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The Disputed Death of an 8-Year-Old Whose Organs Were Donated

The hospital used a once-controversial but increasingly common donation procedure.

This is the part everyone agrees on: A 8-year-old boy died at Ronald Reagan UCLA Medical Center in August 2013. His liver and kidneys were donated for transplant.

The Los Angeles Times reports police are now investigating exactly how he died at the hospital. The boy—though not technically brain dead—had suffered so much brain damage after a near drowning that doctors determined he would never wake from a coma. So his family decided to take him off life support and to donate his organs.

A doctor gave him a dose of fentanyl after his ventilator was removed. She says it was to ease his suffering. But a county coroner who later examined the boy’s body says it was the fentanyl that killed him, raising the question of whether a fatal dose was meant to quicken his death and keep his organs more viable for donation. The coroner has since filed a lawsuit alleging retaliation from her bosses when she relayed these concerns.

This unusual case casts light on a once-controversial but increasingly common protocol called “organ donation after circulatory death,” which occurs after the heart has stopped. (Also sometimes called “donation after cardiac death,” or DCD.) In contrast, the vast majority of organs in the U.S. come from donors who are brain dead.

Brain death is in some ways a logical standard for organ donation because it resolves an inherent paradox: The donor must be dead, but the organ itself alive. People who are brain dead generally have no reflexes; with life support, their organs stay healthy up until the moment they’re removed for transplant. A Harvard Medical School committee first proposed the idea of brain death in 1968 —in part to resolve controversies about organ transplants— and it slowly gained acceptance. Less than one percent of people who die in hospitals are brain dead.

So in the 1990s, in response to long transplant wait lists, experts began pushing to expand the pool of potential donors. They advocated for the return of DCD, a protocol used in the early 1970s before brain death became widely accepted. In DCD, doctors remove ventilators from patients who have suffered severe brain damage but are not brain dead—like the boy in L.A.—and wait for them stop breathing on their own.

But the clock starts ticking as soon as the ventilator comes out. With every minute, the organs can deteriorate. Hearts and lungs from DCD donors are rarely viable. More resilient organs like kidneys and livers can survive 30 to 60 minutes. If the patient does not stop breathing within that time, the whole organ donation is called off.

The time pressure in DCD is part of the reason why critics have raised ethical concerns in the past. In 2007, a doctor in San Luis Obispo stood trial for attempting to hasten the death of a potential organ donor with morphine. The patient actually took seven hours to die. The doctor was eventually acquitted, but the case was a wake up call for transplant surgeons.

Over time, hospitals have refined their DCD protocols to avoid the appearance of conflict of interest. For example, doctors who care for patients are entirely separate from transplant teams who procure the organs. DCD now accounts for about 9 percent of all transplants in the U.S.

But parts of the protocol still vary hospital to hospital, because some ethical questions do not have clear answers. One issue is how far can doctors go to preserve organs before the DCD donor dies. Can they give heparin, a blood thinner, that aid preservation but does not benefit the patient? Can they stick a catheter into the patient, so their blood begins running through oxygenation machines as soon as possible after their heart stops?

These questions come up because doctors are supposed to act in their patient’s interest. “As long as a patient’s heart is beating they’re considered our patient,” says Jeremy Simon , an emergency doctor and bioethicist at Columbia University. One way to address these concerns, says Simon, is to obtain consent for these interventions from the patient or a surrogate beforehand.

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Patients taken off ventilators will often gasp for air. To alleviate the pain from “air hunger,” doctors will administer painkillers, though the medical profession establishes a bright line: The dose cannot be so big as to intentionally kill the patient. (Medical experts said it was difficult to determine whether the dosage was appropriate in the L.A. case based on the few publicly available details.)

“It’s a matter of public trust in the system,” Francis Delmonico, a transplant surgeon at Harvard Medical School, told T he New York Times in 2009. If patients believe doctors are euthanizing patients for their organs, the country’s already low organ-donation rate could only go down.

That Times story also profiles a family whose daughter died after an unsuccessful attempt at donating her organs through DCD. It captures the heartbreak of the moment and the uncertainty inherent to the process:

Paul has some difficulty understanding why, if Jaiden was going to die anyway, she could not have been put under general anesthesia, undergone surgery to donate her organs, and then been declared dead. Removing the breathing tube to attempt D.C.D. had the same effect, only it took much longer and Jaiden breathed irregularly for many hours, which seemed to Paul more distressing. “If it was all up to me,” he explained, “I would have said, ‘Take her organs.’ ”

For these reasons, Robert Truog and Franklin Miller, an anesthesiologist and a bioethicist respectively, have proposed in T he New England Journal of Medicine to do exactly that. The proposal hasn’t gained much traction in the medical community though. “Truog and Miller’s proposal is still very controversial as a point of academic debate, says Armand Antommaria, a doctor and ethicist at Cincinnati Children’s Hospital Medical Center. It’s not even discussed in the realm of official institutional policy.

But brain death was once a controversial idea, too. DCD went from standard practice to controversial idea to standard practice again. Over the decades, advances in medicine have stretched out the gap between life and death. Organ transplants, by necessity, can only exist in that gap. And the very rise of organ transplant has influenced where the boundaries of it are drawn.

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Case Study – Family Opposition to Organ Donation Despite First Person Consent

Print this case study here: Case Study – Opposition to Organ Donation

Case Study: Family Opposition to Organ Donation Despite First Person Consent

By Tarris Rosell, PhD, DMin, 2011

JD is a 25-year-old patient who sustained massive head trauma and neurological injury in a motorcycle accident. He is not brain dead, but after 4 weeks in MICU and several neuro consults, the prognosis for “meaningful recovery” is said to be less than 1%. JD has not regained consciousness and is apt to remain permanently in a vegetative state.

His parents are attentive and religious. After consulting with their priest and their son’s doctors, including palliative care specialists and a hospital ethicist, they decide to withdraw ventilator support and tube feedings and “to allow whatever happens to happen.” The parents say they are “placing JD in God’s hands now.” A decision is made to withdraw life support that very evening since the priest is there with them and extended family members have gathered, also, some from long distances.

With palliative care involved and since death is anticipated soon after extubation, the MICU nurse manager already had notified the regional organ procurement organization (OPO) for assessment of donor potential. When the OPO representative arrives, she discovers that JD’s driver’s license has a little heart and “organ donor” stamped on the front. The backside is scuffed so as to make illegible any signature or date that might have been there. He had not signed up for the online state donor registry and has no healthcare directives on file. Yet on the basis of his driver’s license, it’s determined that JD had authorized donation, a “first person consent,” leaving no record of revocation or refusal of authorization.

The state’s recently revised Uniform Anatomical Gift Act states that, “in the absence of an express, contrary indication by the donor, a person other than the donor is barred from making, amending, or revoking an anatomical gift of a donor’s body or a part if the donor made an anatomical gift . . .. [194.240. 1]

Although JD is not brain dead, he might qualify to be a donor under the hospital’s “Donation after Cardiac Death” protocol. Further evaluation of the potential donor may take several hours, including tissue testing, reviewing the medical record, external communications, and the medical history interview with next of kin. It is already close to 9:00 p.m. when the OPO approaches JD’s family about the donation evaluation that has been ramped up following the parents’ decision to withdraw life support. They had intended that the ventilator be withdrawn an hour ago but were told by MICU staff that they need to wait for some other healthcare personnel to arrive. Per contractual agreement with the OPO, only their representative is allowed to discuss organ donation with families, and MICU staff have been compliant.

When the OPO representative, with a palliative care physician, ushers the parents into a small conference room, she asks if they are aware that JD’s wishes had been to donate organs and tissue to help others. His parents appear startled and say, “No, we never discussed such things as a family. And we don’t want to talk about it now. Please, ask us what you need to, but quickly. We need to go be with our son in his last moments on this earth. As to removing his organs, we will not permit that. He has suffered enough cuts and needle sticks and bruises. Please let us alone with him now.” Soon they get up and leave the room.

The OPO representative does not follow the parents back to the bedside but goes immediately instead to the attending physician. She and the palliative care physician report what happened with JDs parents and review with staff the hospital’s policies on DCD and First Person Consent Opposition. She also cites state law: “When a hospital refers an individual at or near death to a procurement organization, the organization may conduct any reasonable examination necessary to ensure the medical suitability of a part . . .. During the examination period, measures necessary to ensure the medical suitability of the part may not be withdrawn unless the hospital or procurement organization knows a contrary intent had or has been expressed by the individual . . ..” [194.265. 3]

Meanwhile, JD’s family has come looking for his doctor, wondering why it is taking so long to proceed with their decision to remove all the machines and “get out of God’s way.”

Question for discussion

What ought to happen next—and on what moral grounds?

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Home > Books > Organ Donation and Transplantation - Current Status and Future Challenges

Organ Donation and Transplantation: “Life after Death”

Submitted: 13 November 2017 Reviewed: 03 April 2018 Published: 25 July 2018

DOI: 10.5772/intechopen.76962

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Organ Donation and Transplantation - Current Status and Future Challenges

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Organ donation is defined as giving an organ or part of an organ to be transplanted into another person. Organ transplantation is the only option to save lives in patients affected by terminal organ failures and improve their quality of life. However, there is a disparity exists between the supply and demand of donated organs, leads to a loss of many lives. The number of organ transplantation have gradually increased in the last two decades and provide excellent results in children and young adults, and are challenging by the growing proportion of elderly transplant patients with co morbidity. The results of organ transplantation continue to improve, as a consequence of the innovations and the improvements in peri-operative management. This chapter describes organ donation and transplantation and its trends and challenges.

• organ donation
• psychosocial

Author Information

Kanmani job *.

• Amrita College of Nursing, Amrita Vishwa Vidyapeetham, Kochi, India

Anooja Antony

*Address all correspondence to: [email protected]

1. Introduction

Organ donation is defined as giving an organ or part of an organ to be transplanted into another person. Organ transplantation is the only option to save lives in patients affected by terminal organ failures and improve their quality of life. However, there is a disparity exists between the supply and demand of donated organs, leads to a loss of many lives. The number of organ transplantation have gradually increased in the last two decades and provide excellent results in children and young adults, and are challenging by the growing proportion of elderly transplant patients with co morbidity. The results of organ transplantation continue to improve, as a consequence of the innovations and the improvements in peri-operative management.

Organ transplantation currently depends on the availability of human organs. Their scarcity means that there is a waiting list of almost 63,000 in the European Union, and over 100,000 people in the United States according to the recent survey. The process of obtaining organs for donation and transplantation purely depends on the resources of health services and by health professionals’ performance in potential donor identification and management tasks. However, in accordance with the current legislation it is mainly subjected to a personal or family decision, strongly mediated by psychosocial processes. Therefore, the need to analyze and intervene both in the practices of the professionals involved in the process of organ generation and in the attitudes of the general population need to stressed and addressed [ 1 , 2 , 3 , 4 , 5 ].

2. Organ transplantation and organ donation: an overview

Organ transplantation involves the surgical implantation of an organ or section of an organ into a person whose own organ is failing. The donor organ may come from both deceased individual as well as from a living donor. The patients psychological and behavior aspect as well their emotional response and mental health and adherence to medical regimen should be assessed before and after organ transplantation. The living donor’s psychological response towards organ donation (most commonly for kidney and liver segment transplantation) is an important aspect to consider in the transplantation process.

Organ donation is defined as “giving an organ or part of an organ to be transplanted into another person” (Organ procurement of Transplant Network (OPTN), 2015), organ donation has the potential to save lives. The organs donated from one single donor can save up to eight lives. Organ transplantation may be one of the options left to sustain someone’s life. However, the disparity that exists between the supply and demand of donated organs, leads to a loss of many lives. Based on recent OPTN data, approximately 21 people will die each day while waiting for a transplant in the United States (US). Currently, 123, 358 people are awaiting organs and on the transplant list in the US with this number growing and the number of donated organs declining.

Asian Indians are more likely to have higher rates of having obesity and diabetes when compared with other Asian subgroups which make them at an increased risk of needing a donated organ [ 35 ]. These conditions can lead one to develop coronary artery disease and hypertension which then can lead to chronic kidney disease and other chronic illnesses. Patients who suffer from chronic kidney disease need regular dialysis which can ultimately lead them to organ transplantation to improve one’s quality of life. Also, conditions such as diabetes and obesity can be detrimental to one’s life and can lead to fatty liver disease which can lead to chronic liver disease requiring liver transplantation if the liver decompensates.

The development of organ transplantation in the second half of the 20th century has been a remarkable achievement. Recently; organ transplantation is one of the most effective options for those with an end-stage organ failure. Its success has been basically dependent on public awareness, support and active participation. Without these factors, the efficiency of organ transplantation and the consequent saving or extension of lives would have undoubtedly suffered adversely.

The number of patients in need of organ transplantation has increased at a rapid pace; in contrast, the number of available organs has increased only slightly. Expanded criteria for donor selection, such as older age, have resulted in more people who meet the criteria for brain death becoming organ donors although fewer organs are transplanted from each donor. Improvements in automobile and highway safety, as well as increased enforcement of gun control laws, have also contributed to a plateau in the number of young, healthy donors. Public education efforts that encourage organ donation may be effective in getting more people to sign organ donor cards, but most individuals who do so will never be in a position to become organ donors.

Faced with increasing numbers of patients who need transplantation, deaths on the waiting list, and a fixed number of available organs, some transplant programs are working to increase the number of transplants from living donors. Although living donation has always been an option for some types of transplants, many programs have been reluctant to promote it, as living donation requires invasive surgery on a healthy person with associated risks of morbidity and mortality. For example, since dialysis is an option for patients with end-stage renal disease, surgery on a healthy donor may be difficult to justify, despite the dialysis patient’s diminished quality of life.

The most important in organ donation is to maximize the psychological status and well-being of the donors before and after transplantation has become the foremost goal of all transplantation centres. The psychological issues that mainly concern with the living organ donation includes prevention of psychological harm, ensuring the donors are fully informed and decide to donate without coercion, monitoring donor psychosocial outcomes are intimately linked to the factors that historically served as barriers to use of organs from living donors. These barriers can be overcome by the motivating of the public and creating awareness and responsibility among oneself.

Organs that can be transplanted from the living donor includes one kidney, part of intestine, pancreas, islets of Langerhans, bone, part of liver, one testis, bone marrow and blood. The organ that can be transplanted from the deceased donor are heart, kidney, pancreas, stomach, hand, skin, blood vessels, lungs, liver, intestine, testis, cornea and heart valve.

Autograft: Transplanting a person’s tissues from one site and use it in another site of his body and is called autograft. For example, removal of skin from the legs and using it for damaged skin face or other exposed part.

Allograft: Transplant of an organ between two genetically non identical individuals, it is called allograft. Due to the genetic difference, the donor’s organ will be treated as foreign by the recipient and will try to destroy it. This is called s rejection.

Isograft: Transplant of organ/tissue from a donor to genetically identical recipient is called isograft. There will not be any immune response hence no transplant rejection.

Xenograft: Transplantation of organ/tissues forms one species to another species. For example, the heart valve of pig is transplanted successfully to human.

Split transplant: An organ like liver retrieved from the deceased donor can be divided between two recipients, usually an adult and a child.

Domino transplant: When the lungs are to be transplanted, surgically it is easier to replace them along with the heart. If the recipient’s original heart is healthy, it can be transplanted into another recipient in the need of one.

ABO incompatible transplantation: The immune system of young children aged below 12 months might have developed fully. They can receive organs from incompatible donors.

Live donors: A living person, mentally and physically healthy can donate one of a paired organ, part of an organ or a tissue. The organs donated are kidneys, part of live, one of the lung, part of small intestine, skin, bone marrow, one of the testis and one of the ovaries. Live donor can either be related or unrelated.

Unrelated donors: For altruistic reasons, a person can donate one of his organs to an unrelated donor. According to TOHO act, the unrelated donor should be known to the recipient and have some obligation to him. It has to be established that there is no monetary transaction between them. But in many other countries, even a stranger can donate one of his organs to a needy person on altruistic grounds.

Deceased donors: Organs are harvested from brain dead person whose respiration and circulation are maintained artificially. Brain dead has to be certified by a team of doctors nominated by Government I every organ retrieval centers.

Paired exchange: When a living donor is not compatible with the related recipient, but may be compatible for another recipient. That second recipient related donor is compatible to the first recipient, then permission can be granted for transplantation. The surgery for all four donors and recipient are conducted simultaneously and anonymity is kept until after the transplant.

Spousal donation: A spouse can donate an organ to the partner. It has to be recorded that the couple is legally married.

3. Current scenario: trends

Despite advances in medicine and technology, and increased awareness of organ donation and transplantation, the gap between supply and demand continues to widen. Each year, the number of people in the waiting list is increasing in both donor and transplant. The donation statistics according to OPTN Annual report shows that in 2016, total of 41,335 organs were donated. It can be either deceased or living and four out of five donations came from deceased donors and four out of ten from living donors. According to the report by OTPN 2018, 115,033 people need life-saving organ transplant, of those 74,926 people are the active waiting list candidates.

The real reason behind a living person’s interest in donating one’s organ is important to determine but it is often difficult. Now days, money has become the motivation for donation. The relationships also have played a great role in increasing donation rates. The shortage of available organs can be reduced if; people choose to donate their organs after they die. If more people did that the issue regarding organ shortage can be minimized.

The trend is expected to accelerate each year. Many organ procurement and the Joint Commission on Accreditation of Healthcare Organizations actively participate to increase the donation rates. The organizations take various to steps against traditional social taboos.

The approach, known as “donation after cardiac death” (DCD), usually involves patients who have suffered brain damage, such as from a car accident or a stroke. After family members have made the difficult decision to discontinue a ventilator or other life-sustaining treatment, organ-bank representatives talk to them about donation. Sometimes, the donor is suffering from an incurable disease also end up with the decision of organ donation.

According to U.S Department of Health and Human Services, more than 1,23,000 men, women and children currently needed life-saving organ transplants every 10 minutes and another name is added to the national organ transplant waiting list. In 2014, more than 8500 deceased donors made possible approximately 24,000 organ transplants. In addition, there were nearly 6000 transplants from living donors. In India, nationally with a population of 1.2 billion people, the statistics stands 0.08 persons as organ donor populations. Mrithasanjeevani, Kerala network of organ sharing which began in 2012, also states that the need for organ transplantation is high as the patients in waiting list is increasing day by day who requires organ transplantation.

The need for organ has gone up substantially all over the world. India also suffers from acute organ shortage with little to no solution for this issue. It is estimated that every year 1.5 lakh people suffer from renal failure out of which only 3000 people get donors. Similarly, every year around 2 lakh people die of liver failure or cancer and rarely get any help in the form of organ donors. It is the same for heart patients, for every 50,000 heart attack patients there are only 15 hearts available for transplant. Therefore, there is an urgent need for widespread campaigns to spread awareness about organ donation in India and to bridge the gap between supply and demand. The numbers that are mentioned here are estimates and real numbers could be far more than this, it is scary because this means very few people get relief and get a second chance in life.

The main reasons for organ shortage in India are mainly ignorance and lack of knowledge. People are not well informed enough about the benefits of organ donation. Today social media and so many other forums can promote the positives of organ donation and how it will save so many lives if more people register themselves for organ donation. The reason for organ shortage is myth and superstition. Many people do not want to donate their organs even after death because of so many myths and superstition they are instilled with. People with existing medical condition or old people, who wish to donate, do not donate thinking they are not fit or eligible. Almost everyone can donate some part or the other unless you have any extreme medical condition.

The need for organ donation is necessary because out of the 1.5 lakh people who need kidney in India only 3000 people receive them, only 1 out of 30 people receive kidney and 90% of people in the waiting list die without getting any donor. Around 70% liver transplants are dependent on a live donor but 30% dependent on cadaver (corpse) donations. Hence, there is an urgent need to increase the organ donation rates and give a person a second chance in their life.

4. Challenges in organ donation

As far as the challenges concerned it includes mainly donor’s motives for donation, the predominant ways in which donors arrive at the decision to donate, and the donors’ psychological status and its relationship to their fitness as donors.

4.1. Pre-donation challenges

4.1.1. donor’s motives.

Most donors are likely to be motivated by multiple factors. These factors include intrinsic factors (e.g., desires to relieve the suffering of another or to act in according to the religious convictions) and extrinsic factors (e.g., the social pressures or perceived norms) that may operate simultaneously. The particular combination of motivational forces will also differ depending on whether and how the donor is related to the recipient.

Among living related donors, it has long been assumed that family members or emotional partners are motivated primarily for saving the lives of their loved ones. Such motives are indeed the most commonly expressed feelings, as noted in a variety of studies over the past 30 years. Among nondirected living donors (individuals donating to unrelated patients whom the donors did not select)(NDLDs), it was identified as the altruistic/humanitarian motives, along with beliefs that the donor’s self-worth would be improved, and feelings of moral and religious obligation or self- identity.

4.1.2. Donor’s decision-making

The motivation for the organ donation is purely on the donor’s decision of organ donation and it may be influenced by many factors including the relationship to the recipients. Decision-making swiftness may indicate the type of decision being made. There appear to be two decision-making approaches that include the moral decision making and the rational decision making. “Moral decision-making” involves awareness that one’s actions can affect another; ascription of responsibility to oneself; acceptance of the social/moral norm governing the behavior; and taking action consistent with that norm. Because moral decision-making does not involve the costs and benefits of a given behavior but, instead, is based on perceived norms governing that behavior, it is likely to lead to non- deliberative, instantaneous decisions. In contrast, “rational” decision-making includes various steps that focus on gathering relevant information, evaluating alternatives, selecting an alternative, and implementing the decision.

4.1.3. Support

It includes mainly the assessment of the donor’s available physical, financial and emotional support. It is necessary to identify whether the donor have someone to provide care in the recovery period, have sufficient financial support and so on. This important to avoid distress if the donor develops any complications. Finally, does the donor have the support of significant others for being a donor, or is he or she choosing to donate over the objections of persons who have a legitimate interest in the outcome of an autonomous decision.

4.1.4. Family attitudes toward donation

Spouse and family attitudes about donation should also be explored. Collateral interviews with significant others is necessary, especially those who will be providing tangible support to the donor during the recovery period, should be conducted whenever possible. Conflicts between potential donors and significant others should be addressed and, ideally, resolved prior to surgery itself in order to avoid conflicts later. Family members should provide a good understanding of the donor’s wishes and motives, even if they agree to disagree to the donor’s decision.

4.1.5. Behavioral and psychological health

The behavioral and psychological health of the donor should also be considered before donation. It is important to identify donor’s lifestyle is sufficiently healthy to reduce unnecessary risk for both donor and recipient. Many potential donors may have some unhealthy behaviors, such as moderate obesity or smoking. It is necessary to identify that there is sufficient time for the donor to reduce risks (e.g., lose weight, stop smoking). Moreover, it needs to be taken care of that the donor is emotionally stable to cope with stresses which may come up before, during, and after the donation. Hence it is important to identify psychological and behavioral status of the donor or else it may affect the quality of life.

4.1.6. Donor-recipient relationship

The relationship between the donor and recipient is a complex matter. Even when both parties are agree for donation and transplant, family dynamics may be complicated, and other family members may assertively involve themselves in the decision-making process. The donor may have unrealizable expectations that transplant will alter his or her relationship with the recipient. The health care team should not expect an ideal relationship in which all interactions between donor and recipient are harmonious. However, obvious tensions and overt psychological issues should be addressed. Joint interviews, involving both donor and recipient, should be avoided early in the evaluation process in order to preserve privacy and give the potential donor the opportunity to express reservations or “opt out” gracefully.

4.1.7. Diversity issues

Non directed donors may have diversity concerns that may affect the organ donation. The potential donors should be assessed for comfort with donation to recipients of different genders, races, religions, sexual orientations, nationalities, ages, underlying diseases, and lifestyles. Donors who express objections, fears, or concerns about who might receive their organ may need to be deferred until they can receive counseling.

4.1.8. Psychological status of potential donors

The potential donor’s psychological status is of greatest concern for donation and transplantation. Concerns have been particularly high in case of unrelated donation (either directed to a specific patient, or NDLD): the willingness or desire to donate to a stranger has been historically viewed with suspicion and as likely to reflect significant psychopathology. There is no doubt that some potential donors will be psychologically poor candidates to serve as donors.

4.1.9. Post-donation challenges

The donors’ perceptions of their physical functional, psychological, and social well-being were found to be either nonsignificantly different from or significantly better than levels reported in the general population. The post challenges mainly includes recipient death or graft loss, donor medical complications, donor history of mood or other psychiatric problems, and poor donor relationships with recipient or family. The other factor is that it may affect the donor’s quality of life if any complication arises.

The post transplantation challenges are many which include minimizing rejection risks, immunosuppression, organ shortage, handling of the stressors of transplantation, psychosocial adaptation and psychological disorders and so on.

4.1.10. Minimizing rejection risks

The twin conditions of antibody sensitization and antibody-mediated rejection remain challenging and frustrating to treat. The recent drugs which are used to desensitize patients or reverse antibody-mediated rejection, especially chronic antibody mediated rejection is totally unsatisfactory. Development of therapies those are more effective and less toxic should be made available. Recent regimens used for antibody desensitization and reversal of antibody-mediated rejection include plasmapheresis, immunoglobulin (IVIG), and rituximab, an anti-chimeric, anti-CD20 antibody. Recently, the proteasome inhibitor Velcade has also been reported to reverse refractory antibody rejection. Eculizumab, a humanized anti-C5 monoclonal antibody appears to protect the renal allograft despite the presence of donor-specific antibodies (DSA). None of these agents have been tested in rigorous studies.

4.1.11. Immunosuppression

This is one of the major challenges after organ transplantation. Many studies have suggested that most of the late graft loss occurs because of immunologic reasons, frequently antibody-mediated. So the approach of minimizing immunosuppression is necessary with the present drugs to reduce toxicities may actually be helpful in the long-term survival of the graft. The toxicities are minimized by allowing more grafts to be rejected by immune mechanisms. Hence, development of effective agents that lack long-term toxicities so that we can maintain optimum immunosuppression over the long-term.

4.1.12. Stressors after transplantation

In the perioperative period, the focus is on the patient’s physical recovery, with possible rejection episodes and other medical complications causing anxiety and emotional strain. Within the first days after transplantation, a postoperative delirium can occur. The patient can present with symptoms of mental confusion, language disturbances, and occasional hallucinations and delusions are often a frightening experience to patients and their families. Acute brain dysfunction can occur in intensive care patients and patients after surgery. The corticosteroids which are administered for immunosuppression cause these problems. Some of the patients experience problems in accepting the new organ from another individual and suffer with feeling of guilt towards the donor which, in turn, can increase psychological stress and nonadherence [ 6 , 7 , 8 , 9 , 10 , 11 ].

In the long-term postoperative period, medication side effects and associated comorbidities become central stressors impeding patient’s life quality. Most common comorbidities seen are infections, diabetes mellitus, hypertension, lipometabolic disorders, adipositas, cardiovascular diseases, oncological diseases, osteoporosis, and chronic kidney failure [ 12 , 13 ]. Furthermore, psychiatric symptoms (e.g., depression, anxiety, agitation, psychosis) and neurological symptoms (e.g., sleep disturbances, cognitive impairment, delirium) can occur as neurotoxic side effects in patients receiving immunosuppressive drugs.

Faced with the multiple health risks, patients often continue to experience anxiety and worries regarding possible retransplantation, serious comorbidities, and death. Even patients in good physical health are confronted with severe challenges, for example, regaining their previously lost or restricted social roles as family members and partners (including sexual activity) and returning to work or taking up other meaningful activities. Financial constraints and legal disputes with health or pension insurance agencies constitute other possible sources of psychological strain.

5. Psychosocial adaptation and psychological disorders

After the transplantation, the psychosocial burden more severe in preoperative period than postoperative period. Nevertheless, patients themselves have to demonstrate considerable coping skills. In the best case, transplant patients learn to adapt to their new situation, often by reevaluating life goals and by focusing on more positive consequences, for example, personal growth. On the other hand, unsuccessful readjustment can lower the quality of life and psychiatric morbidity. The most common psychological disorders among patients before and after transplantation are affective and anxiety disorders.

The literature review shows that prevalence of depression in 20–25% of cases before and after kidney transplantation. Less information is available concerning patients receiving other organs. Prior to and following lung transplantation, depression seems to be prevalent in approximately 30% of patients. Hence these show that the depression is a major challenge after transplantation. These issues can be reduced by personal and social resources (resilience factors), that is, favorable coping skills, self-efficacy, sense of coherence, optimism, and social support.

6. Factors affecting donor’s motivation

There are many factors affecting donor’s motivation which includes feelings of love and responsibility, spiritual motives, and greater success rate of organ donation.

6.1. Feelings of love and responsibility

Motives for donating organ to their relative patients were that they tended to do something for their loved ones. In fact, they feel responsible for their problems. They do not treat others’ problems with indifference and attempted to do whatever they could for resolving the problems experienced by transplant recipients. It is considered as their own responsibilities to help them to get rid of their problems. The feel like they are the ones who need to support their patients.

6.2. Close and constant companionship

Another factor affecting the participants’ feeling of responsibility for donation to their family members was close and constant companionship with recipients. This close and constant companionship made the participants to clearly understand the recipients’ conditions and hence, it had resulted in their decision on organ donation in order to alleviate recipients’ problems. This close and constant companionship with patients help family members understand patients’ problems well and increase their degree of commitment to do something for patient’s pain and discomfort. They also noted that this had made them experience deeper shared emotions with their patients and hence, required them to feel responsible for minimizing their patient’s problems.

6.3. Inability to tolerate recipient’s discomfort

Another motive for organ donation was one’s difficulty in tolerating recipient’s discomfort. Love for their sick family members had made the participants feel responsible and decide on doing something for solving their patient’s problems. Their patient’s pain, suffering and discomfort cause a great inconvenience and irritation which lead them to the decision of organ donation. They hoped that organ donation alleviate their patient’s problems [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 36 ].

6.4. Spiritual motives for donation

Religious beliefs played a significant role in motivating to organ donation. Some of them believed that donation was a way for expiating their past sins. They referred to faith in God, reliance on Him, and hope for a successful transplant as the important motives for organ donation. Some of them even accused themselves of causing their family members to develop organ failure and believed that donation was a way for alleviating their feelings of guilt. Such a practice was particularly common among the parents of sick children. Some of them considered donation as a God-approved practice, and noted that God has helped them donate their organs. They noted that they donated their organs for gratifying God and believed that he sees it and help them in all bad situations.

6.5. Greater success rate of organ transplantation

The category is the greater success of organ transplantation. In other words, obtaining information and realizing the greater benefits of organ transplantation had motivated the participants to opt for organ donation. Some of them reported that they had never thought about donation until obtaining information from their patient’s physicians. However, after obtaining adequate information, they had made an irreversible decision about organ donation. Accordingly, a major motive for organ donation was the lower likelihood of organ rejection.

7. Measures to overcome challenges for organ donation

The decisions regarding organ donation based on the personal beliefs (religious, cultural, family, social and body integrity) levels of knowledge about organ donation and previous interaction with the health care team. Many maintained positive attitudes to organ donation despite significant reservations about the organ donation process. Resistance to organ donation found to be less in the case of living donation for family.

There are some religious beliefs that can have both positive and negative influences, these often stemmed from uncertainty or misrepresentation of religious edicts. One solution would be to actively engage religious leaders in the transplant community, especially when it has been reported that, across the major religions, there are very few cases where organ donation can be seen to be inconsistent with religious beliefs. Religious leaders should be made available in hospitals and other transplantation setting to assist families in making decisions regarding organ donation and potentially to remove the misperceptions. Staff members who are involved in approaching families to request consent for donation should be part of the awareness programs and resources about religious concerns. Similarly, cultural sensitivity to issues such as apprehensiveness to discuss death among certain groups or individuals and the importance to many of death rituals may improve dialog regarding organ donation.

Studies have shown that engaging some minority groups in the health care system and creating a sense of belonging and ownership can improve compliance with organ donation. As a consequence, more efforts should be made to create positive interactions within the health care team members, especially for minority groups, to improve the organ donation rates. Although many of the studies have showed that higher socio-economic status and education were associated with a stronger willingness to be an organ donor. Some of the strong reservations held, even among those with generally positive views towards donation, such as concerns that agreeing to donation would discourage doctors from caring so much about saving their lives in case of an emergency or that it would result in the premature removal of their organs or indeed prevent them from having an open coffin at their funerals, are examples of very real barriers that can be readily addressed through information. Through a proper awareness and motivation the donation rates can be improved which can save many lives.

7.1. Psychological care

Psychological consultation is essential for all disease stages enabling patients to better cope with their extraordinarily stressful situation. A need for psychological care was found in up to 50% of transplant patients. Educational and supportive therapies are of utmost importance but also cognitive-behavioral interventions including relaxation techniques can also be considered. Less common methods like hypnotherapy and “Quality of Life Therapy” have also been utilized for overcoming the challenges.

Moreover, family members as well as caregivers of transplant patients show increased psychological strain before and after transplantation. Family counseling, and psychotherapeutic support, can help reduce psychological strain, thus also maintaining the valuable social support provided by care givers and family members of the transplant patient. Henceforth, the family and care givers should also be considered in psychosocial evaluation to overcome the problems.

7.2. Alternative methods to increase donation

In view of ethical, legal and political issues, it was deemed important to obtain some opinion about alternative methods to increase organ donation rates. Financial incentives were given to increase organ donation. Many in both donor and non-donor groups were given a reasonable incentive. Education and dissemination of information about donation and transplantation was important to increase organ donation rates. There was nearly universal agreement that implied consent (presumed consent) should not be tried. The use of financial incentives was not markedly opposed (some accepted the idea of funeral expense reimbursement), although there was not strong support either. In general, methods to increase organ donation had not been well thought out by either donors or nondonors indicating, perhaps, that the assumption of altruism or motivation is the best way to increase the donation rates.

8. Responsibilities of nurses in organ donation and transplantation

Organ and tissue transplant nurses need comprehensive and scientific knowledge. They include the evaluation and management of deceased donors, transplant recipients, potential donors or live donors, teaching and counseling of transplant recipients and live donors related to self-care management, healthy life and a peaceful death when this is imminent. This is important in order to improve the posttransplant quality of life.

Nurses have important role in the development of a successful transplantation program. They are key members of the team that works to deliver care to patients and relatives, through the use of technological, logistic and human resources, with a view to coordination, care, education and research on organ and tissue donation and transplantation. Therefore, the nurses need adequate knowledge on the principles of good ethical principles and should have resources available for them to assess patient’s risks and social issues related to organ transplants and donation. The researchers hope that the future studies will encourage further researches on the role and responsibilities of nurses.

9. Conclusion

The organ donation decision is a complex one, based strongly on personal beliefs. There are some factors, such as religious and cultural beliefs, that are seemingly intractable and are often cited as reasons for a refusal to donate. In this chapter, it is shown that these have often been found to be tied in with more complex issues such as a distrust of the medical system, misunderstandings about religious stances and ignorance about the donation process. Interventions to better engage the community, including disadvantaged and minority groups, to foster trust and provide information represent promising opportunities of promoting organ donation in the future.

Donor motives directly contribute to their decision to donate, is not uniform and is influenced by multiple factors. Majority of the donors were relationship oriented donor, whose major motives were desires to relieve the suffering & save the life of their loving ones. Creating awareness to the organ donation will directly influence the donor motives and willingness. By deriving the motives many more intervention to improve the willingness to be a living organ donor can be evolved. Recruitment of living donors represents a medical and moral responsibility. The possibility of organ removal from healthy donor to a recipient needs great inner motivation. Saving one’s life is divine.

The psycho social assessment must be made as a routine part of the nursing process. These assessments are meant to identify patients at risk for poor outcomes, provide guidelines for their management and improve the post-transplant quality of life [ 6 ]. “Because donated organs are a severely limited resource, the best potential, recipients should be identified. The probability of a good outcome must be highly emphasized to achieve the maximum benefit for all transplants” (OPTN/UNOS Ethics committee General Considerations in Assessment for Transplant Candidacy White paper-2010).

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Organ donation and transplantation.

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Case study: Living Kidney Donation - a real story

Living Kidney Donation - a real story

Meet Andrew, 52, and Chris, 50, a husband and wife who have first hand experience of the true gift that living kidney donation can be.

Andrew was given a shock diagnosis of Vasculitis in January 2016. The diagnosis followed weeks of Andrew feeling under the weather, which led to blood tests on a Friday and an urgent phone call on the following Monday to say Andrew's kidney function had dropped to 40%. An urgent appointment was secured at James Cook and blood tests at 2pm led to a call at 5pm to say Andrew's kidney function had now dropped to 20% and he needed to be admitted to hospital.

Andrew immediately started six months of intensive treatment including drugs, steroids and low grade chemotherapy. Clinicians performed a biopsy and at the end of the six months Andrew was given the news his kidneys were damaged beyond repair and he would gradually deteriorate.

Amazingly, Andrew remained at work in his role as a Senior Partnerships Manager at the Department of Work and Pensions full time for around 15 months. However, as an active person he was no longer able to cycle or play football due to his lack of energy and his social life was virtually non-existent. His energy levels reduced as his kidney function continued to fall until, over Christmas 2017 he had a Peritoneal Dialysis (PD) catheter inserted in case he needed dialysis ahead of a transplant, which was expected early to mid-2018.

Andrew's condition deteriorated further after the PD catheter was inserted and, because he was barely eating and lost half a stone in a few days, he was admitted to hospital. The hospital tried PD but the catheter had not had time to settle and an emergency neckline was required. At this moment in time he felt like everything was going wrong and it was the support of family and friends that kept him going. Andrew started haemodialysis three days a week and this helped to some extent, but unfortunately he wasn’t fit enough to return to work.

During this time, hospital staff explained to Andrew that he either needed a living kidney donor or to go on the organ transplant list. Andrew was told by staff he could ask family and friends if they were prepared to be tested and his wife Chris posted on Facebook and put herself forward to donate a kidney, as did several friends.

Chris and a friend came back as the best matches, and whilst Chris was always likely to be the one chosen to go forward, the friend had a historic blood disorder that made him less favourable to be a living kidney donor. Chris had to lose three and a half stone to donate her kidney but her dedication and determination ensured she lost the weight to allow the transplant to go ahead.

The transplant went ahead on 21 March 2018 at the Freeman Hospital in Newcastle.

Professor Caroline Wroe, Deputy Clinical Director at NIHR Clinical Research Network North East and North Cumbria and Consultant Nephrologist at South Tees Hospitals NHS Foundation Trust said: "As the Consultant who treated Andrew when he first presented with kidney disease I am delighted to see how well he is since Christine donated her kidney to him.

"Having a living kidney donor transplant offers kidney patients the best outcomes for health and wellbeing and Christine's generosity is life transforming. I wish them both the best of luck in the future."

We caught up with Andrew and Chris to talk about organ donation, their recovery and how they became involved with the Transplant Games...

So how was your initial recovery.

Andrew:  "The first few days after transplant went quite well for me. I only pushed the pain relief button once and managed with paracetamol and codeine most of the time. I was up and walking after a day but very sore and getting in and out of bed, putting on socks etc was not something I looked forward to!

"I had problems with the amount of fluid I was passing and they kept having to up my liquid intake, at one point I was drinking 4-5 litres as well as some by drip. Eventually they reduced my intake and the kidney quickly started to operate properly. After about a week I was sent home for the bank holiday weekend and only had to go back to be officially discharged which was great for me.

"I started to walk to aid my recovery and over the next two weeks found the pain started to lessen. I returned to work part-time at the end of May 2018 which was about nine weeks after the transplant and was back working full-time four weeks later.

"I also started to run and cycle a bit in August and was doing a good amount of exercise by October - including spinning classes! I trained for a Coast to Coast bike ride which I completed in May this year, 150 miles over three days and lots of steep hills, and am due to do a half marathon in September as part of fund raiser. My fitness is good now but not sure it is quite as it was, I am of course three years older!

Chris:  "In my initial recovery the morphine didn’t agree with me so I felt sick and was given a few different types of anti-sickness tablets after surgery and then had codeine for pain relief for the two days I was in hospital before I was sent home.

"From being sent home I did not take any more pain relief as it was discomfort I felt, rather than pain.

"I returned to work eight weeks after and following my return to work the main problem for me was tiredness, which lasted several months.

What were your first thoughts when you learned Andrew needed a transplant?

Chris  "There was no doubt in my mind, I knew I would get tested and as long as I was a match I would do it.

"I've always been on the organ donation register and before this process I hadn't realised how few people on the register can actually donate an organ.

"I'd encourage anyone who was considering donating an organ to go ahead, I received plenty of advice from donation coordinators at the hospital, they also stressed the risk but that never put me off. When I had my counseling interview it is quite a shock at first but there are always risks in life and it meant Andrew didn't have to join the list to wait for a suitable kidney."

Andrew:  "I recognise that it can be quite intimidating and daunting for some people where live donation is involved and is still a very difficult decision donating a deceased relatives organs. After two and a half years being ill and not being able to do much it has completely changed my life and I still can’t believe what Chris did for me, I can never thank her enough.

"I now have my life back and I/we can enjoy doing the things we always used to. Whilst it is always a hard decision it is something that does make a massive difference to somebody’s life."

How did you get involved with the British Transplant Games?

Andrew : "The Transplant Games were mentioned to me by Professor Caroline Wroe and then I made further enquiries myself.

"I have just returned from the British Transplant Games in Newport after competing, I played snooker and golf as well as running the 800 metres and the 5k donor run. I got a bronze medal in the 800 metres although there were only three of us in the race! I'm really pleased as the other two competitors are both club runners and I did knock 24 seconds off my training best - I probably needed a tougher training schedule but it's not always easy to fit around work!

"As this was my first year competing in the Transplant Games I did not qualify for the World Transplant Games in Newcastle this month but I am going to do the 5k Gift of Life run on the Sunday ahead of the games which I am very excited about."

Chris:  "I did the 5k donor run (not sure that run is the phrase I would use). The British Transplant Games were an inspiration for Andrew and I, especially seeing all the young children and the parents who had lost loved ones but had donated organs.

"We built a real team spirit in the Newcastle team and everyone made us very welcome, Vicky Horan did a great job as team manager and she has been through a tremendous battle herself."

Andrew:  "I'd encourage everyone to go along and enjoy it. Being able to take part is fantastic, and to everyone competing I encourage you all to think about where you were before, being able to take part now is a massive achievement.

"Participating also shows gratitude to your donor, so enjoy it and enjoy sharing the experience with others in same position as yourself. You are all in the same boat and will be made to feel welcome. The Newcastle team I was part of knew each other from previous years but they quickly made us feel part of the family and we have made a lot of new friends"

Chris:  "Good luck to everyone competing!"

Andrew and Chris are fundraising to support the North East Patients Kidney Association and the Renal Unit at James Cook University Hospital in Middlesbrough. To donate visit:  https://www.justgiving.com/crowdfunding/themudds

Karen and Mark’s story

Karen was able to support her husband's decision to be an organ donor, after he died suddenly.

"Mark was my life for 31 years and he was my passion" says Karen.

She agreed to support her husband's decision to be an organ donor after he died suddenly from a spontaneous, catastrophic brain bleed.

Karen and Mark had discussed organ donation several times before, so she knew what he wanted.

Mark went on to help eight people by donating his heart, liver, kidneys, lungs, pancreas, corneas and tissue.

It’s just an amazing feeling to think that my decision, because I knew what he wanted and I’ve honoured his wishes, has gone on to help all those people. Karen

Watch Karen and Mark's story

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205.6: Challenges of deceased organ donation in a low middle income country-A case study from Kerala, India.

Gracious, Noble 1,,2 ; S, Saranya 2 ; N, Visakh 2 ; PV, Aneesh 2 ; Kumar, Vinod 2

1 Nephrology, Government Medical College, Thiruvananthapuram, India.

2 Kerala Network for Organ Sharing, Government of Kerala, Thiruvananthapuram, India.

Kerala the southernmost part of India with a high life expectancy rate and maternal and child health indicators with a population of 34.8 million has shown a sudden growth in deceased organ donation after brain death and an equally abrupt decline.

The study aims to find out the reasons for rise and fall of donations from brain death. Donation after brain death in Kerala was spearheaded by Kerala network for organ sharing formed in 2012 by Government of Kerala to coordinate brain death certification, equitable organ allocation and ensure transparency with accountability in the entire process of donation after brain death. Before that, organ donation after brain death has remained sporadic although a legislation recognising brain death was in place as early as 1994. The observations made in the study is obtained by a qualitative study using purposive sampling of stake holders and conducting in depth interviews and focus group discussions. The newly created KNOS succeeded in creating a sudden increase in donation after brain death in initial years of its inception but soon it plummeted.

At one point of time Kerala topped India in term of deceased donation after brain death with 2.3 pmp while the national average was a meagren 0.08 pmp donors. The organ utilisation rate was also too good as show in the figure.

However, in 2016 media shed light on petition alleging abuses in brain death determination and the program suffered due to misinformation campaign and public loosing trust in the entire process. To regain the trust in the process Government introduced video recording for certifying death and insisted that a doctor working in a public hospital must be a part of certifying team. This action virtually stopped the brain death determination on neurological criteria in private hospitals. This obligations was badly perceived by professional in private sector and they took it as mistrust of the sector and disdain of their professional expertise. Along with that the hospital administrators felt that it could lead to their bad reputation and also there is a growing trust gap between public and private hospitals because of the cost involved in transplantation. In fact many donor families feel that the altruistically donated organs are used as profit making objectives for corporate hospitals as transplant surgeries do yield more money. This public perception may also have contributed to sharp decline in donation after brain death. In spite of Kerala having a high development index, the transplant is accessible mostly to the rich as public hospital transplant activity is sparse to nil. There was general agreement that lack of notification and certification as the single most hinderance in the pathway to donation.

The biggest barrier in donation after brain death is lack of uniform practice pattern in hospitals on brain death diagnosis, inequity in access to transplantation and the expense factor.

Luc P J Noel.

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• Case report
• Open access
• Published: 19 December 2019

At the heart of organ donation. Case reports of organ donation after cardiac death in two patients with successfully repaired AAST grade V cardiac injuries

• Paola Fugazzola   ORCID: orcid.org/0000-0002-6227-9276 1 ,
• Luca Ansaloni 1 ,
• Marco Benni 2 ,
• Alessandro Circelli 2 ,
• Federico Coccolini 3 ,
• Emiliano Gamberini 2 ,
• Andrea Nanni 2 ,
• Emanuele Russo 2 ,
• Matteo Tomasoni 1 &
• Vanni Agnoletti 2  

World Journal of Emergency Surgery volume  14 , Article number:  60 ( 2019 ) Cite this article

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Trauma victims could be an important source of organs. This article presents two cases of successful organ donation and transplant, after Maastricht category III cardiac death in patients with successfully repaired AAST grade V traumatic cardiac injuries.

Case presentation

The first donor was an adult patient with self-inflicted heart stab wound and non-survivable burn injury. The second one was an adult patient with blunt cardiac and abdominal trauma and an anoxic brain injury due to a car accident. The cardiac injury was promptly repaired in both patients. In the first case, adequate organ perfusion ante-mortem was achieved thanks to venoarterial extracorporeal membrane oxygenation and intensive care unit support. The above procedure allowed successful organ donation and transplantation even after Maastricht category III cardiac death. This is the first case reported where, for organ donation purposes, it was made necessary first thing to avoid the immediate death of the patient, due to a rare and frequently not survivable cardiac injury. The challenge of preserving organ perfusion, due to major burn injury effects, was faced afterwards.

Conclusions

The outcomes of these two cases suggest that a repaired heart injury should not be considered as an absolute contraindication to organ donation, even if it is associated with non-survivable major burns. Therefore, cardiac death could provide an opportunity for these kinds of patients to contribute to the pool of potential organ donors.

Trauma victims are an important source of organs. A recent review based on the US Scientific Registry of Transplant Recipients showed that trauma donors generally produce more organs and better kidneys per donor, than non-trauma donors. Furthermore, trauma donors are an extremely important source for all extrarenal organs, aside from the liver [ 1 ]. The reason could be that trauma donors are younger and healthier than their non-trauma counterparts. In addition to that, over the past three decades, the improvements in trauma systems, resuscitative methods, and ICU level care might have led to a decrease in multiorgan failure prior to death [ 1 ].

The great majority (84%) of trauma donors are head trauma patients [ 1 ] with neurologic determination of death. However, in response to an increased demand for organ procurement, non-heart beating or Maastricht category III cardiac death (DCD) have recently re-emerged as possible cases to expand the potential donor pool. It poses ethical challenges to include patients with fatal non-neurological conditions within the potential donor pool, especially in the context of end-of-life care, and medical problems. The challenges are set by severity of hypoperfusion and ischemic organ injury, as these two remain the dominant factors in influencing graft outcomes in these patients [ 2 ]. The proportion of DCD has increased in both trauma and non-trauma donors from less than 5% in 2000 to over 15% in 2016 [ 1 ].

Major burns have traditionally been considered a contraindication to organ donation. This is due to possible risks of splanchnic ischemic injury after burn shock, together with high risks of bacterial contamination and sepsis in burnt patients [ 2 , 3 , 4 , 5 , 6 ].

Here below, we present two cases of successful organ donations and transplantations after Maastricht category III DCD, with successfully repaired AAST grade V traumatic cardiac injuries (Fig.  1 ). The first donator was an adult patient with self-inflicted heart stab wound and non-survivable burn injury; the second one was an adult patient with blunt cardiac and abdominal trauma after a car accident and an anoxic brain injury.

AAST Injury Scale: cardiac injuries

Cases presentation

A 30-year-old male was admitted to the Emergency Department for a penetrating self-inflicted left chest stab wound, extensive (80% total body surface area, TBSA) full-thickness burn injury, and carbonization. During the pre-hospital phase, the patient was intubated and the initial resuscitation was performed through crystalloids infusion. He was transferred to the nearest “hub” Trauma Center by air ambulance. At the arrival, he was hypotensive (systolic blood pressure (SBP) 80 mmHg) and tachycardic (heart rate (HR) 150 bpm). The stab wound was in the left third intercostal space, medial to the midclavicular line. The chest x-ray showed a left hypertensive massive hemopneumothorax. An E-FAST was performed, but in the subcostal window, the pericardium was not assessable, probably because of the acoustic barrier caused by skin carbonization. A left minithoracotomy was performed and a chest drainage was put in place; this was followed by the immediate return of 3000 ml of blood and air. A thromboelastography (ROTEM) and an arterial blood gas test (ABG) were performed: pH 6.8, base excess (BE) − 22, lactates 14. Tranexamic acid 1 g, two units of red blood cells, and two plasma units were transfused. The patient was transferred to the operating room (OR) to perform a thoracotomy. During the resuscitation phase, the specialist carried out a burn evaluation. A very bad prognosis was determined due to the severity of the burn injuries.

In the OR, a clamshell incision was performed and a pericardial lesion was found. A pericardiotomy showed a left ventricular full-thickness injury (grade V according to OIS-AAST system). After placing a Foley catheter in the cardiac wound, a direct prolene and metal staples suture were performed. The Foley catheter was removed without residual bleeding. Bilateral chest drainages were put in place and the thoracic wall was closed (Additional file  1 ). A bilateral lower limb escharotomy was performed. After the procedures, the SBP was 120 mmHg, the HR 120 bpm, and the ABG test showed the following results: pH 7.28, BE − 8.9, lactates 12, Hb 8.9 mg/dL. Thereafter, it was applied a goal directed therapy of the coagulopathy according to ROTEM results.

The patient received continuous support in intensive care unit. Due to hemodynamic instability, venoarterial extracorporeal membrane oxygenation (V-A ECMO) was initiated. This procedure allowed to preserve organs, to allow appropriate family consultation and palliative care planning. During family discussions regarding end-of-life care, the feasibility of organ donation was raised.

The further resuscitation (Table  1 ) allowed confirmation of medical suitability (Table  2 ).

Death ascertainment took place 23 h after the arrival of the patient at the ED. The necessary procedures for DCD process for therapeutic transplantation purposes started only after the ascertainment of death with cardio-circulatory criteria and family approval.

Medical suitability for liver and kidneys donation was assessed by the Regional Reference Center for Transplants. Normothermic regional perfusion was started according to the standard procedure [ 7 ]. After the reperfusion phase, the liver was considered unusable due to ischemic injury. One kidney was not transplanted because of technical problems. However, one kidney was successfully transplanted.

A 47-year-old female was admitted to the Emergency Department for a blunt chest and abdominal trauma. Her car crashed against a bus near the Trauma Center. Her body was extricated with difficulties. During the pre-hospital phase, the patient had GCS 7, not detectable SpO2, and evident signs of hemorrhagic shock. She was quickly transferred to Trauma Center. At the arrival, she had a clear hemorrhagic shock. It was administered a rapid-sequence induction for emergency endotracheal intubation with Ketamine 100 mg and Succinylcholine 100 mg. A bilateral minithoracotomy was performed, but there was a rapid evolution in pulseless electrical activity (PEA). Chest X-ray showed an upper mediastinal widening and multiple broken rib fractures. The pelvis X-ray was negative. An E-FAST showed cardiac tamponade and fluid in the right abdomen upper quadrant. It was administered 1 mg of Adrenalin, and a resuscitative thoracotomy with pericardiotomy was performed together with circle restoration. A ROTEM and an ABG were carried out. Tranexamic acid 1 g, two units of red blood cells, and Fibrinogen 2 g were infused. Furthermore, she reported a right knee exposed fracture. The patient was transferred to the OR.

In OR, a clamshell incision was performed, and a blast full-thickness left auricle injury (grade V according to OIS-AAST system) was found (Additional file  2 ). A direct prolene suture was carried out. Internal cardiac massage and defibrillation (30 J) was required for rhythm restoration, due to onset of ventricular fibrillation. Sodium bicarbonate 8.4% 200 mL, calcium chloride 3 g, magnesium sulfate 1 g, and Amiodarone 300 mg were infused. It was also given noradrenaline infusion with target SBP 110 mmHg. After fluid resuscitation, due to the sudden appearance of abdominal distension, an urgent laparotomy with evidence of hepatic laceration and an abdominal packing was executed. A panaortography was carried out in the OR; it ruled out active bleeding. Having reached a partial hemodynamic stabilization, a temporary thoracic and abdominal closure was performed. During the surgical intervention, six units of red blood cells, two units of fresh frozen plasma, one unit of platelets, and Fibrinogen 1 g were infused. The patient was transferred to the Radiological Department to receive a total-body CT scan and, after excluding other immediately life-threating injuries, to the ICU.

The patient received continuous support in ICU (Table  1 ). Rapid hemodynamic stabilization and gradual improvements in respiratory exchanges took place. Due to the onset of acute kidney injury, CVVHDF was initiated. Seventy-two hours after the trauma, the patient underwent a surgical intervention of packing removal, definitive abdominal closure, pericardium plastic with porcine biological prosthesis (leaving an open upper window), and costal stabilization. Five days after trauma, the first neurologic window was made with a GCS of 6. A percutaneous tracheostomy was performed. Thirteen days after trauma, the following was observed: GCS 3t, myotic, isochoric, and non-reactive pupils, hypertonic lower limbs. An electroencephalogram and a brain MRI scan showed a diffuse hypoxic-ischemic damage. Sixteen days after trauma, the patient showed persistent GCS 3t, non-reactive pupils, presence of respiratory trigger, carinal reflex, and diffuse flaccidity. All the necessary neurological assessments have been performed in order to formulate a correct prognosis from the neurological point of view.

In light of the poor prognosis and after appropriate family consultation, a palliative care plan was initiated. During family discussion regarding end-of-life care, the feasibility of organ donation was raised.

Table  2 reports the clinical status of the patients before withdrawal of cardio-respiratory support.

The ascertainment of death took place 16 days after the arrival of the patient at the ED. After death ascertainment with cardio-circulatory criteria and following the non-opposition from the family, the necessary procedures for DCD process for therapeutic transplantation purposes were started.

The determination of medical suitability for the donation of the liver, lungs, kidneys, skin, and corneas was assessed by the Regional Reference Center for Transplants. Normothermic regional perfusion was started by positioning two femoral cannulas (venous and arterial) and aortic balloon in the contralateral femoral artery, according to the standard procedure [ 7 ]. The lungs were considered unusable due to the traumatic contusions. The liver and kidneys were successfully transplanted.

Discussion and conclusions

Cardiac trauma is one of the most lethal injuries. Autopsy reports suggest that severe cardiac injury may carry a prehospital mortality as high as 95% [ 8 ]. Mortality among those surviving to ED evaluation remains high, estimated at approximately 80% [ 9 ], and surgical intervention is associated with poor outcomes for atrial or ventricular injuries with mortality between 40 and 70% [ 8 ]. Mortality is higher in cases of left ventricular injury [ 10 ]. This article reports two cases of successful management of severe cardiac trauma. In both cases, the patient died due to the associated lesions (non-survivable burn injury in case 1 and anoxic brain injury in case 2). However, the surgical treatment associated with the optimal ICU management allowed to maintain an adequate organ perfusion ante-mortem which has, in turn, allowed the procurement of transplantable organs.

Current literature on organ retrieval in donors with severe burns is limited. It mainly relates to brain-dead donors (DBD), who died as a result of associated anoxic brain injury [ 3 , 4 , 5 , 6 ]. Widdicombe et al. reported two successful cases of organ donation and transplantation after Maastricht category III cardiac death, in adult patients with non-survivable burn injuries. Good outcomes were achieved for both cases [ 2 ]. DCD in burn injured patients raises medical challenges related to the potential risks of splanchnic ischemic injury following burn shock, together with a high risk of bacterial contamination and sepsis [ 2 , 3 , 4 , 5 , 6 ].

Furthermore, DCD poses some ethical challenges, as it directly affects the timing of withdrawal of cardio-respiratory support (WCRS). This is mainly due to donor evaluation requirements, potential recipient identification, and general logistics, in order to coordinate surgical and theater resources (2). For a DBD donor with non-survivable burns, interventional support is maintained after declaration of death, in order to enable donor evaluation and donation feasibility. While, for DCD donors, interventional support is required ante-mortem.

In the past, the risk of ischemic organ injury, caused by burn shocks, was the rationale for considering major burns as a contraindication to organ donation. With acute intensive care progresses and innovations, this contraindication has lost absoluteness [ 2 , 6 ]. As a matter of fact, the reported organ survival rates for major burned donors reached 86% [ 5 ] and the long-term outcomes are good too [ 4 ] (3). However, there is no published literature advising on early resuscitation in patients with non-survivable burns to facilitate organ donation, including fluid formulae and fluid type, use of adjuncts such as inotropes, optimal monitoring, and clinical endpoints. Moreover, there are no clinical nor laboratory indices able to determine a donor’s suitability in burns [ 2 ]. Furthermore, no clear indications are given about an optimal timeframe to retrieve organs from fatal burns donors, in order to reduce the development of severe systemic inflammatory response syndrome [ 2 ].

In our cases the V-A ECMO, together with the optimization of circulating volume during the 19 h in the ICU, allowed to maintain an adequate organ perfusion ante-mortem which has, in turn, allowed the procurement of a transplantable kidney.

Case 1 is the first reported where, even before facing the challenge of preserving organ perfusion from major burn injury effects, it was made necessary for organ donation purposes, to avoid the immediate death of the patient for a rare and frequently not survivable cardiac injury.

In case 1, the pericardial hemorrhage drained into the left pleural cavity, and resulted in a hemothorax without a cardiac tamponade. Clinical signs of cardiac tamponade were not present, and it was impossible to perform a US to evaluate the pericardium, because of the acoustic barrier caused by the carbonization of the skin. Therefore, this scenario prevented us from formulating a diagnosis of cardiac injury, before bringing the patient to the operating room.

In case 2, a cardiac tamponade was found.

It is a matter of debate whether the development of pericardial tamponade is a protective factor in cardiac injuries [ 10 , 11 , 12 ]. According to some authors, in the absence of pericardial tamponade, fatality rate is higher, as a diagnosis of heart injury can be more challenging [ 12 ]. In other studies, the presence of pericardial tamponade is a critical independent predictive factor for mortality in a multivariate analysis [ 10 ].

The outcomes of these cases suggest that trauma donors have a vital role in meeting organ demands. Consequently, trauma surgeons and intensivists, in particular, should consider the potential for organ donations, while evaluating and resuscitating even the most gravely injured patients. In this context, repaired heart injuries, even associated with non-survivable major burns, should not be considered as an absolute contraindication to organ donation. Furthermore, cardiac death provides opportunity for these kinds of patients, to contribute to the pool of potential organ donors.

Availability of data and materials

Not applicable

Abbreviations

American Association for the Surgery of Trauma

Arterial blood gas test

Base excess

Continuous venovenous hemodiafiltration

Donors after brain death

Donation after cardiac death

Extended focused assessment with sonography for trauma

Glasgow Coma Scale

Intensive care unit

Operating room

Pulseless electrical activity

Rotational thromboelastometry

Systolic blood pressure

Total body surface area

Venoarterial extracorporeal membrane oxygenation

Withdrawal of cardio-respiratory support

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PF analyzed and interpreted the patient data. MT took the video footage and did the video editing. PF, LA, and VA were the major contributors in the writing of the manuscript. LA, VA, PF, FC, EG, GS, MB, AC, AN, and ER participated in the patient management. All authors read and approved the final manuscript

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Fugazzola, P., Ansaloni, L., Benni, M. et al. At the heart of organ donation. Case reports of organ donation after cardiac death in two patients with successfully repaired AAST grade V cardiac injuries. World J Emerg Surg 14 , 60 (2019). https://doi.org/10.1186/s13017-019-0279-5

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Illegal organ trafficking is big business, and vulnerable people are at risk. Could an ethical organ trade solve this?

In the 1990s, there was a terrifying urban myth about a person going to a party, being drugged and waking up to find their kidneys have been snatched and traded.

At the time, organ donor programs were horrified about the false story. 

But in recent years, international organisations have become increasingly concerned about the "hidden" crime of the commercial trade in human organs. Many experts believe this is big business in some countries.

Vulnerable people, mostly in developing nations, sell their kidneys to patients, many of whom travel from more affluent countries such as Australia.

Reliable figures on the illegal trade are hard to track down but, in 2008, the World Health Organization (WHO) estimated 5 per cent of all transplants performed worldwide were illegal . And living kidneys — the organ most commonly in demand — are the most highly reported traded organ.

While it's commonly believed the illegal organ trade is underground, experts argue the opposite is actually happening.

"The trade is quite deeply embedded within the medical sector and other legal industries," Frederike Ambagtsheer, an organ trafficking researcher, criminologist and assistant professor at the Erasmus University Medical Centre in Rotterdam (one of the largest kidney transplant centres in Europe), tells ABC RN's Law Report .

"One cannot perform an illegal transplant without the involvement of highly specialised medical staff, infrastructure and equipment," Professor Ambagtsheer says.

Illegal trafficking rings

In March 2023, Nigerian senator Ike Ekweremadu and his wife were convicted in a high-profile case of organ trafficking when they attempted to purchase a kidney for their daughter.

"[Their daughter] was on dialysis in the UK, she was living there, she needed a kidney and they tried to traffic a prospective young kidney seller to the UK in order to harvest his kidney and have that be donated to their daughter," Professor Ambagtsheer explains. 

The case came to light when a Nigerian man from Lagos went to police saying he had been trafficked to the UK in order for his kidney to be harvested.

Senator Ekweremadu was sentenced under Britain's modern slavery act to more than nine years in jail. The senator's wife and doctor were also jailed.

While this case demonstrates the illegality of the organ trade, Dominique Martin, professor of health ethics and professionalism at Deakin University, says the majority of the trade is embedded within legitimate transplant programs.

"Each case is supposedly reviewed by a transplant ethics committee and approved as being legitimate and free of commerce," Professor Martin explains.

However, she explains, in most cases it's only when the individual selling the kidney goes to police that "it's revealed that there's been a trafficking ring taking place".

In recent years, Professor Martin says there have been several organ trafficking rings busted throughout India and the Philippines.

She says it's only occasionally that there are reports of more underground operations.

"There was a horrific report in Pakistan where there was a surgeon who was operating in private hotel rooms and houses, the person administering the quasi-anaesthetic to the patients was in fact a mechanic … but that kind of real backwoods stuff is the exception," she says.

What is being done to curb the trade?

Commercial trade in human organs is currently illegal in all countries except Iran .

However, there are no restrictions on Australians travelling overseas to receive an organ transplant.

"We don't currently have what they call extra-territorial jurisdiction covering the laws that in Australia prohibit trade in organs," Professor Martin explains.

For example, if an Australian was to illegally purchase an organ in the Philippines, they could be prosecuted there but not under Australian law.

Last year, a private members' bill focusing on Australians who travel abroad to buy organs was put before federal parliament .

"So the essence of the bill is that there would be a declaration that passengers coming into Australia would be required to make, attesting to whether they had received an organ transplant while they were overseas … in the past five years," Professor Martin says. 

The rationale behind this is that individuals would disclose if they had received a transplant overseas, which would prompt further investigation.

Professor Martin is sceptical of this approach.

"The first stumbling block [is] what would be the motivation for someone to disclose that information and how confident could we be that the majority were disclosing?" she asks.

An all-party parliamentary committee recommended the bill not be passed, instead calling on the federal government to deliver more public awareness campaigns.

Professor Martin believes a more effective approach would be to create a mandatory reporting system for doctors, which would focus on collecting data rather than information that identifies patients. 

This is an approach supported by both the WHO and the United Nations.

A 2019 study, led by the University of Adelaide, surveyed transplant professionals working in Australia. It asked them specifically about providing care to patients who had received transplants overseas.

More than half of the doctors surveyed had treated patients who had returned from overseas after having had a transplant.

Professor Martin points out the majority of patients who travel for transplants have done so legitimately. For example, they could be returning to their home country to receive a transplant and be cared for by family.

"Not all cases of travel for transplant actually involve organ trafficking," she says.

An ethical organ trade

Professor Ambagtsheer is focused on researching the most effective incentives to increase both deceased and living organ donations, specifically kidney donations.

"It might help to reduce the black market abuses within the organ trade but also help us increase the supply, so that there is less incentive on the black market for people to trade and sell," she says.

Professor Ambagtsheer also advocates for the exploration of an ethical organ trade. The main stipulation would be that "you never allow patients to pay".

She says the model would require anonymous donation and full government oversight.

"The government would be the institution that gives an incentive to kidney donors, so there is no transaction between donors and recipients …. I think that would be an ethical way of incentivising organ donations," Professor Ambagtsheer says.

She says the incentive would not necessarily be cash, but could instead be something like free health insurance.

However, Professor Martin is fundamentally opposed to the suggestion "on both ethical grounds and also practical grounds".

She says countries like Spain, a world leader in donation and transplantation rates, can provide better solutions.

"They've done that, not by relaxing the ethics or taking ethical shortcuts or exploiting people; [instead] they've had a government that's really invested in the donation program," Professor Martin says.

"They've had a really concerted effort to engage the community and they're doing a lot of interesting things in terms of optimising the recovery of organs from as many potential donors as they can."

Both Professors Martin and Ambagtsheer remain concerned for the welfare of those who sell their kidneys or other organs.

"They don't receive appropriate after care, they're very often cheated in terms of the money that they were promised and they experience all kinds of financial, physical and psychological distress because of the deception that we see inside these black markets," Professor Ambagtsheer says.

She says a criminal justice approach to reducing the illegal organ trade often results in the prosecution of the kidney seller as there is a reluctance to prosecute "the medical elite".

"I don't think that the system that we have in place is really serving those we are aiming to protect," she says.

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Mohap celebrates 1,000 organ donations by hayat program.

DUBAI, 13th August, 2024 (WAM) -- The Ministry of Health and Prevention (MoHAP) has announced that the National Program for Donation and Transplantation of Human Organs and Tissues (Hayat) has successfully completed 1,000 post-mortem organ donations since its inception in 2017. This milestone was made possible thanks to the integrated efforts of federal and local entities, as well as collaboration with the health and academic sectors, showcasing the UAE's leadership in organ transplantation. It reflects the significant progress made by the UAE's health system and aligns with the aspirations of the leadership as well as the "We the UAE 2031" vision, which aims to position the UAE prominently on the global stage.

Coinciding with World Organ Donor Day, 13th August, this achievement will support the UAE's steadfast commitment to being a role model for regional and global excellence. It is attributed to the non-stop government efforts seeking to raise awareness about the noble act of organ donation and the nation's robust capabilities, including skilled medical professionals, advanced health facilities, cutting-edge technological infrastructure, and strategic international partnerships with leading global institutions.

Hayat Program follows the highest international standards, forming a key part of the UAE's strategy to enhance the health sector's competitiveness on the global stage. Recently, the country hosted 11 visits from approximately 20 international experts to thoroughly review organ transplantation facilities. Such visits played a vital role in transferring knowledge, building capacity, and validating the readiness of the UAE's healthcare system and its specialised competencies.

This global recognition adds to the track record of achievements by the Hayat Program, which has been named the fastest-growing programme worldwide over the past five years based on performance improvements and high donor rates per million people. The UAE has achieved a remarkable 417% increase in organ donation and transplantation growth over the last five years, according to the Congress of the International Society for Organ Donation and Procurement (ISODP).

The programme's success also reflects significant progress in promoting organ donation culture among citizens and residents, reinforcing the values of sustainability, and contributing to the objectives of the Wellbeing Index.

The programme, which showcased community solidarity and tolerance, has provided patients in need of organ transplantation with renewed hope for a new life, leveraging the efficiency of the UAE's health system and its advanced human and technological capabilities.

During its meeting in May 2024, the General Assembly of the World Health Organisation adopted a series of recommendations for member states to build sustainable organ and tissue donation and transplantation programmes. Many of these recommendations have been incorporated into the new federal law, highlighting the UAE's proactive approach in adopting best international practices, such as health insurance coverage, international cooperation, and embracing innovations in the field.

The Ministry, in collaboration with partners in the health sector, regularly organises ongoing campaigns to educate the community about organ donation, highlighting how individuals can offer others a chance at life and ways to prevent organ failure diseases. Guided by a strategic vision and specialised programmes, the Ministry also takes part in exhibitions and community events to showcase the programme's benefits, in addition to sharing live testimonies from patients who have regained hope following successful transplants. This helps raise awareness among community members and both public and private institutions while taking advantage of the UAE's rapidly developing health infrastructure, which attracts global expertise.

Dr. Ali Abdulkarim Al Obaidli, Chairman of the National Committee for Organ Transplantation, emphasised that the "Hayat" programme is a national initiative designed to bolster the country's efforts in promoting organ and tissue donation in line with global practices, aiming to provide care for patients suffering from organ deficiencies. He highlighted that organ donation not only renews hope for patients and their families but also improves community health and individual quality of life, supporting the prevention of various organ failure diseases and promoting healthy lifestyles.

Dr. Al Obaidli added that the recent positive evaluations by international experts of the country's kidney transplant programmes, along with their praise for the world-class services provided, affirm MoHAP's commitment to excellence and reinforce the UAE's position as a regional and global leader in organ transplantation. He clarified that the ministry's licensed and specialised facilities for multiple organ transplants ensure life-saving treatments without the need for patients to travel abroad.

Dr. Maria Gomez, Director of the National Centre for Regulating Donation and Transplantation of Human Organs and Tissues at MoHAP, stated that "Hayat" programme is a collective achievement of various government bodies focused on streamlining organ donation and transplantation. She called on adults, both citizens and residents, to participate by registering their intent to donate organs, thus contributing to the prevention of diseases leading to organ failure and providing hope to those waiting for a transplant. Additionally, she encouraged people to learn from the inspiring success stories of both donor families and transplant recipients.

Dr. Maria Gomez added that "Hayat" programme has marked World Organ Donor Day with a ceremony held in collaboration with local health authorities and healthcare partners. This included a special event with Emirates Health Services and Fujairah Hospital designed to raise awareness and educate the community about the critical importance and role of organ donation in saving lives. Additionally, another event is planned in cooperation with the Dubai Health Authority to further these educational efforts.

The "Hayat" programme has seen 26,825 individuals register their willingness to donate. Of these, more than 255 have become donors. Importantly, one donor has the potential to save the lives of eight patients. Living donors can contribute kidneys and parts of their liver to relatives up to the fourth degree. They may also donate kidneys and parts of their liver to non-relatives. Post-mortem donors can donate vital organs such as the heart, liver, kidneys, lungs, pancreas, and parts of the intestine, in addition to tissues.

WAM 14th August 2024, 03:34 GMT+10

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ORIGINAL RESEARCH article

Causal associations between severe covid-19 and diseases of seven organs: a proteome-wide mendelian randomization study.

• 1 College of Mathematics and Computer Science, Zhejiang A&F University, Hangzhou, China
• 2 The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
• 3 Songyang County People’s Hospital, Lishui, Zhejiang, China
• 4 MobiDrop (Zhejiang) Co., Ltd., Tongxiang, Zhejiang, China
• 5 Zhejiang Provincial Key Laboratory of Ophthalmology, Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China

The coronavirus disease 2019 (COVID-19) pandemic poses an enormous threat to public health worldwide. Many retrospective studies and case reports to date have shown associations between severe COVID-19 and diseases of multi-organs. However, the research on the causal mechanisms behind this phenomenon is neither extensive nor comprehensive. We conducted a proteome-wide Mendelian randomization (MR) study using summary statistics from a Genome-Wide Association Studies (GWAS) of severe COVID-19 and diseases related to seven organs: lung, spleen, liver, heart, kidney, testis, and thyroid, based on the European ancestry. The primary analytical method used is the radial inverse variance-weighted (radial IVW) method, supplemented with the inverse variance-weighted (IVW), weighted-median (WM), MR-Egger methods. Our findings have confirmed the association between severe COVID-19 and multiple organ-related diseases, such as Hypothyroidism, strict autoimmune (HTCBSA), Thyroid disorders (TD), and Graves’ disease (GD). And we have also identified certain proteins that are associated with organ-related diseases, such as Superoxide Dismutase 2 (SOD2) and TEK Receptor Tyrosine Kinase (TEK), which are also considered potential drug targets. Phenotype scanning and sensitivity analyses were implemented to consolidate the results for Mendelian randomization. This study provides a compelling foundation for investigating COVID-19 caused diseases in future studies.

Introduction

During the COVID-19 pandemic, the global public health system has faced a significant crisis. Infection with SARS-CoV-2 is associated with symptoms such as chest pain, difficulty breathing, and muscle pain ( Ballering et al., 2022 ). According to a report from the World Health Organization on 9 August 2023, more than 760 million cases and 6.9 million deaths have been recorded globally since December 2019, but the actual numbers may be higher. Despite the effective control of COVID-19 effects post-vaccination, challenges persist ( Hall et al., 2022 ).

Davis et al.'s review details the severe impact of long COVID-19 on organs such as the lungs, heart, pancreas, kidneys, spleen, and liver ( Davis et al., 2023 ). Many patients present with multiple symptoms across multiple organ systems ( Davis et al., 2021 ). Therefore, elucidating the correlation between severe COVID-19 (very severe respiratory confirmed COVID-19) and organ-related diseases holds significant value for public health.

Mendelian randomization (MR) is an analytical method for testing causal relationships between exposures or risk factors and clinically relevant outcomes ( Davey Smith and Ebrahim, 2003 ). The impact of confounding variables and reverse causality on the precision of correlation discovery can be effectively reduced by Mendelian randomization. The number of publicly available Genome-wide association study statistics (GWAS) databases has increased in recent years, and Mendelian randomization is now widely applied in epidemiological research ( Ge et al., 2023 ; Kim et al., 2023 ).

In previous studies, most Mendelian randomization studies on COVID-19 have focused more on causal analysis between single-type diseases ( Li et al., 2022 ; Zhang et al., 2022 ). In this study, we systematically analyzed the association between severe COVID-19 and diseases related to seven organs, aiming to explore the causal relationship between severe COVID-19 and diseases in these seven organs. We used the significant single nucleotide polymorphisms (SNPs) in the severe COVID-19 phenotype as instrumental variables (IVs). However, due to the high false positive rate in MR analysis caused by the presence of numerous instrumental variables, and thanks to the irreplaceable role of proteomics research and the progress made in COVID-19 studies ( Bi et al., 2022 ; Babacic et al., 2023 ), there are now COVID-19-related proteomics datasets available for effectively screening strongly associated instrumental variables. We utilized multi-organ proteomics data from COVID-19 autopsies to screen for corresponding organ diseases before conducting two-sample MR to explore this causal relationship ( Nie et al., 2021 ). Through these analyses, we seek to gain deeper insights into the impact of severe COVID-19 on various organs, providing novel perspectives and treatment strategies for addressing COVID-19-related complications. Additionally, we utilized corresponding databases for drug target exploration and phenotype screening, and constructed Protein-Protein Interaction (PPI) networks.

Materials and methods

In this study, we used a two-sample MR analysis to explore the causal association between exposure and outcome and based on three hypotheses: first, there is a robust correlation between IVs and the exposure factor. Second, IVs are independent of confounding factors that are associated with the outcome. Third, IVs affect the outcome only through the exposure and not through any other mechanisms ( Lawlor, 2016 ). We used the phenotype associated with severe COVID-19 as the exposure. Then, we selected diseases related to seven organs (lung, spleen, liver, heart, kidney, testis, thyroid) as the outcome. The specific workflow of the study is illustrated in Figure 1 . In order to ensure the scientific validity and reliability of the MR analysis, we follow the STROBE-MR guidelines developed by Skrivankova (SAppendix 1) ( Skrivankova et al., 2021 ).

Figure 1 . Description of the study design in this MR study. SNPs, single nucleotide polymorphisms; IVs, instrumental variables.

Data sources

We have used the GWAS summary statistics of severe COVID-19 phenotypes compiled from the COVID-19 Host Genetics Initiative (HGI). ( Initiative et al., 2021 ) ( https://www.covid19hg.org/results/r7/ ), which have been widely utilized in previous studies ( Huang et al., 2022 ; Ge et al., 2023 ). The summary of the information for the corresponding data on severe COVID-19 is presented in Table 1 . GWAS summary statistics of seven organ-related diseases were then filtered from The FinnGen Consortium ( https://www.finngen.fi/en ), and the information for specific diseases is presented in Supplementary Table 1 . The proteomic data used to screen for organ-associated SNPs were obtained from Nie et al.’ study ( Nie et al., 2021 ). In this study, using tandem mass tagging (TMT)-based shotgun proteomics, they quantified 11,394 proteins and found that 5,336 of them were significantly dysregulated in at least one organ in COVID-19 patients (Lung:1606; Spleen:1726; Liver: 1969; Heart: 919; Kidney: 2227; Testis: 10; Thyroid: 1297) ( Nie et al., 2021 ). In our study, we directly downloaded the list of differential proteins provided by this research for subsequent analysis.

Table 1 . Description of the data involved in Mendelian randomization studies.

IV selections

We selected appropriate IVs for MR analysis from two different GWAS summary statistics through a rigorous series of screens to meet the three fundamental assumptions. Initially, a genome-wide significance threshold ( p < 5 × 10 −5 ) to select SNPs that are stably associated with severe COVID-19, and the reasonableness of this threshold setting has been confirmed in previous studies ( Ge et al., 2023 ).

The characteristic of Linkage Disequilibrium (LD) is the non-random correlation between two or more genetic loci with advantageous hereditary traits. r 2 > 0.001, kb > 10000 was set to screen the appropriate SNPs, thus reducing the impact of chain-imbalanced LD on the results. The threshold used in this study was determined by analyzing a large dataset including European genomes. Previous multiorgan proteomics data on COVID-19 autopsies were used to screen for SNPs for corresponding organ diseases that correlate with COVID-19 ( Nie et al., 2021 ). To ensure a strong association between exposure and outcome, we estimated the F-statistics to assess the strength of IVs, which is calculated by dividing the square of beta by the square of the standard error (SE). Strong IVs with F-statistics greater than 10 were used ( Burgess et al., 2011 ). Furthermore, we conducted phenotype screening of IVs to confirm the exclusion of confounding factors affecting the results.

Statistical analysis

In this MR study, we used radial inverse variance-weighted (radial IVW) and inverse variance-weighted (IVW) as the primary analysis method. The Radial MR method removes the corresponding outliers and reduces the effect of pleiotropy on the results ( Bowden et al., 2018 ). IVW assumes that all genetic variants can be used as valid instrumental variables. it is very stable in detecting causality and can provide impact estimates with significantly lower variance. The p -value of radial IVW less than 0.05 was then used as a screening criterion to screen out relevant diseases for the next analysis. Building upon the second-order weighted radial framework, the study also supplemented two additional methods, MR-Egger regression and weighted median (WM). The MR-Egger method was able to analyze the possible genetic pleiotropy of the IVs involved in the study ( Bowden et al., 2015 ). In MR-Egger regression, if the intercept term is zero or lacks statistical significance, the regression slope can be interpreted as the estimated causal effect of exposure on the outcome. The weighted median (WM) method can provide consistent causal estimates in the presence of numerical errors for half of the IVs ( Bowden et al., 2016 ). According to the standard of previous studies ( Freuer and Meisinger, 2023 ; Wang et al., 2023 ), it is generally believed that in a study, the radial IVW result less than 0.05 indicates statistical significance and suggests the presence of a corresponding causal relationship.

Then we evaluate the heterogeneity of IVs based on the second-order weighted radial using I 2 statistics and Cochran’s Q test. When the I 2 statistic fell between 0% and 25%, it indicated only mild heterogeneity. When the value falls within the range of 25%–50%, it indicates moderate heterogeneity, and an I 2 statistic above 50% indicates the presence of significant heterogeneity. If the p -value of Cochran’s Q test is less than 0.05, it indicates the presence of heterogeneity. Conversely, if the p -value is equal to or greater than 0.05, it indicates the absence of heterogeneity. Additionally, the pleiotropy test and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test are employed to assess horizontal pleiotropy. If the p -value of the pleiotropy test is less than 0.05, it indicates the presence of pleiotropy; if the p -value is greater than 0.05, it suggests no pleiotropy. In the MR-PRESSO test ( Verbanck et al., 2018 ), a global test p -value less than 0.05 indicates the presence of pleiotropy, while a p -value greater than 0.05 suggests no pleiotropy. All these analyses were conducted using the “TwoSampleMR”, “RadialMR”, “MendelianRandomization”, and “MR-PRESSO” packages in R (version 4.2.2).

Druggable proteins identification, phenotype scanning and PPI network

We mapped the SNPs obtained from the MR analysis to their corresponding proteins, and assessed the druggability of these proteins. We searched these proteins in the DrugBank database. For the proteins identified in the drug database, we documented information regarding the drug names and the associated diseases.

We also conducted phenotype scanning, searching previous GWAS to reveal the associations of identified proteins with other traits. Phenotype scanning was performed using the LDtrait Tools ( https://ldlink.nih.gov/ ). SNPs were considered pleiotropic under the following criteria ( Ballering et al., 2022 ): significant associations at the genome-wide level ( p < 5 × 10 −5 ) ( Hall et al., 2022 ); GWAS conducted in European ancestral populations ( Davis et al., 2023 ); SNPs associated with known risk factors, including metabolic traits, proteins, or clinical characteristics.

To further evaluate the protein networks of individual organ proteins associated with COVID-19, we constructed protein interaction networks using the STRING (Search Tool for the Retrieval of Interaction Gene/Proteins) database ( https://cn.string-db.org/cgi/input.pl ).

The results of the MR analysis for all diseases are presented in Figure 2 and Supplementary Table 1 , showing both IVW and radial IVW results. We selected 13 diseases with positive radial MR results and conducted a literature search on PubMed. This confirmed that there is clinical evidence for nine of these diseases—namely, pneumonia, Streptococcus pneumoniae (SP), liver disease, kidney cyst (KC), other specified disorders of the kidney and ureter, other disorders of the kidney and ureter, thyroid disorders (TD), Graves’ disease (GD), and hypothyroidism (HTCBSA). Detailed information on these diseases can be found in Table 1 . All SNPs used for the analysis are listed in Supplementary Table 2 .

Figure 2 . Association of severe COVID-19 in MR analysis with organ-related diseases. Higher bars represent lower p -values and stronger causal associations.

The casual effect of severe COVID-19 on lung-related diseases

According to Figure 3 , the radial IVW analysis indicates a causal association between severe COVID-19 and pneumoniae (OR and 95% CI: 0.938, 0.88 to 1.00; p = 0.041). Due to the absence of outliers identified through second-order weighted radial regression, the results of the original IVW and radial IVW remain consistent. The results from MR-Egger (OR and 95% CI: 1.017, 0.88 to 1.17; p = 0.831) and WM (OR and 95% CI: 0.949, 0.88 to 1.03; p = 0.206) did not show significant associations. According to the Cochran’s Q test results (I 2 = 0.0%, p = 0.754) in Table 2 , there was no heterogeneity observed among severe COVID-19 and pneumoniae. In addition, the pleiotropy test ( p = 0.270) and MR-PRESSO results ( p = 0.791) indicate no horizontal pleiotropy between severe COVID-19 and pneumonia.

Figure 3 . Forest plots of causal effects of severe COVID-19 in organ-related disease. CI, confidence interval; OR: odds ratio; SNPs, single nucleotide polymorphisms.

Table 2 . Heterogeneity and pleiotropy tests of the Mendelian randomization studies.

In Figure 3 , the IVW results for severe COVID-19 and SP were consistent with the radial IVW results, both of which were significant (OR and 95% CI: 0.626, 0.42 to 0.93; p = 0.021). MR-Egger (OR and 95% CI: 1.388, 0.55 to 3.27; p = 0.547) and WM (OR and 95% CI: 0.694, 0.41 to 1.18; p = 0.178) analyses do not yield significant results. The results of Cochran’s Q test (I 2 = 4.2%, p = 0.381) in Table 2 indicate no heterogeneity between various COVID-19 phenotypes and SP. Pleiotropy test ( p = 0.115) and MR-PRESSO results ( p = 0.428) also fail to demonstrate pleiotropy between the two.

The casual effect of severe COVID-19 on liver-related diseases

According to the radial IVW results in Figure 1A , there was a causal association between severe COVID-19 and liver diseases (OR and 95% CI: 0.906,0.82 to 0.99; p = 0.038). A correlation was also not presented in the other models. According to the results of Cochran’s Q test (I 2 = 0.0%, p = 0.707) in Table 2 , no heterogeneity was found between the results of COVID-19 and liver diseases, and the results of the pleiotropy test ( p = 0.769) and MR-PRESSO ( p = 0.715) similarly showed no pleiotropy.

The casual effect of severe COVID-19 on kidney-related diseases

According to Figure 3 , after employing radial MR to remove horizontal pleiotropy from IVs, the VW analysis of severe COVID-19 and KCI shows an association (OR and 95% CI: 1.248,1.00 to 1.55; p = 0.048), and the global IVW results did not show a correlation (OR and 95% CI: 1.139,0.90 to 1.44; p = 0.280). No significant associations were found in the other models. According to Table2 , Cochran’s Q test ( p = 0.724), pleiotropy test ( p = 0.903) and MR-PRESSO ( p = 0.762) also showed no interference from heterogeneity and horizontal pleiotropy.

In both types of other disorders of kidney and ureter, the overall IVW did not show a significant association, but after removing outliers, the radial IVW analyses for both exhibited significant results ( Figure 3 ). Furthermore, results from Cochran’s Q test, pleiotropy test, and MR-PRESSO all indicate the absence of heterogeneity and horizontal pleiotropy interference ( Table 2 ).

The casual effect of severe COVID-19 on thyroid-related diseases

In the IVW analyses, a corresponding causal relationship between severe COVID-19 and TD is found (OR and 95%CI: 0.919, 0.85 to 1.00; p = 0.046) ( Figure 3 ). After conducting second-order weighted radial regression, it was found that the presence of two outliers could cause horizontal pleiotropy in the MR analysis. Despite the removal of horizontal pleiotropy, the radial IVW results remain significant (OR and 95%CI: 0.926, 0.87 to 0.98; p = 0.008) ( Figure 3 ). The Cochran’s Q test results indicate no heterogeneity between severe COVID-19 and TD. Furthermore, both pleiotropy test and MR-PRESSO results suggest that the use of radial MR, after removing outliers, has mitigated the interference of horizontal pleiotropy ( Table 2 ).

The results of Severe COVID-19 and HTCBSA did not present a correlation under the IVW model (OR and 95%CI: 0.895, 0.80 to 1.01; p = 0.062). Following the exclusion of three outliers’ impact on horizontal pleiotropy, the results under the radial IVW model showed significance (OR and 95%CI: 0.897, 0.83 to 0.96; p = 0.003) ( Figure 3 ). Moreover, Cochran’s Q test results (I 2 = 0.0%, p = 0.843) indicated the absence of heterogeneity afterward, and pleiotropy test ( p = 0.551) and MR-PRESSO ( p = 0.848) results also demonstrated the complete removal of horizontal pleiotropy ( Table 2 ).

The IVW analysis of severe COVID-19 and GD risk as shown in Figure 3 also did not show an identifiable causal relationship (OR and 95%CI: 0.823, 0.66 to 1.02; p = 0.080). After removing the influence of a single outlier on the outcomes, the radial IVW results suggest the existence of a correlated causal relationship (OR and 95%CI: 0.757, 0.65 to 0.94; p = 0.011). The results of MR-Egger and WM did not present a recognizable causal relationship. Results from Cochran’s Q test (I 2 = 0.0%, p = 0.803), pleiotropy test ( p = 0.392), and MR-PRESSO ( p = 0.793) also indicate no interference from heterogeneity and horizontal pleiotropy ( Table 2 ).

Druggability of identified proteins, phenotype scanning and PPI network

Among them, Superoxide Dismutase 2 (SOD2, P04179) and TEK Receptor Tyrosine Kinase (TEK, Q02763) have been confirmed as drug targets for COVID-19 ( Supplementary Table 3 ). Desmoplakin (DSP, P15924) is a relevant drug target for the treatment of pneumonia, while SOD2 is used in the treatment of Hepatitis B. Currently, no drug targets have been found for the treatment of kidney and thyroid-related diseases. Information on drug targets and their associated drugs and diseases can be found in Supplementary Table 3 .

Through phenotype scanning, we did not find any pleiotropic SNPs that could interfere with the experimental results. DSP is associated with idiopathic pulmonary fibrosis, lung dysfunction, chronic obstructive pulmonary disease, interstitial lung disease, and advanced glycation end product receptor levels. Phospholipid Scramblase 1 (PLSCR1, O15162) is associated with COVID-19. Lamin A/C (LMNA, P02545) is correlated with white blood cell count, and Nephronectin (NPNT, Q6UXI9) has been identified as a major gene influencing lung function, respiratory system diseases, chronic obstructive pulmonary disease, and peak expiratory flow rate.

After uploading all the genes used as instrumental variables in MR analysis to the STRING online database, we obtained a PPI network with color modification ( Supplementary Figure 1 ).

As shown in previous studies, long and severe COVID-19 affect multiple organ systems ( Davis et al., 2023 ). We further verified the association between severe COVID-19 and some organ-related diseases, such as Hypothyroidism, strict autoimmune (HTCBSA), Thyroid disorders (TD), and Graves’ disease (GD). This study builds upon the research of Nie et al. ( Nie et al., 2021 ), further exploring the existing associations between COVID-19 and potential organ diseases, providing valid support for previous clinical results and retrospective studies.

Our study demonstrated an observable causal relationship between severe COVID-19 and pneumonia, as well as between severe COVID-19 and streptococcus pneumoniae (SP) ( p = 0.021 and p = 0.041). The damage of COVID-19 to lung has long been confirmed by numerous studies ( Berlin et al., 2020 ; Blanco et al., 2021 ; Su et al., 2021 ). Pneumonia is one of the main clinical manifestations of severe forms of COVID-19 ( Li et al., 2020 ). The study by Angela et al. also confirmed the existence of an effect of COVID-19 on SP ( Brueggemann et al., 2021 ) O'Toole’s study revealed the multifaceted impact of COVID-19 on bacterial infections, with the presence of infectious bacteria in patients admitted to the hospital with severe COVID-19 ( O’Toole, 2021 ). It is worth noting that our study did not observe a potential causal relationship between idiopathic pulmonary fibrosis or interstitial lung disease and COVID-19 ( p = 0.329 and p = 0.436). However, Wendisch et al.'s study established a correlation between COVID-19 and idiopathic pulmonary fibrosis ( Wendisch et al., 2021 ). Additionally, several previous studies have confirmed that COVID-19 can lead to interstitial lung disease ( Myall et al., 2021 ; Barash and Ramalingam, 2023 ).

In our MR analysis, we observed a causal relationship between severe COVID-19 and liver disease ( p = 0.0384). In the review by Dufour et al., they are pointed out that liver injury may be caused by multiple factors, including the direct cytopathic effects of viruses, exaggerated systemic immune responses, vascular damage, coagulation disorders, and drug use ( Dufour et al., 2022 ). In our study, although no significant causal association between severe COVID-19 and chronic hepatitis was found ( p = 0.053), Dufour et al. noted that the risk of adverse outcomes after SARS-CoV-2 infection was increased in patients with chronic liver disease and cirrhosis ( Dufour et al., 2022 ). Based on this finding, we reasonably speculate that there may be a clinical association between severe COVID-19 and chronic hepatitis. It is important to note that MR analysis relies on statistical models and data analysis, which may not fully capture the complexities of the real world. Due to the possibility of false negatives in genetic marker screening and validation during the MR analysis process, some causal relationships may not have been fully captured. According to Portincasa et al.‘s study, patients with COVID-19 are usually associated with metabolic disease, and in the presence of metabolic abnormalities, COVID-19 may exacerbate nonalcoholic fatty liver disease through the interaction of inflammatory pathways and direct or indirect effects of the virus on the liver ( Portincasa et al., 2020 ). Our study still fails to reflect this point ( p = 0.841).

In studies of severe COVID-19 and kidney-related diseases, COVID-19 is thought to trigger chronic kidney diseases and acute kidney injury ( Pecly et al., 2021 ; Long et al., 2022 ). in our study, although an association between severe COVID-19 and chronic kidney diseases was not found, the presence of a false negative ( p = 0.083) could not be ruled out. In addition, we also found an association between severe COVID-19 and kidney cyst ( p = 0.048), although we did not find direct evidence of an association, as chronic kidney diseases may trigger kidney cyst. In the study by Chan et al., it was found that out of 3993 COVID-19 hospitalized patients, 1835 (46%) patients developed acute kidney injury ( Chan et al., 2021 ). However, in this MR analysis, none of the individual acute kidney diseases demonstrated an association with COVID-19. ( Supplementary Table 1 ).

The thyroid disorders caused by COVID-19 has been widely demonstrated ( Khoo et al., 2021 ; Lui et al., 2024 ). HTCBSA is one of the major subtypes of hypothyroidism. Some previous studies have provided evidence of COVID-19-related hypothyroidism ( Muller et al., 2020 ; van Gerwen et al., 2020 ; Burekovic et al., 2022 ). In our study, a causal association between severe COVID-19 and HTCBSA was observed, but results for some other rare subtypes of hypothyroidism were negative. In a previous MR analysis, COVID-19 was confirmed to be a risk factor for hypothyroidism and there was no evidence to support an association between COVID-19 and hyperthyroidism ( Zhang et al., 2022 ). This is consistent with the results we obtained. It is important to note that while our study did not find direct evidence linking severe COVID-19 with hyperthyroidism, we did observe a correlation between severe COVID-19 and GD ( p = 0.011). COVID-19 has been recognized as a potential trigger for GD, and there have been several case reports and studies of patients who developed symptoms of GD after infection with COVID-19 ( Harris and Al, 2021 ; Tutal et al., 2022 ). For such results above, we believe that although GD is a common cause of hyperthyroidism, there are still other causes that induce hyperthyroidism, and severe COVID-19 and hyperthyroidism may not be directly linked.

In our MR analysis of severe COVID-19 and heart-related diseases, only one condition (cardiovascular disorders originating in the perinatal period, p = 0.024) showed a correlation. However, there is a lack of corresponding clinical studies to validate the potential causal relationship with COVID-19. Although some studies suggest that COVID-19 infection may increase the risk of myocarditis and pericarditis ( Lindner et al., 2020 ; Patone et al., 2021 ), our research did not find a direct causal relationship between the two.

In our research, we only identified one spleen-related disease associated with COVID-19 (spleen cyst, p = 0.047). Despite studies by Jana et al. indicating that severe COVID-19 pneumonia can lead to loss of B cells in the bone marrow or spleen ( Ihlow et al., 2021 ), there is no direct evidence to establish a direct or indirect association between COVID-19 and spleen cyst.

A large number of previous studies have shown that COVID-19 affects the human reproductive system ( La Marca et al., 2020 ; Seymen, 2020 ). In fatal cases of COVID-19 infection, viral infection associates with activation of interferon pathways and downregulation of testis-specific genes involved in spermatogenesis ( Basolo et al., 2023 ). However, due to the design of our methods, after multiple layers of screening, we were unable to find IVs that could be used in this study to infer the potential association that exists between sever COVID-19 and testis. This limitation highlights the challenges we face in studying the effects of COVID-19 on the male reproductive system and suggests directions for future research, such as improving data collection and research methods to better understand the specific mechanisms by which the virus affects the testis.

Limitations

While this MR study offers a comprehensive and effective causal analysis for COVID-19 and various organ-related diseases, there are still some limitations. First, COVID-19 presents with a wide range of clinical manifestations and comorbidities, and some of these potential factors may predispose to the development of related diseases. In this study, although we used proteomic data related to COVID-19 for screening to minimize confounding, we could not guarantee that all potential factors were excluded. Second, in this study, we only used Genome-Wide Association Studies (GWAS) summary data from European populations due to the lack of data from other populations, and therefore we cannot guarantee that our conclusions will hold true in other populations. Finally, although we ruled out weak IVs, pleiotropy, and LD through our experimental design, the IVs we used usually failed to account for most of the variance, which may result in MR analyses that do not have a high degree of statistical validity and are at risk of false-negative or false-positive results.

Our research has confirmed the association between severe COVID-19 and multiple organ-related diseases. However, with some proven organ-related diseases, such as chronic hepatitis, chronic kidney disease and hyperthyroidism, we did not find a causal link. In addition, we have identified some proteins associated with organ-related diseases and corresponding drug targets. We hope that future MR studies can utilize larger and more precise GWAS data to refine our findings.

Data availability statement

Publicly available datasets were analyzed in this study. This data can be found here: The COVID-19 Host Genetics Initiative (HGI) data repository ( https://www.covid19hg.org/results/r7/ ) and the FinnGen database ( https://www.finngen.fi/en ).

Author contributions

YS: Data curation, Investigation, Methodology, Resources, Visualization, Writing–original draft, Writing–review and editing. YZ: Funding acquisition, Investigation, Supervision, Writing–review and editing. Y-yX: Investigation, Supervision, Writing–review and editing. XL: Investigation, Writing–review and editing. JW: Investigation, Writing–review and editing. HP: Funding acquisition, Supervision, Writing–review and editing. LW: Investigation, Project administration, Supervision, Writing–review and editing. TZ: Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Writing–review and editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study was funded by 2023 Faculty-level Supporting Disciplines - Ophthalmology (Zhejiang Provincial Hospital of Chinese Medicine Discipline High-quality Development Boosting Program) (2D02320), Leading Innovative and Entrepreneur Team of Zhejiang Province (2022R02005), the grant from startup found of Zhejiang A&F University under Grant (203402007101). The funders had no role in the study design, data collection, data analysis, interpretation, or writing of the report.

Acknowledgments

The authors thank all scientists and individuals involved in the COVID-19 Host Genetics Initiative and FinnGen Consortium for their kind contribution to data. During the preparation of this work the author(s) used ChatGPT3.5 in order to polish the language of the initial draft for better readability.

Conflict of interest

Author HP was employed by MobiDrop (Zhejiang) Co., Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2024.1421824/full#supplementary-material

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Keywords: severe COVID-19, causal effect, mendelian randomization (MR), organ-related diseases, proteome

Citation: Shen Y, Zhang Y, Xu Y-y, Li X, Wu J, Pei H, Wang L and Zhu T (2024) Causal associations between severe COVID-19 and diseases of seven organs: a proteome-wide mendelian randomization study. Front. Genet. 15:1421824. doi: 10.3389/fgene.2024.1421824

Received: 23 April 2024; Accepted: 29 July 2024; Published: 13 August 2024.

Reviewed by:

Copyright © 2024 Shen, Zhang, Xu, Li, Wu, Pei, Wang and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Tiansheng Zhu, [email protected] ; Linyan Wang, [email protected]

† These authors have contributed equally to this work and share first authorship

‡ These authors share last authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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New clue into the curious case of our aging immune system

by Walter and Eliza Hall Institute

A WEHI study could help solve a long-standing mystery into why a key immune organ in our bodies shrinks and loses its function as we get older. The thymus is an organ essential for good health due to its ability to produce special immune cells that are responsible for fighting infections and cancer.

In a world-first, researchers have uncovered new cells that drive this aging process in the thymus —significant findings that could unlock a way to restore function in the thymus and prevent our immunity from waning as we age.

T cells, also known as T lymphocytes, are a type of white blood cell that plays a crucial role in our immune system. T cells are essential for identifying and responding to pathogens, such as viruses and bacteria, and for eliminating infected or cancerous cells .

The thymus is a small, but mighty, organ that sits behind the breastbone. It is the only organ in the body that can make T cells.

But a curious feature of the thymus is that it is the first organ in our bodies to shrink as we get older. As this happens, the T cell growth areas in the thymus are replaced with fatty tissue, diminishing T cell production and contributing to a weakened immune system .

While the thymus is capable of regenerating from damage, to date researchers have been unable to figure out how to unlock this ability and boost immunity in humans as we age.

WEHI Laboratory Head Professor Daniel Gray said the new findings, published in Nature Immunology , could help solve this mystery that has stumped researchers for decades.

"The number of new T cells produced in the body significantly declines after puberty, irrespective of how fit you are. By age 65, the thymus has virtually retired," Prof Gray said.

"This weakening of the thymus makes it harder for the body to deal with new infections, cancers and regulate immunity as we age.

"This is also why adults who have depleted immune systems, for example due to cancer treatment or stem cell transplants, take much longer than children to recover.

"These adults need years to recover their T cells—or sometimes never do—putting them at higher risk of contracting potentially life-threatening infections for the rest of their lives.

"Exploring ways to restore thymic function is critical to finding new therapies that can improve outcomes for these vulnerable patients and find a way to ensure a healthy level of T cells are produced throughout our lives."

The new study, an international collaboration with groups at the Fred Hutch Cancer Center (Seattle) and Memorial Sloan Kettering Cancer Centre (NYC), provides crucial new insights that could help achieve this goal.

"Our discovery provides a new angle for thymic regeneration and immune restoration, could unravel a way to boost immune function in vulnerable patients in the future," Prof Gray said.

Scarring effects

Using advanced imaging techniques at WEHI's Centre for Dynamic Imaging and animal models, the research team discovered two new cell types that cause the thymus to lose its function.

These cells, which appeared only in the defective thymus of older mice and humans, were found to form clusters around T cell growth areas, impairing the organ's ability to make these important immune cells.

The researchers discovered these clusters also formed 'scars' in the thymus which prevented the organ from restoring itself after damage.

Dr. Kelin Zhao, who led the imaging efforts, said the findings showed for the first time how this scarring process acts as a barrier to thymic regeneration and function.

"While a large focus of research into thymic loss of function has focused on the shrinking process, we've proven that changes that occur inside the organ also impact its ability to function with age," Dr. Zhao said.

"By capturing these cell clusters in the act and showing how they contribute to loss of thymic function, we've been able to do something no one else has ever done before, largely thanks to the incredible advanced imaging platforms we have at WEHI.

"This knowledge enables us to investigate whether these cells can be therapeutically targeted in future, to help turn back the clock on the aging thymus and boost T cell function in humans as we get older. This is the goal our team is working towards."

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