, March 18, 2016. Surgeons to test use of infected kidneys for transplants
15. Orandi, Babak J., et al. "Survival benefit with kidney transplants from HLA-incompatible live donors." New England Journal of Medicine 374.10 (2016): 940-950. http://www.nejm.org/doi/pdf/10.1...
16. The Guardian, Amanda Holpuch, May 1, 2016. Drug overdose epidemic has driven increase in organ donors, data shows
17. Tirumalai Kamala's answer to Is xenotransplantation remotely possible?
18. Tirumalai Kamala's answer to What would happen to humans if they were affected by endogenous retroviruses as a result of xenotransplantation?
19. Yang, Luhan, et al. "Genome-wide inactivation of porcine endogenous retroviruses (PERVs)." Science 350.6264 (2015): 1101-1104. http://arep.med.harvard.edu/pdf/...
20. Delmonico, Francis L., et al. "A call for government accountability to achieve national self-sufficiency in organ donation and transplantation." The Lancet 378.9800 (2011): 1414-1418. http://www.who.int/transplantati...


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Sunday, October 9, 2016

Why do women make up a majority of live organ donors but not of organ recipients?


Several Studies Do Find Women Predominate Among Living Organ Donors

Studies ranging from Germany (1) to Oman (2) find that among medically suited living donors, women tend to donate more than men.

Kidney: In 2005, 59.2% of living US kidney donors were women while 58.2% of kidney recipients were men (3). Predominance of female kidney donors is seen not just in the US but also in Brazil (4). Global estimates for living kidney donors is ~65% female with ~65% of kidney recipients being male (3). Spousal differences are more striking compared to generic estimates. A University of Michigan study found 69% of spousal donations were female (5).

Liver: In 2005, 58.3% of living US liver donors were women while 58% of living liver segment recipients were men (6). Again, spousal differences are more striking compared to generic estimates. A Canadian study found 36% of women suitable for donating to their husbands were willing to do so while only 6.5% of suitable husbands were willing to be donors for their wives (7).

Examination of published literature suggests a combination of
  • Different solid organ disease prevalence rates between men and women,
  • Greater cultural pressure on women to carry the burden of caregiving,
  • Gender selection bias in the healthcare system,
all of these factors contribute to why women predominate in living organ donations and yet receive fewer organ transplants.

Different solid organ disease prevalence rates between men and women
Several studies have documented pronounced gender bias in transplantation. However, while examining these, onus is on us to account for gender-based disease prevalence rate differences, especially where the rates are higher in men.

Kidney: Renal disease tends to be more common in men compared to women (8). Mortality rates of men on dialysis is also higher compared to women (9). Speculation is baseline creatinine clearance is better in elderly women compared to men.

Heart: In 1996, 81.2% of US heart transplant recipients were men and this only decreased to 76.8% by 2005 (6). Part of this has to do with greater preponderance of coronary artery disease in young men compared to young women. Even among those aged 55 to 64 years, congestive heart disease rates in US men are twice those in women.

Liver: Liver disease rates are higher among US men (10).

Greater cultural pressure on women to carry the burden of caregiving
Studies suggest women may offer kidneys more often from a greater drive to alleviate suffering and/or a greater inability to resist subtle pressures (11). Some authors speculate preponderance of bearing the burden of caregiving in a family may extend the woman's role to becoming a living kidney donor (12). Some studies support this conclusion (13). In fact, women are considered more vulnerable and more easily persuaded/pressured to donate (14). This is the reason the multi-disciplinary living donor assessment process in Australia and the US focuses on the living kidney donor's autonomy and decision making in the absence of coercion (15). Cultural differences may also play a role. Even today, in many societies the woman is the main caregiver with the man the breadwinner. When a woman undergoes transplantation, the man would need to take time off work to take over household management. Some authors (3, 12) speculate transplant centers may inadvertently reinforce such gender roles in the manner they offer, discuss and foster women's access to transplantation.

Gender selection bias in the healthcare system
Studies find men are often preferentially placed on transplant waiting lists (16, 17).

Kidney: A French study on 9497 men and 5386 women on dialysis found that women had both a lower probability of being registered on the waiting list and waited longer after starting dialysis before being registered (18). This study found older, unemployed and diabetic women were more likely to be victims of such disparities. A large southeastern US study found women were less likely to be perceived suitable for kidney transplants compared to men, and this was independent of medical factors (19). Gender bias favoring men was found in other US studies as well (20, 21).

Heart: Of US heart transplants in 2005, 52.3% of heart transplant recipients in 2005 were aged 50 to 64 years and 10.3% >65 years. With age, especially >65 years, coronary artery disease rates between US men and women are similar (22). Yet, gender bias persists even among this older age group of heart transplant recipients (3). Studies show that women decline heart transplantation at greater rates compared to men (23). One reason proffered for this implies surgeons prioritizing vanity over vocation, i.e., women presented with this option in a manner inclined to discourage them for the simple reason that post-transplant mortality rates tend to be higher for women compared to men, and heart transplant surgeons may be motivated by concern for their success rates (3).

Liver: One US study found women were less likely to get liver transplants (24) while another one found twice as many men as women get liver transplants (25) even though disease rates aren't twice higher.

According to JoAnn Grif Alspach (26), gender bias in medical care can thus be the unintentional product of implicit, insidious bias in the culture of medicine itself. She then lists the following implicit cultural biases as possible reasons,
'• Underestimating or misunderstanding a woman’s risk for health problems or complications 8
• Differences in the way women experience (cardiac) symptoms 30
• Differences in the way women perceive themselves and their illness 30
• The most likely explanations are at the patient level, the physician level, or both. Patients may have misperceptions of indications, risks, or benefits of surgery.
• One factor may be the differences in style that women and men use to describe their symptoms or injuries to the physician. Women tend to describe what they experience as a more personal, narrative commentary compared to men, who typically describe symptoms in a more straightforward, factual manner with fewer comments. 49 Women’s narrative presentation style reportedly contributed to physicians making more diagnostic errors in their evaluations of chest pain in women. 50
• Unconscious prejudices among physicians—social stereotyping 29
• Overt discrimination based on sex. Some physicians take women’s symptoms less seriously, attribute symptoms to emotional rather than physical causes, and refer women less often than men for specialty care, even women with a relatively greater degree of disability. 29
• Cultural biases, especially among older male physicians 51
• Women thinking of stroke and heart disease as men’s diseases 51
• Perceived differences in injury severity or perceived benefits of trauma center care, or from subconscious gender bias 48'
Ironically, transplants in women have also often been pioneering.
  • In August 1966, Dr. Michael E. DeBakey implanted the 1st extracorporeal left ventricular assist device in a 37-year old woman who couldn't be weaned from bypass following a double valve replacement (27). The pump was successfully removed after 6 days and she survived for 6 years with good cardiac function only to tragically die from an automobile accident.
  • The 1st pancreas allograft occurred on December 17, 1966 at the University of Minnesota when Drs. William Kelly and Richard Lillehei simultaneously transplanted a kidney allograft plus a duct ligated segmental pancreas into a 28 year old woman (28).
Gender Bias Matters Medically Because Gender Mismatch In Transplants Is Often Counter-Productive

Gender mismatch between donors and recipients is often counter-productive. Specifically, men with allografts from women have greatest risk of long-term allograft failure (29). This is especially true for kidney transplants (30).  Risk also runs both ways. In donations after circulatory/cardiac death (DCD), transplanting a male liver into a female recipient is a risk factor for primary non-function (31). Female recipients of male hearts is a risk factor for acute cellular and antibody-mediated rejection of heart transplants (32, 33, 34, 35, 36). Studies suggest gender matching may protect against heart transplant rejection (37).

Bibliography
1. Decker, Oliver, et al. "Between commodification and altruism: gender imbalance and attitudes towards organ donation. A representative survey of the German community." (2008): 251-255.
2. Mohsin, N., et al. "Donor gender balance in a living-related kidney transplantation program in Oman." Transplantation proceedings. Vol. 39. No. 4. Elsevier, 2007.
3. Csete, Marie. "Gender issues in transplantation." Anesthesia & Analgesia 107.1 (2008): 232-238.
4. Lima, Daniel Xavier, Andy Petroianu, and Heather Lynn Hauter. "Quality of life and surgical complications of kidney donors in the late post-operative period in Brazil." Nephrology Dialysis Transplantation 21.11 (2006): 3238-3242. Quality of life and surgical complications of kidney donors in the late post-operative period in Brazil
5. Kayler, Liise K., et al. "GENDER IMBALANCE IN LIVING DONOR RENAL TRANSPLANTATION1." Transplantation 73.2 (2002): 248-252.
6. US Department of Health and Human Services. "2008 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1998-2007." (2008).
7. Zimmerman, Deborah, et al. "Gender disparity in living renal transplant donation." American Journal of Kidney Diseases 36.3 (2000): 534-540.
8. Reyes, Daisy, Susie Q. Lew, and Paul L. Kimmel. "Gender differences in hypertension and kidney disease." Medical Clinics of North America 89.3 (2005): 613-630.
9. Lindeman, Robert D., Jordan Tobin, and Nathan W. Shock. "Longitudinal studies on the rate of decline in renal function with age." Journal of the American Geriatrics Society 33.4 (1985): 278-285.
10. Kim, W., et al. "Burden of liver disease in the United States: summary of a workshop." Hepatology 36.1 (2002): 227-242. https://www250.safesecureweb.com...
11. Biller-Andorno, Nikola. "Gender imbalance in living organ donation." Medicine, Health Care and Philosophy 5.2 (2002): 199-203.
12. Gordon, Elisa J., and Daniela P. Ladner. "Gender inequities pervade organ transplantation access." Transplantation 94.5 (2012): 447-448. https://www.researchgate.net/pro...
13. Mohs, Anja, and Gundula Hübner. "Organ donation: the role of gender in the attitude–behavior relationship." Journal of Applied Social Psychology 43.S1 (2013): E64-E70. https://www.researchgate.net/pro...
14. Dobson, Roger. "More women than men become living organ donors." BMJ: British Medical Journal 325.7369 (2002): 851.
15. Spital, Aaron. "Ethical issues in living organ donation: donor autonomy and beyond." American Journal of Kidney Diseases 38.1 (2001): 189-195.
16. Alexander, G. Caleb, and Ashwini R. Sehgal. "Barriers to cadaveric renal transplantation among blacks, women, and the poor." Jama 280.13 (1998): 1148-1152. http://citeseerx.ist.psu.edu/vie...
17. Bayat, S., et al. "Individual and regional factors of access to the renal transplant waiting list in France in a cohort of dialyzed patients." American Journal of Transplantation 15.4 (2015): 1050-1060.
18. Couchoud, Cécile, et al. "A new approach for measuring gender disparity in access to renal transplantation waiting lists." Transplantation 94.5 (2012): 513-519.
19. Soucie, J. Michael, John F. Neylan, and William McClellan. "Race and sex differences in the identification of candidates for renal transplantation." American journal of kidney diseases 19.5 (1992): 414-419.
20. Thamer, Mae, et al. "US NEPHROLOGISTS’ATTITUDES TOWARDS RENAL TRANSPLANTATION: RESULTS FROM A NATIONAL SURVEY." Transplantation 71.2 (2001): 281-288. https://www.researchgate.net/pro...
21. Segev, Dorry L., et al. "Age and comorbidities are effect modifiers of gender disparities in renal transplantation." Journal of the American Society of Nephrology 20.3 (2009): 621-628. Age and Comorbidities Are Effect Modifiers of Gender Disparities in Renal Transplantation
22. Young, Lynne, and Maureen Little. "Women and heart transplantation: an issue of gender equity?." Health care for women international 25.5 (2004): 436-453.
23. Aaronson, Keith D., et al. "Sex differences in patient acceptance of cardiac transplant candidacy." Circulation 91.11 (1995): 2753-2761. Sex Differences in Patient Acceptance of Cardiac Transplant Candidacy
24. Myers, Robert P., et al. "Gender, renal function, and outcomes on the liver transplant waiting list: assessment of revised MELD including estimated glomerular filtration rate." Journal of hepatology 54.3 (2011): 462-470.
25. Thuluvath, P. J., et al. "Liver transplantation in the United States, 1999–2008." American Journal of Transplantation 10.4p2 (2010): 1003-1019. https://deepblue.lib.umich.edu/b...
26. Alspach, JoAnn Grif. "Is there gender bias in critical care?." Critical care nurse 32.6 (2012): 8-14. Is There Gender Bias in Critical Care?
27. DeBakey, Michael E. "Left ventricular bypass pump for cardiac assistance: clinical experience." The American journal of cardiology 27.1 (1971): 3-11.
28. Kelly, W. D., et al. "Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy." Surgery 61.6 (1967): 827-837.
29. Kittleson, Michelle M., et al. "Donor–recipient sex mismatch portends poor 10-year outcomes in a single-center experience." The Journal of Heart and Lung Transplantation 30.9 (2011): 1018-1022.
30. Gratwohl, Alois, et al. "HY as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study." The Lancet 372.9632 (2008): 49-53.
31. De Vera, M. E., et al. "Liver Transplantation Using Donation After Cardiac Death Donors: Long‐Term Follow‐Up from a Single Center." American Journal of Transplantation 9.4 (2009): 773-781. http://www.custodiol.com/hansjb/...
32. Kobashigawa, J. A., et al. "Pretransplantation risk factors for acute rejection after heart transplantation: a multiinstitutional study. The Transplant Cardiologists Research Database Group." The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12.3 (1992): 355-366.
33. Jarcho, J., et al. "Influence of HLA mismatch on rejection after heart transplantation: a multiinstitutional study. The Cardiac Transplant Research Database Group." The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 13.4 (1993): 583-95.
34. Lones, Mark A., et al. "Clinical-pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients." The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 14.1 Pt 1 (1994): 151-162.
35. Kubo, S. H., et al. "Risk factors for late recurrent rejection after heart transplantation: a multiinstitutional, multivariable analysis. Cardiac Transplant Research Database Group." The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 14.3 (1994): 409-418.
36. Michaels, Paul J., et al. "Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease." The Journal of heart and lung transplantation 22.1 (2003): 58-69.
37. Patel, Nishant D., et al. "Impact of donor-to-recipient weight ratio on survival after heart transplantation analysis of the United Network for Organ Sharing database." Circulation 118.14 suppl 1 (2008): S83-S88. Impact of Donor-to-Recipient Weight Ratio on Survival After Heart Transplantation


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