Nephrology - The Best Transplant Field?

I'm in Philadelphia at the American Society for Nephrology Kidney Week.  For me, it's a busy four days of meetings for their medical student program, the ASN Workforce Committee, and the Nephcure Foundation.  Of course, as a medical student attending a specialty meeting, the ubiquitous question is "What do you want to go into?"  I've been telling people something along the lines of "I want to go into transplantation but not sure about what specialty, since there are a lot of possibilities."  The obvious response, it seems, is that the best field for someone interested in transplant is nephrology!  They make some good points:

• The kidney is the most commonly transplanted solid organ, by a pretty wide margin.  There are just more kidney transplants out there.
• Related to the first point, it's feasible to practice transplant nephrology or kidney transplant surgery full time, while specializing in other organs usually requires more non-transplant-related work.
• The immunology of transplant rejection has been best studied in the kidney, both in the pioneering work and in newer research on donor specific antibodies and antibody mediated rejection.
• Renal disease affects many recipients of nonrenal solid organ transplants, due to some immunosuppressant drugs and damage during the serious illness of organ failure.  Luckily, the hearts, lungs, livers, etc. of transplant patients don't tend to be as uniquely harmed.

Anyway, nephrology deserves at least a few days of intense exploration, so tomorrow at 6:30 AM it begins again.

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St. Louis Children's Hospital

I spent the past couple weeks shadowing/observing at St. Louis Children's Hospital. I'm still not at all clear on the best practices for blogging about clinical experiences, so this post will be pretty short and far from a complete recap. Let's just say that they have the largest pediatric heart and lung transplant programs in the country, and that may have been a motivation for my visit.

For what it's worth, I was really impressed. The physicians there shared a realistic understanding of what transplants can and cannot do.  At the same time, they were innovative in trying new things, in the hope that transplantation can do better.  Families were very engaged and involved, which is a credit to both the families and the staff--the relationship definitely needs effort on both sides.  Finally, they were extremely welcoming when a medical student e-mailed from the middle of nowhere saying "I have an interest in transplantation--can I visit and learn about what you do?"

There's a mural outside the entrance to the Cardiac ICU, and the message made me smile every time I saw it.

Thank you, St. Louis.

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Videos

I'm not a guru of videos by any means, but vacations from school are typically a time to vegetate in front of a screen.  Of course, for this blog, it's all about transplant videos.

From the touching (the story of a young girl's heart transplant at UCLA)...




...to the fascinating (a living donor liver transplant operation at Children's Hospital of Pittsburgh)...




...to the catchy (organ donor awareness from the Department of Health and Human Services).




Enjoy!

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Book Review: Breathless

The history of lung transplantation is inexorably linked to the University of Toronto in the 1980s and the surgeons and medical team there at that time. The first lung transplant was performed in Mississippi in 1967, and patients with end-stage lung disease started receiving successful heart-lung transplants at Stanford and Pittsburgh in the early 1980s, but Toronto developed the procedures of single and double lung transplants as they're done today. The names of Drs. Joel Cooper, Alec Patterson, and Griff Pearson are mentioned most as the pioneers, but another member of this team, Dr. Thomas Todd, has documented the history of lung transplantation firsthand in his book Breathless: A Transplant Surgeon's Journal.

Breathless is almost a Midnight's Children of lung transplantation; when the first lung transplant in Toronto is performed, Dr. Todd is a senior resident still in training, and when the field is mature, Dr. Todd is retiring. In between, he takes on the roles of doctor to many lung transplant patients, donor surgeon traveling the country to procure lungs, a position at another hospital, and finally the director of the thoracic surgery department in Toronto. Compared to many books by physicians, he doesn't focus extensively on the medical details of his experience, but does a great job telling the stories of the hospital environment, the politics, and the patients. Some of the stories are inspiring (the first patient's recovery), some are frustrating (departure of the pioneering surgeons), and some are funny (a patient's question of "Can we have sex?").

One downside of the book is that the author's role was somewhat outside the historical limelight, so it's sometimes challenging to connect the stories he tells with the history of lung transplants as it's usually reported. He also takes some diversions into the non-transplant work of a general thoracic surgery service, but I found these to be interesting as well. Overall, this book provides a very interesting account of the history of lung transplantation and how it became the field it is today.

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Pediatric vs. Adult Transplants

Pediatric transplantation has been a focus of this blog, mainly because I'm especially interested in the stories and unique issues of children who need organ transplants. Many aspects of transplantation are similar between children and adults, but there are some key differences.

Kidney

Percent pediatric: 5%

Indications in adults

• Diabetes
• Hypertension
• Glomerulonephritis

Indications in children

• Renal dysplasia
• Posterior urethral valve
• Focal segmental glomerulosclerosis

Differences in surgical approach

In adults, a kidney transplant is placed in the pelvis and attached to the blood vessels going to the leg (usually the external iliac vessels). For children between 10 kg and 20 kg, the kidney is placed in the abdomen and attached to the main blood vessels in the body (aorta and inferior vena cava). For children under 10 kg, dialysis is generally preferred to a kidney transplant. Young children actually do better with adult kidneys rather than kidneys from other children.

Liver

Percent pediatric: 12%

Indications in adults

• Hepatitis C infection
• Alcoholic cirrhosis
• Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)

Indications in children

• Biliary atresia
• Metabolic diseases
• Fulminant hepatic failure

Differences in surgical approach

Children can often receive the left lateral lobe of an adult liver, either from a deceased donor (split liver transplant) or a living donor (living donor liver transplant). The left lateral lobe is relatively easier to identify and divide than the right lateral lobe (relatively easier--both are very challenging operations!), and children were the first recipients of partial liver transplants. Children can also receive a whole organ liver transplant from another child.

Heart

Percent pediatric: 13%

Indications in adults

• Ischemic cardiomyopathy
• Idiopathic cardiomyopathy

Indications in children

• Cardiomyopathy (particularly dilated cardiomyopathy)
• Congenital heart disease (particularly hypoplastic left heart syndrome)

Differences in surgical approach

Patients receiving heart transplants for congenital heart diseases (usually children, sometimes adults) often need a longer segment of donor aorta with the transplant. The native aorta may have been part of the original problem and reconstructed as a "neoaorta" as part of the Norwood operation, so the aorta may also need replaced at the time the heart needs replaced.

Lung

Percent pediatric: 4%

Indications in adults

• COPD (chronic obstructive pulmonary disease)
• Cystic fibrosis
• Idiopathic pulmonary fibrosis

Indications in children

• Cystic fibrosis
• Pulmonary hypertension
• Congenital lung malformations

Differences in surgical approach

The younger and smaller a lung transplant patient is, the more likely they are to receive a double lung transplant and need cardiopulmonary (heart-lung) bypass for the operation. However, the operation is generally the same in children and adults.

Small bowel

Percent pediatric: 57%

Indications in adults

• Mesenteric ischemia
• Crohn's disease
• Intestinal tumors (desmoid and carcinoid)

Indications in children

• Gastroschisis
• Necrotizing enterocolitis (NEC)
• Malrotation and midgut volvulus

Differences in surgical approach

One of the challenges with intestinal transplants is that the donor usually needs to be of a smaller body size than the recipient. Since children needing intestinal transplants are small already (because of their intestinal failure and...because they're children), finding a smaller donor than the recipient can be especially challenging.

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Underlying Diseases

Organ transplants don't often "just happen." For a vital organ to lose so much function that it needs to be replaced, some disease has progressed to the point that it's causing serious problems. While the underlying cause is sometimes unknown (a single-digit percentage of cases), some underlying diseases are pretty frequent in the transplant world. Despite the commonalities of the transplant experience between patients, specific diseases tend to share an even more common experience. Also, many of these diseases have effects, stories, and communities that go beyond the subset that are transplant-specific. To highlight some of the places where transplant patients come from, this post is a summary of four specific underlying diseases.

Diabetes

Diabetes mellitus is what happens when the body has a lack of insulin activity, either because insulin can't be produced (Type 1 diabetes) or it can't be used (Type 2 diabetes). It's an extremely common disease, affecting 20.8 million Americans in 2005. Diabetes doesn't just affect sugar metabolism, but the use of carbohydrates, fats, and proteins. It can affect almost every organ system, including kidneys, peripheral nerves, eyes, and blood vessels of all types. A number of treatments are available, from medications of all types to injected insulin to insulin pumps to better regulate blood glucose levels to transplants.

Diabetes has a strong interplay with transplantation. It isn't just the indication for essentially all pancreas transplants; diabetic nephropathy is also the #1 disease causing the need for kidney transplants as well. Beyond those who have a transplant for diabetes, many transplant patients have diabetes as an additional disease. Also, diabetes can be a side effect of immunosuppression after transplantation, which is categorized as post-transplant diabetes mellitus (PTDM). Finally, type 1 diabetes is an autoimmune disease, and both diabetes and chronic rejection of transplants affect blood vessels, so basic research in diabetes and transplantation play off each other to lead to new advances for both groups.

Any disease that is so common is bound to have a large community on the Internet and in medicine in general. The American Diabetes Association is the center of this community, supporting everything from educational resources to research funding and advocacy. Unfortunately, there aren't too many blogs about diabetes or kidney or pancreas transplants related to diabetes. There are a couple in the "Adult Kidney & Pancreas Transplant Blogs" section, and other great blogs about diabetes in general such as Diabetes Mine and Six Until Me. Still, beyond the blogs or broadcasted stories, diabetes is an important part of transplantation.

Biliary Atresia

Biliary atresia is the most common underlying disease for pediatric liver transplants, responsible for about half of all pediatric cases and a much greater proportion of those in the youngest age groups. Biliary atresia is a rare and poorly understood disease. The number of new cases each year number in the hundreds, and the cause is not congenital, not genetic, not contagious (though possibly infectious), and...not known. The ultimate problem is that bile ducts "drop off" and don't develop fully enough to drain bile from the liver. No organ does well when it's not drained, and the liver is no exception, which leads many biliary atresia patients into cholestatic liver failure. The stories between patients are shockingly similar: initially assuming it was typical neonatal jaundice, undergoing a Kasai portoenterostomy to attempt to restore bile flow, and children going through the transplant experience at a very young age, with parents and families thrown into this world with them. Even though the condition is extremely rare, and everyone's life is different, the number of commonalities can make biliary atresia quickly seem like a relatively familiar disease.

Those with biliary atresia seem to have taken to blogging in great numbers, and an incredible number of individual stories are available in the "Pediatric Liver Blogs" section here. In addition, there are a few blogs of people facing biliary atresia but not requiring transplants, such as Imagine Bright Futures. Beyond blogs and Internet communities, those affected by pediatric liver diseases have assembled larger organizations such as Liver Families and C.L.A.S.S. (Children's Liver Association for Support Services).

Short Bowel Syndrome

Short bowel syndrome has a unique position in transplantation: the most common indication for the rarest type of transplant (intestinal transplant). The causes of short bowel syndrome fill an entire textbook of pediatric surgery, but the consequences are surprisingly uniform. The problems include intolerance to feeding (malabsorption, diarrhea, etc.), difficulties with vascular access for total parenteral nutrition (TPN), and the need for transplantation either from liver damage due to TPN or from losing sites for vascular access. "Tummy problems" sound a lot less exciting than heart, lung, or brain diseases, but the complications of short bowel syndrome can be as serious or deadly as any condition out there.

Short bowel syndrome and intestinal transplantation are a uniquely cloistered community. Only a handful of centers even attempt intestinal transplantation, and only a few of these have programs of any significant volume. Most people with short bowel syndrome end up at one of the institutions that have dedicated efforts in this area. Furthermore, many patients go between centers for second opinions, which leads to an even tighter network in this group. The short bowel community uses the Internet to the fullest, with a web site and mailing list (Gifts From Heaven), several blogs (such as The Short Gut News) and even a wiki.

Cystic Fibrosis

Cystic fibrosis is both simple and complex. For the simple part, it's caused by mutations in a single gene, for a single protein, with the general effect of impairing salt movement across membranes (specifically chloride ions). Water follows salt, and a lack of water movement makes various secretions thicker than usual. The complex part is the effects. Thick mucus in the respiratory system causes chronic and repeated lung infections (and sinus abnormalities) which get worse over time. In the gastrointestinal system, it can cause bowel obstruction in infants, liver disease, and pancreatic damage leading to diabetes. Cystic fibrosis is also unique in that it is always present from birth (though may not be recognized for years) and is a lifelong affliction. The survival of cystic fibrosis patients has improved incredibly, but just about all patients born with cystic fibrosis will die of cystic fibrosis, which means that there's far more to be done.

The vast majority of transplanted cystic fibrosis patients have lung transplants, with a few needing liver transplants, intestinal or multivisceral transplants, or heart-lung transplants. Cystic fibrosis is one of the top three diseases leading to the need for lung transplantation, and about two-thirds of pediatric lung transplants are for cystic fibrosis.

The cystic fibrosis community is uniquely organized and expressive. For the organizational end, the Cystic Fibrosis Foundation has led efforts ranging from research funding to center establishment to patient support. A recent New Yorker article by Atul Gawande discusses the extreme persistence and diligence needed in cystic fibrosis care, and the role of specific CF centers, the Cystic Fibrosis Foundation, and the CF community in striving for the absolute highest quality of care possible. As for Internet resources, the web site CysticFibrosis.com consolidates an incredible number of resources on the Internet, from foundations and support groups to mailing lists, blogs and wikis. The "Lung Blogs" section here has a number of blogs by cystic fibrosis patients and they tend to be especially well-written and vivid descriptions of living with both an organ transplant and chronic illness in general.

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Donation After Cardiac Death (DCD)

The very first experimental organ transplants came from donors who had recently died, whose hearts had stopped beating. These were superceded by living organ donations between twins and other relatives for the first "successful" kidney transplants, but "dead donors" would ultimately make up the bulk of organs donated. The earliest and most logical definition of "dead" was supremely intuitive--those whose heartbeats and breathing had stopped. Over the course of several years, brain death came into the picture as a new definition of death, and the 1968 Harvard Ad Hoc Committee on Brain Death formalized its definition and criteria. Brain death generated some controversy, but has become accepted as a medical and legal definition of death, and brain-dead patients became the pool of candidates for organ donation. However, some in the transplant profession had not forgotten the early donors, and in the mid-to-late 1990s the practice of recovering organs from donors whose hearts had stopped was resurrected as "donation after cardiac death" or DCD.

The principles of each are simple. Brain death is when the brainstem has been damaged beyond repair, when someone cannot breathe or maintain essential life functions without artificial support. Brain death can be diagnosed and declared by standard criteria, and after brain death is declared, death is declared as well and life support is removed. This time period is also the window for possible organ donation. DCD is for donors who do not meet brain death criteria but still have no meaningful chance of survival. In these cases, mechanical support is withdrawn as it commonly is for many people in these circumstances. The only difference from the usual practice is that organs are recovered after death for transplantation.

UNOS

In the decades between the early and the recent use of DCD, the biggest change in the US transplant system was the development of UNOS. Its history is another very long post, but the end result is that UNOS allocates organs for transplant, sets up the rules and systems by which organs are allocated, and sets conditions that member hospitals have to follow to legally get organs for transplant. UNOS is responsible for current DCD practices, and it also holds responsibility for an extremely long waiting list and a huge number of transplant centers. Recently, faced with criticism over its effectiveness, incoming UNOS President Sue McDiarmid, a pediatric liver transplant specialist at UCLA, set the amazing goal of eliminating death on the waiting list of children. No child would die waiting for a transplant...this is a result that could definitely show UNOS's effectiveness to be beyond question. It would obviously require an increase in organ donations (in addition to tweaking current practices) and this increase could logically come from DCD donation.

UNOS set forth with proposals to increase DCD donations, including requiring all hospitals to have a DCD policy. This effort was not met with unbridled enthusiasm, but instead with a lot of resistance. The report of a recent meeting of the UNOS Pediatric Committee details the resistance, which is especially strong for pediatric donors. This is ironic given that the push was partly designed to help children needing transplants, but it is also very understandable given the medical uncertainty of prognosis in children and the pure tragedy of a child's death. To understand and work through this concern, UNOS recently held a Summit on Pediatric Organ Donation and Transplantation, including both pediatric transplant professionals and pediatric intensivists (ICU physicians). A report from this summit is not available, but one fact that has been brought up is that pediatric intensivists are often in the unique position of caring for both potential organ donors and recipients. While most in the transplant field aren't in this same position, they are experienced medical professionals, so have undoubtedly dealt with issues surrounding the death of a patient.

Just as the initiatives to increase DCD were gaining momentum, a devastating blow was dealt to the practice by the misconduct of a transplant surgeon. The Los Angeles Times exposed the story of a transplant surgeon seeming to order medications for a potential DCD donor. The intent may or may not have been to hasten the donor's death, but even the presence of the transplant surgeon before death is improper and filled with conflict. Faced with such a blatant violation of DCD practices, the reaction of the transplant community was relatively poor, with a response from UNOS that was essentially a non-response of "we can't comment on an ongoing investigation" and grumblings from others in the transplant world that "The LA Times is at it again..." (my reaction being "don't shoot the messenger"). While this incident never should have happened, and cast DCD donation in a poor light, confusion is not limited to the DCD situation, with the LA Times recently reporting confusion in declaration of brain death of a potential organ donor. This confusion isn't even limited to cases where organ donation is a consideration, with the story a couple of years ago about a girl in California who was declared dead but was actually alive.

Current Opinions

Unfortunately, current opinions about DCD seem to be drastically negative. The Washington Post recently ran a feature article on DCD, discussing the resistance and including a number of quotes that are quite questionable. Jerry Menikoff of the University of Kansas stated that "we're starting to remove the organs a few minutes before they meet the legal definition of death" which is completely contradicted by the multiple statements earlier about how organ recovery begins several minutes after death, not a moment before. Dr. David Crippen of the University of Pittsburgh asks if "we're going to take organs from patients who have a prognosis of death but who do not meet the strict definition of death, might we become more interested in taking organs from patients who are not dead at all but who are incapacitated or disabled?" which is also false since organs are not taken from patients when they "have a prognosis of death" but rather when they are dead. The only published reply from the transplant community was a brief letter to the editor by UNOS President Sue McDiarmid, stating generally that some statements were not fully true. Since this article has been circulated so widely in the blogosphere and beyond, it's concerning to me that it's been contested or debunked so little.

Blogs have a great deal of insight into current opinions of DCD, insight that builds on the published works and expands on them. A comment to a post on the popular blog Kevin, MD include the information that all of the pediatric anesthesiologists at St. Louis Children's Hospital have refused to participate in the practice. A similar feeling has been reflected at other hospitals, but the bluntness and honesty of this response is particularly telling. A more deeply insightful post on pediatric DCD comes from Donorcycle, a blog by a transplant procurement coordinator with an excellent post titled "When You Watch A Child Die".

My opinion on DCD donations is that they're as rough as everything else. Donations after brain death also come under tragic circumstances and strike a family at the time of a loved one's death, and living organ donation is fraught with worries of its own. DCD strikes me as being equally viable and as beneficial as other forms of organ donation, so I see no reason why it shouldn't be supported and expanded. That said, it does seem like the transplant community's efforts in this area haven't panned out as well as they could. My suggestion for the transplant community is (1) set clear policies and regulations to enable DCD to happen in an ethical and respectful manner and (2) show no tolerance for breaches of these policies, affirming that we strive for maximal organ donation within strict bounds of ethics and dignity. My request to the rest of the world is much simpler: please bear with the transplant community during changing times, understand just how valuable organ donations are, and how profound it is to "donate life."

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