BONE TRANSPLANTATION

Bone transplantation or bone grafting, as it is more commonly known is a surgical procedure where surgeons use an external source of a bone or a bone substitute to replace bone tissue lost due to cancer, trauma or infection.

A human bone has the ability to heal itself by forming new bone. Sometimes, this ability is hindered due to extensive bone loss after severe trauma, surgical removal of bone tumors or after removal of bone infections. This leaves a large defect, which typically would not heal without a bone graft.

Bone grafts can usually be obtained from three sources:
A) autologous – bone harvested from a different area from the patient’s own body.
B) allograft – bone harvested either from a deceased donor or from a living donor who has donated a small part of his bony skeleton, as happens after a hip replacement, where the donor agrees to donate a part of the hip bone being removed during the procedure that would normally be discarded.
C) synthetic – using an artificial substance with similar mechanical properties as a bone.
Most bone grafts are finally reabsorbed and replaced as the natural bone heals after a few weeks.

Autologous bone grafts use bone from a non-essential area such as the iliac crest or the hip bone, the leg (fibula), ribs, mandible (jaw) and the skull. Advantages of using one’s own bone is that it reduces the chance of getting an infection from another donor and of graft rejection. Disadvantages include another potential source of pain, infection and other complications at the second site from where the bone graft is obtained.

Allograft bone is obtained either from a deceased or a living donor. These are typically obtained from bone banks after they have gone through stringent testing requirements in order to enhance their safety.

Synthetic bone substitutes include materials like hydroxylapatite, which occurs naturally and can sometimes be used in combination with other minerals or polymers. Ceramics have been used extensively to create artificial bone substitutes as well. Corals from the ocean have been found to be excellent bone substitutes as well.

Common uses of bone grafts include their use as support structures for dental implants and for reconstruction procedures after bone loss from infections, tumors and trauma involving the jaw bone. The fibula is also used as a bone graft for long bone reconstructions involving the lower or upper limbs.

Recent advances in biotechnology has an Israeli company use a lab-grown semi-liquid bone graft, grown from a patient’s own fat cells, be used as a viable replacement for lost areas of the jaw bone in 11 patients, with great long term results. This would undoubtedly lead to more research and innovation to come up with safer, more abundant natural sources of bone substitutes at a lower cost to benefit a wider section of mankind.

WHAT IS INTESTINAL FAILURE?


Intestinal failure is a serious condition that prevents a person from digesting and absorbing food and other essential nutrients, which leads to malnutrition, prevention of normal development (especially in children), a reduced quality of life and even death.

The most common cause of intestinal failure is short bowel syndrome, where at least half or more of the small intestine has been removed surgically. Ideally, a length of at least 200 cms of small bowel would ensure adequate nutrient absorption. If the large bowel is still present, a minimum length of 100 cms of small intestine is needed to ensure that adequate digestion of food occurs that would be enough to sustain life.

In children, conditions such as congenital anomalies, infections of the small bowel, extensive bowel surgeries and an inborn inability to absorb food can lead to intestinal failure.
In adults, extensive bowel surgeries, inflammatory bowel disease such as Crohn’s disease, radiation induced enteritis, severe celiac disease and tumors involving the small bowel or the mesentery can lead to short bowel syndrome and ultimately intestinal failure. The mesentery is a fold of tissue that connects the stomach and intestines to the abdomen.

What are some symptoms of intestinal failure?
These include diarrhea, poor appetite, weight loss, bloating, increased gas, foul smelling stool and vomiting.

What are some of the treatment options for a patient with intestinal failure?
This depends on how much of the small intestine is actually functional in a particular patient. We have already discussed how long the small bowel should be for adequate digestion and absorption of the food one eats.
In its initial stages, most patients require TPN, also known as total parenteral nutrition. This involves placing a catheter in the neck, chest, arm or groin in order to give liquid nutrition directly into the blood stream. TPN fluids are carefully created for each individual patient’s metabolic requirement and contains carbohydrates, fats, proteins, minerals and electrolytes in a precise formula. This can be given over 24 hours when the patient is unable to eat or drink anything by mouth or over a shortened period, say 12 or 18 hours, when a patient can take in some nutrition by mouth but not enough for his or her daily requirements.
Oral intake is then gradually introduced and advanced, as tolerated. Specialized oral solutions providing most of the nutrition is used to wean the patient off the TPN. As much as possible, regular food intake with adequate additional supplements would be the ultimate goal.

In some patients, adequate oral intake is not achievable and therefore the patient is TPN dependent for life. Complications related to TPN occur frequently and include catheter related infection or sepsis, glucose related abnormalities (high glucose or low glucose), liver dysfunction, serum electrolyte and mineral abnormalities, bone disease such as osteoporosis, stones in the kidney or gall bladder (gall stones) and allergic reactions to the contents of TPN. TPN also happens to be expensive and can therefore add to the burden of the disease itself.

Long term outlook for intestinal failure is dependent on how much of the intestine can be used normally without depending on TPN or any other specialized tube feedings. Severe complications related to long term TPN such as liver failure or severe catheter related access issues should prompt an evaluation for intestinal transplantation. This requires a referral to a transplant center that specializes in this procedure. As progress is being made on every front, the results of intestinal transplantation are constantly improving, providing a ray of hope to those afflicted with this dreadful disease.

OBESITY AND KIDNEY TRANSPLANTATION


Obesity in the general population is a growing problem in the US and is especially problematic when viewed from the standpoint of a patient who has chronic kidney disease and is awaiting a kidney transplant. Research has shown that there is a higher chance of death while on dialysis – almost 20 % per year, with this rate almost 9 times higher if you are also obese. This is probably because obese patients with kidney disease happen to be older, have a higher incidence of diabetes and are more likely to be African American. It is estimated that more than 60 % of kidney transplant recipients today are obese or overweight, a number that has almost doubled since 1990.

Obese patients also tend to wait longer for a kidney on the waiting list. Compared to a person who has normal BMI (25 kg/m2), an obese patient (> 30 kg/m2), at an average waits almost a year and a half longer for a transplant. This no doubt increases the chance that he may never get a kidney in time and likely die on the waiting list.

Let’s look at what happens after an obese patient gets a kidney transplant. There is a higher chance that the transplanted kidney may not work right away, a phenomenon known as delayed graft function or DGF. This is especially true for recipients of a kidney donated by a brain dead donor. This in turn decreases the life span of the transplant in the long term. Obese patients are more likely to suffer from wound infections as well. Because of pre-existing diabetes and hypertension, obese patients also tend to have higher rates of cardiovascular problems such as heart disease and stroke. All these together combine to significantly shorten an obese person’s chances of having a functioning kidney transplant long term. Obesity has also shown to have a direct adverse effect on the functioning of the kidney.

Approximately 50 % of recipients will gain weight after a kidney transplant. This happens because dietary restrictions are no longer in place, there is improvement in a person’s appetite and also due to some post-transplant medications such as steroids that play a role in this weight gain.

Dietary interventions with regular and aggressive follow up have shown to be helpful in the first few months after a kidney transplant in controlling weight. Physical activity is also highly encouraged and has been found to be beneficial in preventing excessive weight gain and increasing the sense of well-being. Some transplant programs have also encouraged pre-transplant bariatric or weight loss surgery which has had beneficial results.

YOU NEED A KIDNEY TRANSPLANT – WHAT WORKUP IS REQUIRED?

Kidney transplantation is offered to patients who are already on dialysis or are going to need this treatment soon. In the latter case, receiving a transplant prior to being on dialysis is called pre-emptive transplantation. Multiple studies have shown that a successful kidney transplant enhances the quality of life and can also add years to your life as well. In short, a kidney transplant can be a life-saving operation, if it is well taken care of.

Exhaustive evaluations are generally required for all potential transplant candidates. This is done to make sure that any potential issue that could harm the transplanted kidney or the patient is identified and corrected prior to listing. After most of the testing has been done, the candidate is required to meet the transplant team which comprises of a transplant nephrologist, transplant surgeon, pre-transplant co-ordinator, transplant social worker and a financial advisor working with the program. Therefore, not only are medical issues looked into, social and financial issues are carefully evaluated as well.

Most work-ups start with lab studies. These include:

a) Blood chemistries (includes electrolytes, kidney function etc)
b) Liver function tests
c) Complete blood count (hemoglobin, platelet and white blood cell counts)
d) Coagulation profile (to check the ability of the blood to clot)

Further testing is ordered to rule out potential infections, especially certain viral infections. These include:

a) Hepatitis B and C
b) Epstein Barr virus
c) Cytomegalovirus
d) Varicella zoster virus
e) Syphilis testing
f) HIV
g) PPD for TB

The transplant team carefully looks at all organ systems, especially the heart, particularly if there is a prior history of heart related issues, if the patient has type 1 diabetes or if high blood pressure is the cause of renal failure.
This starts with:

a) Chest x-ray
b) EKG
c) Stress test
d) Echocardiogram
e) Heart catheterization, if required.
In addition to the blood tests outlined above, tests to identify the blood group and certain pre-existing antibodies that could cause rejection of the organ are done as well. Specifically, the transplant team would want:

a) ABO blood group determination
b) HLA typing
c) Antibodies to HLA phenotypes
d) Crossmatching


While these tests are standard in all potential candidates, further tests may be required, which are:

a) PSA to rule out prostate cancer
b) Pap smear
c) Colonoscopy, if age > 50 years or if  family history of colon cancer is present
d) Upper endoscopy with history of peptic ulcers
e) Dental check up to rule out infections
f) Urine testing in patients who still make some urine
g) Carotid duplex to look at carotid arteries for atherosclerotic plaques
h) Ultrasound of the native kidneys
i) Doppler studies of the arteries in the legs and arms

Any of these tests could reveal abnormalities that could either rule out a patient from being considered for a transplant. For example, a colonoscopy might reveal colon cancer, which will require further treatment and possibly being ruled out from getting a transplant for at least 2-3 years.
Most centers take a very close look at obesity. Most transplant centers will not consider a patient as a candidate if the BMI is more than 40.

A significant part of the evaluation process is looking at the candidate’s psychosocial and family support situation. If there is a history of a major psychiatric condition, this needs to be evaluated by a psychiatrist prior to listing.
Also, it is very important to have some kind of family support for the care that is going to be required for the patient before and after transplantation.
Compliance with treatment is looked at seriously. Any issue with non-compliance may rule a patient out because the transplant team needs to make sure that a scarce resource such as an organ will not be wasted on someone who does not comply with the treatment regimen after the transplant.

During all this, any potential living donor is also worked up with some basic tests and an interview by the transplant team. He is evaluated to see if he would be a good match from the immunologic standpoint and to see if he is under any coercion or pressure to come forward as a donor.

TISSUE DONATION

Every year, there are approximately 20,000 tissue donors in the United States. Nearly a million tissue transplant surgeries are performed each year in the US and it is estimated that 1 in 20 Americans will need some type of tissue transplant. Almost 2.5 million people are helped through tissue and eye donation every year.

Tissues that can be donated include bone, heart valves, veins, skin, ligaments and tendons. These can be recovered upto 24 hours after death has occurred.

Tissue donation is different from organ donation. Organs that can be recovered for transplantation include kidneys, liver, heart, lungs, pancreas and intestine. Usually a tissue donor has died a biological death, meaning the person’s heart and lungs have permanently stopped functioning. In many instances, an organ donor has had a sudden death and is declared “brain dead” prior to becoming an organ donor. Approximately 24.000 people are declared brain dead each year. Only 2-3 % of all deaths meet the criteria for organ donation.

One tissue donor can enhance the lives of more than 50 recipients. Anyone, regardless of age is a potential tissue donor. Donated heart valves can help replace damaged ones and special bone grafts can help patients with spinal deformities. Skin/bone grafts can help replace tissue lost due to trauma, congenital deformities, cancer, arthritis and other conditions. Skin donations could be life saving for burn victims and are also used for reconstructive and plastic surgery applications

SALLY’S STORY – THE MIRACLE OF PAIRED KIDNEY DONATION

Sally M. (not her real name) was born with polycystic kidney disease (PKD), a condition that afflicts almost 600,000 people in the US. She was diagnosed with this dreadful disease when she was in her early 30’s. Just a few years ago, she had had her second child and she was busy being a mom and having a thriving small business that she ran with her husband, Chris.

Sally had known about PKD ever since she was a child.  Her own father also had PKD, which caused him to stop working when he was in his 40’s as his kidneys had stopped working completely and he had to undergo dialysis three times a week to stay alive. Upon the insistence of his kidney doctor, he was put on the transplant waiting list since he did not have anybody who could donate a kidney to him. After waiting for about four years, Sally’s father received a deceased donor kidney and he went on to live on for many years without having to be on dialysis.

Sally’s own family physician had referred her to a nephrologist many years ago so that he could keep an eye on her kidney function. At some point, he warned her, her own kidneys were going to start to shut down and she was going to have to be on dialysis, just like her dad. Now in her early 40’s, Sally’s kidneys had begun to get larger because of the growing cysts, which meant that she was moving closer to being on dialysis and needed to be evaluated for a kidney transplant.

Chris could no longer see his wife’s medical condition decline in front of his very eyes. He went to Sally’s nephrologist to be evaluated for being a live kidney donor. Based on the initial blood tests, he was found to have a different blood group and was therefore not a match for Sally. The nephrologist suggested paired donation and referred them to the university medical center for this procedure.

Paired donation is a relatively recent concept as a treatment option for kidney failure. The first live donor kidney transplant was between a set of identical twins in Boston. Transplant between these two brothers meant that as they were genetically identical, the donated kidney would not have any rejection episodes in the new recipient. Chris could not be a donor to Sally because his kidney would be immediately rejected by Sally’s body as their blood groups were not identical. With the help of paired donation, the transplant center was able to link them up with Jane and Fred (not their real names) who also were in a similar situation. Based on extensive testing, Jane could donate her kidney to Sally and Chris could donate his kidney to Fred. In this way, both Sally and Fred could avoid going on dialysis and receive healthy, live donor kidneys and have a long productive lives ahead of them.

The two couples lived approximately forty miles from each other. Therefore, on the day of the transplants, Chris became a donor to Fred at his transplant center while Sally received a kidney from Jane at her own hospital.  Both pairs did extremely well after their respective surgeries and continue to live healthy productive lives.

Paired donation has been able to save countless lives since it was first thought of in 1986. The first formal paired donation program was started in South Korea in 1991 and the first US paired donation was carried out at Rhode Island Hospital in 2000. After Johns Hopkins started the first US paired donation program in the US, many other similar programs have been started in different parts of the country. The National Kidney Registry carried out the longest chain of paired transplants in the country by having a 70 participant chain in 2014.

Today, both Sally and Jane are close friends, as are Chris and Fred. They serve as an inspiration to the power of collaboration and progressive scientific innovation to help combat the critical organ shortage in this country. More such pairs are needed to not only save lives but also millions of dollars that can serve to advance education and research to help end the agonizing wait for a transplant that thousands of people have to endure every year.

POST – TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD)

PTLD is a common cancer that occurs after an organ or stem cell transplant. In almost every case, this type of cancer is associated with Epstein-Barr virus or EBV. The virus can be acquired after the transplant procedure is done, known as a primary infection or can get re-activated if the patient already had the virus prior to the transplant. Primary infection of this virus can be acquired through the donor of the organ or from the environment.
Most cases of PTLD occur within the first year of the transplant. This is because the most intense immunosuppression is given right after the transplant procedure in order to prevent rejection. This unfortunately causes the virus to proliferate and cause PTLD. There is a higher incidence in children who receive a transplant compared to adults. Higher rates are also seen after heart, heart-lung or small bowel transplants. Approximately 0.6 to 1.5 percent of kidney transplant recipients will develop PTLD compared to approximately 5 percent in heart transplant recipients.
Clinically, there is a wide range of features that PTLD can present with, from a rapidly spreading disease to a localized, painless lump, usually in the armpit, neck or groin. General symptoms of malaise, fever and night sweats can occur.
When a suspicious lesion is found, a biopsy is usually performed which will then confirm the diagnosis of PTLD.
Treatment of PTLD involves the transplant team and the cancer specialist. It involves lowering the dose of the immunosuppressive medications and monitoring the condition of the transplant and the PTLD.  In early cases, lowering the dose is usually enough. This will give the body’s immune system to fight the PTLD. If lowering immunosuppression is not working or not possible for fear of rejection of the organ, other treatment options are employed.
This includes:
a) Rituximab, an antibody drug, which is part of treatment for a type of lymphoma, known as B-cell non-Hodgkin lymphoma.
b) Chemotherapy, this is either given alone or in combination with rituximab
c) Radiotherapy, for localized PTLD or if PTLD is in the brain or spinal cord
d) Surgery, when it is localized and can be removed

LONG TERM RISKS TO LIVING ORGAN DONATION


Most living organ donors are screened and worked up extensively prior to their surgery and are usually picked as donors because they are in good health. Most donors remain healthy and go on to live long and healthy lives.

The post-operative recovery is usually 4 to 6 weeks, depending on the type of operation that has been performed. For example, the laparoscopic procedure for kidney donation involves one larger incision and two to three smaller ones. These tend to heal faster with less pain compared to the larger flank incision for open nephrectomy.

Some donors have long term problems associated with surgery such as pain due to nerve damage, hernia or intestinal obstruction. These are serious issues which may require long term follow up with the physicians at the transplant center and may also need surgical intervention, if serious. Currently, no long term data is available regarding these complications for living donors in the United States.

Donors are highly encouraged to have regular follow up visits with their family physicians after organ donation. Kidney donors should be regularly monitored for high blood pressure, proteinuria and reduced kidney function in their remaining kidney. There have been some instances of the donors themselves requiring a kidney transplant later because of kidney failure. This should be discussed with the transplant team prior to the surgery so that risk factors could be identified which will predispose to kidney failure later in life.

The majority of donors can live a healthy life after kidney donation. Most transplant centers will caution the donors to restrict contact sports like football, wrestling, boxing, soccer, hockey and martial arts or wear padded vests under clothing for protection.

Pregnancy is usually not recommended for at least six months following donation. Female donors are encouraged to talk to their transplant teams and their og-gyn physicians to ensure good pre-natal care once they do get pregnant. Please be advised that some additional problems can occur after kidney donation as a result of the pregnancy such as pregnancy-induced hypertension, proteinuria  and pre-eclampsia.

KIDNEY TRANSPLANT PRIOR TO DIALYSIS- THE ADVANTAGES OF PRE-EMPTIVE KIDNEY TRANSPLANTATION

Pre-emptive kidney transplantation is when a kidney transplant is performed prior to starting dialysis. There have been multiple studies that show that avoiding dialysis and performing a transplant prior to initiating dialysis is advantageous to the recipient in many ways.

Some of these advantages are:

a) improved patient survival
b) transplanted kidneys last longer
c) recipients tend to return to work much faster
d) the quality of life is much better when compared to receiving a transplant after being on dialysis
e) lower medical costs in the long-term

Advantages of avoiding dialysis include:

a) decreased infections in the dialysis catheters
b) there is no need for a permanent dialysis access, therefore no surgery required and hence no surgery related complications
c) decreased heart attacks, strokes and sudden deaths associated with dialysis

The average waiting period for a deceased donor transplant is between 3 to 5 years. Keeping this time frame in mind, performing a transplant earlier is advantageous due the reasons mentioned above, and also if the recipient has a potential living donor.

Potential advantages of a living donor transplant, compared to a transplant from a deceased donor include:

a) If the donor and recipient are family members and genetically related, the match between them is better and hence have a lower chance of rejection.
b) The transplanted kidney from a live donor usually works immediately as compared to a deceased donor kidney, that could take some time to start working.
c) The procedure can be done at a convenient time and can be planned in advance which works better for both the donor and the recipient.

KIDNEY ALLOCATION SYSTEM FOR TRANSPLANTATION FROM DECEASED DONORS

The new kidney allocation system (KAS) went into effect in December, 2014. This was initiated by the United Network of Organ Sharing (UNOS), which is the nation’s transplant system, also known as the Organ Procurement and Transplantation Network (OPTN).
This new system will better match kidneys and donors based on new discoveries and data that is available currently. This involves creating a new classification system for kidneys and the patients or candidates who are waiting for those kidneys to become available.

How are kidneys classified?

Each kidney that is available for transplant now has a Kidney Donor Profile Index (KDPI). This is a percentage score between zero to 100 percent. It helps calculate how long a kidney is likely to function when compared to other kidneys. For example, a KDPI score of 20 percent means that the kidney is likely to function longer than 80 % of other available kidneys. In other words, the lower the percentage score, the better the quality of the kidney.

How is the KDPI score calculated?

This score is calculated by using certain facts from the donor. These include:
a) Age
b) Height
c) Weight
d) Ethnicity
e) Whether the donor died from loss of brain function or heart function
f) Stroke as a cause for death
g) History of high blood pressure in the donor
h) History of diabetes in the donor
i) Whether the donor had hepatitis C
j) Serum creatinine

How are transplant candidates classified?

Each candidate has an individual Estimated Post-Transplant Survival (EPTS) score. This is a percentage score between zero to 100 percent. This score calculates how long the candidate on the wait list will need a functioning kidney transplant compared with other wait list candidates. For example, a candidate with an EPTS score of 20 percent is likely going to need a kidney longer than 80 % of other candidates. This score is calculated by the listing transplant center.

How is the EPTS score calculated?

This score is calculated by looking at certain candidate facts. These are:

a) Age
b) Length of time spent on dialysis
c) Any previous organ transplants?
d) Current diagnosis of diabetes?

How are KDPI and EPTS scores used to allocate kidneys?

The kidneys with a KDPI of 20 percent- those that are expected to last the longest, are offered to candidates with an EPTS score of 20 percent or less- those who are expected to need the transplant the longest.
If an organ with a KDPI score of 20 percent or less is not accepted for a lower EPTS patient, they are then offered to any other person who would match, regardless of their EPTS score.
Kidneys with a high KDPI score are expected to last for a shorter period of time and are offered to candidates who are not able to stay on dialysis for a long time.
Kidneys with KDPI score of 85 percent or greater are offered first to a wider area of the country than other kidneys so that they are used as quickly as possible.
Children and teenagers receive priority for kidneys with a KDPI score of 35 percent or below.

How does the new system help patients who are hard to match?

Patients with blood type B and those with pre-existing antibodies (either because of previous transplants, pregnancy or blood transfusions) have been found to be hard to match and sometimes have to wait for years before they can get a suitable kidney.  For a patient with blood type B, certain donors with blood type A have a “subtype” that allows them to donate to the type B candidates.
In both these instances, the candidates are given priority in the new KAS.

JIMMY AND HIS JOURNEY WITH KIDNEY DISEASE

Jimmy is a young man in his twenties and is a passionate rock musician. Like every other rock band, Jimmy and his three other bandmates believe they will one day become the next Rolling Stones. They have been playing together for the past many years, in fact right out of high school. Jimmy remembers the exact time when he and his friends decided to come together to form their band.

For Jimmy though, he has had to deal with a greater struggle- chronic kidney disease and his journey through transplantation. He remembers getting fevers and sore throat very frequently as a young child. His pediatrician at that time had told his mother that he had strep throat on a number of occasions. As he grew, these frequent infections ultimately caused his kidneys to fail and he and his family were faced with him needing to go on dialysis. As a budding teenager with higher ambitions, a life with chronic kidney disease and dialysis can be extremely challenging. After talking to his physicians, his parents decided to get tested to become potential kidney donors. They were referred to their downtown university transplant program where Jimmy and his parents went through a battery of tests. Jimmy’s mother turned out to be the best match for him. A month later, Jimmy received his mom’s left kidney. They both did well and were back home in 5 days.

Jimmy was put on multiple medications in order to prevent rejection of his mom’s kidney. One of these medications is prednisone, which is a steroid. Steroids have been in use for many decades for the purposes of treatment and prevention of rejection after organ transplantation. They are powerful and effective, but have a lot of side effects. In a few months, Jimmy started to see those side effects. The most distressing ones for him was the changes he was seeing in his body and the way he had started to look.  He had gained a lot of weight, his face started to look bloated and round and he put on extra weight around his chest and waist area. These changes started to distress Jimmy but based on what his doctors were telling him, he could not really do much as he was on the lowest possible dose of the steroid and he risked rejecting his kidney if they lowered the dose any further.

One other change was that Jimmy was getting moodier, which is another side effect of the steroid. There were days when he felt depressed and lonely and couldn’t really verbalize what he was going through to anyone. His parents took him to a psychiatrist, which did help, but not enough. Jimmy’s response to all these changes was that he started to skip his medications and very soon was in the acute rejection of the kidney. He had to be admitted to the hospital and after a biopsy of his kidney transplant, was given strong medications to fight the rejection. After a few days, he returned home, but unfortunately, the damage had been done. The kidney never really recovered and Jimmy had to be put on dialysis.

By now Jimmy was ready to graduate high school, which he did. Despite the disappointment of losing his kidney, he soldiered on and started his college career. He and his friends would meet on weekends to perform at various locations in the city. Jimmy had to be very careful with his diet and fluid intake since he did not have a fully functioning kidney. He needed thrice weekly dialysis treatments to keep him alive. He had now started seeing a different kidney specialist since he was now an adult. His new doctor suggested to him and his parents to re-consider another kidney transplant. After his initial reluctance, he was evaluated for another kidney transplant at the nearby transplant center. The physicians at the transplant center were initially reluctant to list him, as they deemed him “non-compliant” since he had voluntarily stopped taking his medications the first time around and caused his kidney to fail. He had to meet the psychologist and the social worker and show that he had learnt now that he had to be compliant with his treatment in order to be listed. Transplant physicians are by nature very wary of the issue of non-compliance. As Jimmy found out the hard way, strict adherence to the treatment regimen life-long is a must for proper functioning of a transplant. Moreover, Jimmy had now formed certain antibodies, proteins that can attack any new transplant and cause it to fail. After a prolonged process, Jimmy was finally accepted and listed for a deceased donor kidney transplant. In about three years, Jimmy received that phone call in the middle of the night to report to the hospital right away, as there was a potential kidney that had become available for him. A few hours later, Jimmy had a brand new kidney, which worked right away and got him off dialysis.

Today, approximately five years later, Jimmy is doing well and has had no rejection episodes with his new kidney. He continues to perform with his band and hopes to start a family of his own very soon.

The issue of non-compliance is a serious one, especially in teenagers. They are by far more prone to risky behaviors which could be life threatening at times. In Jimmy’s case, he had to go through a period of uncertainty and inconvenience before he could a new lase on life. He now goes around and speaks to people about his experiences and hopes that no-one has to lose their transplants to risky teenage behavior.

IS ORGAN DONATION POSSIBLE IF THE DONOR HAS CANCER ?

There is an increasing demand for organ transplants because of a dramatic rise in the number of patients who have organ failure and can benefit from an organ transplant. Transplant physicians, in order to alleviate this critical shortage are always looking for ways to increase the number of people who could potentially be organ donors. One way to expand this pool is to consider a donor who has cancer. This can be detrimental in certain kinds of malignancies where it has been shown to spread from the donor to the recipient. However, when carefully screened, there are a number of donors who have a history of cancer who can qualify to become organ donors.

Based on numerous studies, certain types of cancers fall into the minimal risk category, where there is a < 0.1 % chance of cancer transmission from the donor to the recipient. These include:
a) basal cell carcinoma of the skin
b) squamous cell carcinoma of the skin without metastases
c) other early skin cancers that are not melanomas
d) early cervical cancer
e) early vocal cord cancer
f) superficial, non-invasive bladder cancer
g) small papillary or follicular thyroid cancer
h) small, early stage renal cell cancer which have been removed

Low risk category has a 0.1 to 1 % transmission risk. This includes the following cancers:
a) small, early stage renal cell cancer (slightly bigger in size, 2.5 cm, removed)
b) low grade brain or spine tumors
c) slightly larger papillary or follicular thyroid cancers
d) treated cancer more than 5 years prior with a > 99 % possibility of cure

Intermediate risk category (1 to 10 % transmission risk) includes:
a) early breast cancer
b) early colon cancer
c) removed renal cell cancer, 4-7 cm, early stage
d) treated cancer more than 5 years prior with a 90 – 99% chance of cure

High risk category (> 10 % transmission) includes:
a) Malignant melanoma
b) Active breast or colon cancer, higher than stage 0
c) Choriocarcinoma
d) Advanced brain or spinal tumors
e) Leukemia or lymphoma
f) Any cancer that has spread or metastasized
g) Sarcoma
h) Lung cancer
i) Advanced renal cell cancer
j) Neuroendocrine tumor

It must be mentioned that accepting donors with any history of previous cancers is a complicated problem. The decision to proceed with transplantation should be made with as much information that can be found on that particular donor’s medical history and after consultation with a cancer specialist and the transplant team. The list above is meant to serve as a risk assessment tool and the final decision is made after careful deliberation. Sometimes, if the transplant is urgent and the donor’s history is unknown, inadvertent transmission of cancer can occur. However, such incidents are extremely uncommon and the potential benefit of receiving an organ that can save a life is immense.

IS BARIATRIC SURGERY THE ANSWER FOR OBESE TRANSPLANT CANDIDATES

It is estimated that a third of the US adult population is obese, defined as a BMI above 30 kg/m2. Approximately 35 to 40 percent of renal failure patients are obese as well, a condition that makes it hard for them to receive a timely kidney transplant. Studies show that for dialysis dependent patients with a BMI more than 40 kg/m2, it is 44 percent less likely that they are offered a new lease of life in the form of a kidney transplant. Transplant centers all across the nation have strict inclusion criteria and most of them will not put someone with a BMI more than 40 kg/m2 on the waiting list. This condition has been put in place because research shows a higher complication rate and shorter survival time for obese transplant recipients.

Bariatric surgery has been suggested as an option for patients on the waiting list and for recipients of a kidney transplant. Most bariatric procedures are fall under the following three procedures:

a) Laparoscopic adjustable gastric banding (LAGB) which is the least invasive option and involves placing a silicone band around the stomach to decrease its size. Another advantage is that it does not alter the anatomy of the stomach and therefore does not cause any malabsorption, which may affect the patient’s ability to absorb the medications required to prevent rejection of the transplant. Disadvantages include the presence of a foreign body which could cause stomach erosion and infection as well as a slower rate of weight loss compared with other procedures.
b) Laparoscopic Roux-en-Y gastric bypass (RYGB) has been shown to have the most weight loss but does cause malabsorption. Multiple studies have shown the safety and effectiveness of this surgery to induce weight loss while on the waiting list.
c) Laparoscopic sleeve gastrectomy (SG) is a relatively newer option and involves stapling of a part of the stomach to decrease its size. No malabsorption is encountered but long term data is currently lacking.

Factors to consider when choosing the best option include:

a) Which organ is being transplanted
b) Amount of weight loss necessary to get on the list
c) How urgent is the transplant
d) Any past surgeries that could make it a challenge to do the procedure
e) Co-morbidities

Bariatric surgery has been shown in many but small studies that it has immense benefits to induce a dramatic and rapid weight loss in both the pre- and post-transplant setting. Secondary benefits to weight loss include decrease in hypertension, decreased need for medications to treat diabetes, improved cardiovascular health and an improvement in kidney function.

INTESTINAL TRANSPLANTATION

Approximately 274 candidates are currently on the waiting list for an intestinal transplant, with 147 transplants performed in 2016. It still remains as one of the most challenging and least frequently performed abdominal transplant procedure. This has been mainly due to poor long term survival and a higher rate of post-procedure complications in the recipients. Recent and continuing advancement in surgical techniques and better monitoring and management of post-operative complications have improved outcomes in this challenging group of patients.

The most common indication for intestinal transplantation is intestinal failure with the development of severe complications due to total parenteral nutrition (TPN).

The most important cause for intestinal failure is short bowel or short gut syndrome. This refers to a serious condition where there is a lack of well functioning small intestine which can result in diarrhea and failure to absorb adequate nutrients leading to weight loss and severe malnutrition.

There are multiple causes of short gut syndrome. In children, congenital malformations , infections, extensive surgical removal and an inability to absorb nutrients are the major reasons for which TPN is required for survival. Similarly, in adults, extensive resections because of conditions like Crohn’s disease, tumors or ischemia are responsible for the need for TPN.

Most patients will do well with chronic home TPN. Recent data has shown more than 80 % survival in a 3 year period. Severe complications due to TPN such as recurrent catheter related infections, lack of central venous options, chronic liver failure and a poor quality of life will be the major reason for considering intestinal transplantation.

Surgical procedures for intestinal failure are divided into intestinal transplant alone or in combination with the liver or other abdominal organs. Donors are usually deceased but some live donor intestinal transplants are being performed as well. Extensive pre-operative testing that includes blood tests, xrays of the remaining bowel, liver biopsy if there is any liver dysfunction and tests to ensure that the heart and lungs are healthy enough to undergo this major surgery are done prior to listing a patient for transplantation.

Post-operative care is in the ICU where there is close monitoring to make sure all the organs are functioning well. Antibiotics are used to prevent infections and immunosuppressive medications are given to prevent rejection of the transplanted organ. Once there is good functioning of the intestinal transplant, oral diet is started. Close monitoring after discharge is standard to prevent complications such as severe infections, drug reactions, post-transplant cancers and rejections.

Recent data suggests improving survival rates with better patient and graft selection, improved monitoring of post-transplant related complications and transplants performed at relatively high volume centers.

HOW ARE LIVERS ALLOCATED TO PATIENTS ON THE WAITING LIST?

The liver allocation system in the US is managed by UNOS (United Network for Organ Sharing), which is a charitable organization under contract with the federal government that creates policies that evaluates the process of organ allocation.

For the purposes of allocating livers, UNOS developed a system to prioritize the allocation of livers to the patients who need them most urgently. The formula that predicts the urgency of a liver transplant in patients ages 12 and over is called MELD (model for End Stage Liver Disease) and PELD (Pediatric End Stage Liver Disease model) for children aged 11 and lower.

MELD looks at four lab tests, which are:
a) Bilirubin (measures how effectively the liver excretes bile)
b) INR (measures the liver’s ability to make clotting factors)
c) Creatinine (a measure of renal function as kidney dysfunction is more prevalent as the liver function declines)
d) Serum sodium (measures severity of portal hypertension)
Once these labs are obtained, they are entered into a statistical formula which then gives a score for that particular patient. Scores range from 6 (less ill) to 40 (gravely ill) and predicts survival of these patients if a liver transplant is not received in the next three months. For example, a MELD score of 38 has a mortality of 80 % and a score of 22 10 % without receiving a liver transplant in the next three months.

The priority exceptions to MELD are for Status 1A and 1B patients.
Status 1A is for patients with acute or fulminant liver failure where survival would not be possible beyond a few hours to days without a transplant.
Status 1B is for sick, chronically ill pediatric patients (less than 18 years).

In 2015, a new UNOS policy regarding patients who have hepatocellular carcinoma (HCC) was implemented. Patients who have HCC will be listed at their calculated MELD scores for the first six months. If they continue to meet criteria at 6 months, MELD candidates will have a score of 28 and PELD candidates will have a score of 34.

MELD scores typically go up or down depending on how well the liver is functioning. Patients with higher MELD scores need to have their blood work done frequently to ensure that they are monitored closely for any deterioration.

Once a donor is available, the patients are prioritized based on:
a) donor’s age
b) medical urgency
c) geographical proximity to the donor

Therefore, the list looks at the status 1A and 1B candidates first, then to:

a) MELD score higher than 35 locally or regionally
b) MELD more than 15 locally or regionally
c) National status 1A or 1B
d) National score higher than 15
e) Others with scores less than 15, local, regional or national

Waiting times are not known to predict the need for a liver very accurately, therefore this criterion is used only if two candidates with identical MELD scores are offered a liver.

HISTORY OF ORGAN AND TISSUE TRANSPLANT


Organ transplants became possible because of the pioneering efforts of many.  The first clinically successful organ transplant occurred in 1954 between identical twins at the Peter Bent Brigham Hospital in Boston performed by Dr. Joseph E. Murray, who was later awarded the Nobel Prize for Medicine in 1990. However, few know that it was the successful transplantation of bone, skin and corneas that started between 1900 and 1920 that paved the way for further development of other tissues and organs to be transplanted successfully. The US Navy established the first bone and tissue storage facility in 1949.

The first successful recorded bone graft was in in 1668 when Job van Meeneren used bone from a dog’s skull to repair a defect in a human in the Netherlands.  Fresh skin autograft was demonstrated by Berger in 1822 and the first skin allograft was performed by Swiss surgeon Reverdin in 1868. The first successful corneal transplant was in 1906 by Edward Zirm followed by a cadaveric knee joint transplant by Eric Lexer in 1908.

Dr Thomas Starzl performed the first liver transplant at the University of Colorado in 1963, which was quickly followed by the first lung transplant by Dr James Hardy at the University of Mississippi in in 1964 and the first heart transplant by Dr Christiaan Barnard in 1967 at Groote Schuur Hospital in South Africa.

The Uniform Anatomical Gift Act was set up in 1968, drafted by the National Conference of Commissioners on Uniform State Laws (NCCUSL) with the intention of harmonizing state laws for the purposes of organ donation. The Harvard Criteria for the Determination of Brain Death was the first to define brain death based on neurologic criteria.

Dr Lillehei performed the first pancreas transplant at the University of Minnesota in 1969. Tissue transplantation was taken to greater heights in the 1970’s by the use of cryopreserved heart valves by O’Brien in Australia  and Angell in the US, use of cryopreserved skin allografts and the use of a cryopreserved venous allograft by Dent and Weber (1973).

Use of immunosuppressant medications was also introduced in 1978 (cyclosporin) which was developed in Cambridge by Dr Roy Calne and by Dr Starzl in Pittsburgh.

Dr Norman Shumway is credited for being the first to do a combined heart/lung transplant at Stanford in 1981. The National Transplant Act, which was set up in 1984, legislates federally funded centralized waiting list for organ recipients, outlaws buying and selling of human organs and mandates establishment of scientific registries to monitor transplant centers, Organ Procurement Organizations and hospitals.

By 1996, almost 500,000 tissue transplants were performed in the US.
The first partial face transplant was performed in France in 2005 followed by first successful near total face transplant  was performed at the Cleveland Clinic by Siemionow. Barret and colleagues in Barcelona performed the first full face transplant in 2010.

Extremity transplants started in Germany  with the first successful complete double arm transplant (2008) and the first double leg transplant in 2011 in Spain.

HEATHER’S SAGA – THE MIRACLE THAT IS TRANSPLANTATION

Heather (not her real name) was airlifted to our hospital, a large tertiary care teaching institution, with a very serious medical condition. She had fulminant liver failure, a life threatening condition that causes severe liver injury which in turn can cause kidney failure, brain swelling and ultimately death if not treated urgently by performing a liver transplant.

Just twenty four hours prior, Heather was at work as a primary school teacher, wrapping up the day and about to head home to her family. She woke up that morning feeling under the weather with a head cold and body ache and also had a slight fever as well. Never the one to complain or take a sick day off, Heather got ready, had an extra large cup of coffee on her way to work and started her day in earnest, like she did every single day. As the hours passed by, Heather continued to feel sick and at 4 p.m., was looking forward to going home and get in bed. It was in the next few hours that things started to unravel. Upon reaching home, she felt extreme weakness and nausea and soon began throwing up. Her husband John, who fortunately was home early, decided to take her to the nearest ER. By this time, Heather was barely responding to any of John’s questions and was breathing heavily. Upon reaching the ER, she was immediately taken in and a slew of nurses and physicians gathered around her. Very soon, the ER physician came in to talk to John about Heather. He told him that Heather had severe liver failure and she was in serious danger of losing her life unless she was airlifted to the nearest transplant center, which is where I first met Heather and John.

The ER had intubated Heather and she was breathing via the ventilator. She was completely unresponsive to any kind of stimulus and most of the history I got was from talking to John. Other specialists had also been summoned to Heather’s bedside. Based on our collective evaluation, it became very clear that Heather needed an urgent liver transplant. Fortunately, all her other organ systems were still in good shape and we listed her as a status 1 A, the highest status possible and reserved only for the sickest patients who would otherwise if not for an urgent liver transplant in the next few hours. Now, all we had to do was to keep Heather alive and wait for an appropriate donor liver to become available.

We got a call that night about a local organ donor, whose blood group matched Heather’s. We set out to retrieve this incredible gift this donor and his family were making. Not only were we trying to save Heather’s life, there were other potential recipients for the heart, lungs, kidneys, intestine and pancreas in other hospitals who would get a new lease of life due to the generosity of this donor.

After a few hours of work at the other hospital, my colleagues and I were back to now begin the transplant operation on Heather. We first removed Heather’s own liver while a different team of surgeons worked on removing some extra tissue on the donor liver. Once we were ready, we brought the donor liver and started sewing the blood vessels, the vena cava, the portal vein and the hepatic artery, in that order. We had just finished sewing the portal vein when the anesthesiologist informed us that Heather had lost her pulse, which meant that her heart had stopped beating. We looked up and saw a flat line on the monitor. We had to do something fast or we were going to lose Heather right there. My attending transplant surgeon, who was assisting me with this procedure, looked up at me and said, “ Let’s open the diaphragm”. The diaphragm is a muscle that helps with breathing and separates the chest and abdominal cavities. We opened the diaphragm from below and I reached inside and started to manually pump Heather’s heart, while the anesthesia team and others worked frantically to save Heather’s life. After a few tense minutes, Heather’s heart started to beat on its own, and very soon, it regained its normal rhythm and started to pump blood like it was doing before. Once this happened, we sutured the diaphragm and were able to continue to work on sewing the remaining blood vessels and the bile duct. A few hours later, Heather was in the ICU, with a new working liver and her family at her bedside.

In a few hours, Heather opened her eyes and we were able to disconnect her from the ventilator. She was breathing well, her heart and liver both doing great as well. Heather made an uneventful recovery and was able to be discharged home in less than a week.

Even though this happened many years ago, I still remember that night as if it was yesterday. We brought Heather back from the jaws of death, not once but twice. Heather is doing well, still working full time as a teacher and living a full life with John and the rest of her family. In reviewing what caused her own liver to fail, we were able to point to a herbal supplement that Heather had just started to take for energy and vitality, something she picked up just a few days prior from the local drug store.

FREQUENTLY ASKED QUESTIONS ABOUT ORGAN DONATION


1) WHO CAN DONATE AN ORGAN ?

Almost anyone could be an organ donor. There is no real age limit where an individual is not considered an organ donor. Donors under the age of 18 years would need the consent of a parent to be able to donate.

2) I AM A REGISTERED DONOR. IS THAT ENOUGH ?

No, even if you are a registered donor on your driver’s license, your state’s donor registry or a donor card, your next of kin could still refuse to move forward with organ donation at the time of your death. Please make sure you talk to your family and let them know of your wishes to be an organ donor or by putting this information in your will or any other legal document.

3) I AM NOT IN GOOD HEALTH. COULD I STILL BE AN ORGAN DONOR?

Yes. Almost every donor has to go through extensive testing before they can be considered suitable for donation. If tests show that you have advanced cancer or a severe infection, you may not be an appropriate candidate for donation. This will be determined by the treating physicians and the rest of the team.

4) AFTER DONATION, COULD I STILL HAVE AN OPEN CASKET FUNERAL?

Yes. After organ donation, all incisions are surgically closed and the body is suitable for clothing and hence is appropriate for open casket funeral.

5) WILL FUNERAL COSTS BE COVERED AFTER ORGAN DONATION?

No, the funeral costs are the family’s responsibility.

6) COULD I REGISTER TO DONATE A SINGLE ORGAN AFTER MY DEATH?

Yes, you could choose to give as many organs or tissues you want for donation.

7) WILL I HAVE TO PAY FOR THE MEDICAL EXPENSES IF I CHOSE TO BECOME
A LIVING DONOR ?

No, the entire health care related expenditure is covered by the recipient’s insurance or the recipient himself.

FATTY LIVER DISEASE – TREATMENT WITH LIVER TRANSPLANTATION

Hepatology is a branch of medicine that studies the liver and its various disorders. Hepatologists, or doctors that specialize in hepatology, today feel that there is a growing problem that is on the horizon. This entity is called NAFLD or non-alcoholic fatty liver disease. This is a spectrum of disorders of the liver that ranges from a fatty liver (also called steatohepatitis) to a more severe form called NASH or non-alcoholic steatohepatitis. The difference between the two is the amount of injury sustained by the liver cells that ultimately causes liver failure and the need for a liver transplant.

This entire spectrum of NAFLD is the manifestation in the liver of the so called “metabolic syndrome”. Underlying common cause of the metabolic syndrome is insulin resistance seen as obesity, type 2 diabetes and lipid abnormalities. Obesity is a growing problem in the Western Hemisphere with approximately 30 to 40 percent of adults and 17 percent of children in the obese category (BMI > 30. Normal BMI is below 25) in the US. It is estimated that NASH will be the number one reason for liver transplantation worldwide in the next 10 to 20 years, with an estimated 20 % of all NAFLD patients with NASH. Today, there are more than 2 million patients with NASH in the US, all potentially requiring a liver transplant in the next few years. It is currently the third most common reason to require a liver transplant, only after hepatitis C and alcohol related cirrhosis.

What this also means is that all potential liver donors, whether deceased or live, are also vulnerable to having fatty liver. It is a well established fact that fatty livers do not do well if used for transplantation. There is a higher incidence of these livers not working at all, a phenomenon called primary graft non-function or that they have poor long term function. One way to avoid this problem is to be selective when assessing a potential donor. A liver biopsy to assess for the amount of fat in the liver cells is sometimes required. If there is more than 30 % steatosis or amount of fat in the liver, it is generally not used for transplantation. This puts an additional burden on the already critical shortage of livers that are available out there for transplantation.

Studies have shown overall good results after liver transplantation for NASH. Compared to hepatitis C or alcoholic cirrhosis, patients with NASH tend to have a higher incidence of death from cardiovascular causes and infections. The same studies also show recurrence of NASH in a third of the recipients of the new liver after transplantation, but very few will progress to requiring another transplant. Interestingly, about a third of recipients in the non-NASH category also have been shown to develop NAFLD in 1 to 3 years after transplantation.

ESSENTIAL BLOOD TESTS PRIOR TO A TRANSPLANT

Three blood tests are done sequentially during the transplant work up to determine if the potential donor is a match. These tests are:

1) Blood typing (ABO compatibility)
2) Tissue typing (HLA typing)
3) Cross match

ABO COMPATIBILITY

This is the first test performed to see if the blood groups between the donor and the recipient are a match.
There are 4 blood groups – A, B, O and AB.

Blood group O is the “universal donor” which means he can donate to any of the four blood group recipients.

Blood group AB is the “universal recipient” and can receive from any of the four blood groups.

In short, then:

Recipients with:
a) blood group O, can receive from blood group O only
b) blood group A, can receive from blood groups A and O
c) blood group B, can receive from blood groups B and O
d) blood group AB, can receive from blood groups A, B , O and AB

TISSUE TYPING (HLA TYPING)

Once it is determined that the blood groups between the donor and recipient are a match, tissue typing or HLA typing is done to see how well they match.

HLA stands for Human Leukocyte Antigen. HLA are proteins that are located on the surface of the white blood cells and other tissues of the body.
When two people share the same HLA, their tissues are immunologically compatible with each other. The better the HLA match, the longer a transplant will last, generally speaking.

There are three general groups of HLA – HLA-A, HLA-B and HLA-DR.
Each person has 2 sets of HLA in their cells.
Each child inherits one set of HLA from each parent. Therefore, there is a 1 in 4 chance of being an identical match with the siblings.

CROSSMATCH
This test looks for antibodies that a recipient might have to a specific donor.
Antibodies are proteins that look for “foreign cells” and can attack the HLA of the donor, if they are specific to the donor. This causes the recipient to reject the organ.

Crossmatch is performed by mixing a sample of the recipient’s serum to the white blood cells of the donor. If the antibody is present in the recipient’s blood to the donor HLA, it will be read as a “positive” crossmatch, which means that the transplant should not be performed with this specific donor’s organ. A ”negative” crossmatch means that there are no antibodies specific to the donor and therefore, the transplant can proceed.

EPSTEIN-BARR VIRUS IN ORGAN TRANSPLANT RECIPIENTS

Epstein-Barr virus or EBV is a member of the herpesvirus family of viruses, just like CMV. It is very common and approximately 50 % of children by age 5 and about 90 % of adults have been infected with this virus.

In children, there are usually no symptoms after infection. In adolescents and young adults, EBV causes infectious mononucleosis or “mono”. Just like the other members of this virus family, EBV can be spread via bodily fluids such as saliva, blood and semen.

This virus usually lies dormant in the body and can get “re-activated” when the body’s immune system is weakened, usually after an organ transplant or with AIDS. New infections can also be transmitted via the transplanted organ in a recipient who previously did not have EBV infection.

The most dangerous consequence of EBV infection after organ transplantation is PTLD or post-transplant lymphoproliferative disorder. It is estimated that 70 % of PTLD is caused by EBV. This complication can range from having a benign growth of B cells to non-Hodgkin’s lymphoma, a form of blood cancer that needs to be treated aggressively and has a poor prognosis.

Currently, there are no vaccines that can prevent EBV. Antiviral drugs cannot prevent re-activation of the virus either. Therefore, treatment will depend on the serostatus of the patient and if the patient has PTLD. Serostatus is the presence or absence of EBV in the body. Seropositive status means that the person has been infected with EBV and has certain proteins known as antibodies in his blood. Seronegative status means that the person has not been infected with EBV and does not have the antibodies in the blood. Some transplant centers advocate using anti-viral medications to decrease the viral load in patients who are seronegative who receive organs from seropositive donors.

Treatment for PTLD involves reducing the immunosuppression drugs so that the body’s immune system could fight off the virus.  If this is not effective, further treatment with a drug called rituximab or even more aggressive treatment with chemotherapy is undertaken.

END STAGE RENAL DISEASE – AN INTRODUCTION

End stage renal disease or ESRD is a term used for advanced kidney failure which is usually irreversible and needs to be treated with either dialysis or a kidney transplant.

Dialysis is a term for different methods used to filter the blood and remove toxins that can then keep a patient alive in the absence of working kidneys.

Transplantation is a surgical procedure that is performed to implant a kidney from either a living or a deceased donor in a patient with ESRD.

EXTENT OF ESRD IN THE US

According to the most recent data, approximately 660.000 individuals have ESRD in the US.

Almost 58 % of these patients are male and most of the patients are between the ages of 45 to 64 (44 %).

Six out of 10 patients are white and three out of 10 are African-Americans.
ESRD is increasing by 5 % every year.

The most common condition leading to ESRD is diabetes (37 %), followed by high blood pressure (25 %), glomerulonephritis (17 %) and cystic kidney disease (5 %). Other less common conditions are responsible for the remainder of cases.

Approximately 90,000 patients die annually due to ESRD.

After one year of treatment, those on dialysis have a 20-25 % mortality rate, with a five year survival rate of 35 %. On the other hand, patients who have received a transplant have a 3 % mortality rate after 5 years.

COST OF TREATMENT OF ESRD IN THE US

According to data released by Medicare, approximately  $ 31 billion was spent in 2016 for the treatment of ESRD.

Patients with ESRD are 1 % of the US Medicare population but account for 7 % of  the Medicare budget.

Hemodialysis treatment costs an average of  $ 89,000 per patient every year.

Kidney transplant costs an average of $ 32,000 (surgical cost) and $ 25,000 per year post-surgery.

DOMINO LIVER TRANSPLANT

It was during my training in a large transplant center that I was fortunate enough to participate in a relatively rare procedure – the domino liver transplant.

The procedure involves two recipients receiving liver transplants almost simultaneously. A deceased donor liver is used for the first recipient A, who has a rare hereditary disease, in most cases this being a metabolic disease called amyloidosis. This disease is characterized by a build up of abnormal protein called amyloid in various organs of the body, which causes organ failure. This protein is made by the liver from birth but the manifestations of the disease, called amyloidosis, is seen at a much later age, usually when the patient is middle aged. The only treatment for this disease is liver transplantation. The liver that is removed from this recipient A can then be re-used in recipient B, who has liver failure from another cause. Even though the amyloid will continue to be produced in recipient B, it will take a few decades for it to manifest itself, by which time the recipient has usually lived out his life span. In 2008, a study looking at recurrence of the amyloidosis in the recipient found 2 cases out of 500 that had this problem recur.

My colleague and I were picked up very early morning from our hospital and driven to another large hospital in the same city, where we procured the liver from a brain dead donor. Almost simultaneously, recipient A, who had amyloidosis, was taken to the operating room by a second team that removed the liver at our center. Once we arrived back, I went in with the liver we had procured into recipient A’s room and started to help with the transplant procedure. My colleague took the amyloid liver from recipient A to recipient B’s room, where his diseased liver was removed and replaced with the liver from recipient A. By the end of the day, both patients were doing well in the recovery room, their livers working well and both of them well on the road to recovery.

A day that I will never forget when two lives were saved because of the miracle we call transplantation and by the advances made by science and medicine. This kind of bold and progressive thinking has decreased the critical organ shortage we face in the US for people with liver failure, waiting for a transplant. We still have a long way to go and efforts are under way for more advancements in the field of transplantation and immunology.

CAN BEING OBESE DECREASE SURVIVAL AFTER A KIDNEY TRANSPLANT?

It is estimated that 35 % of adults and 17 % of children are obese in the US. Obesity is related to an increased incidence of a number of serious health issues such as type 2 diabetes, cardiovascular disease, asthma, osteoarthritis, gallbladder disease and certain forms of cancer. Recent data suggests that increasing obesity is an independent risk factor for the development of end stage renal disease (ESRD). Treatment options are limited to dialysis and kidney transplantation after ESRD develops. Each treatment modality has its pros and cons as far the obese patient is concerned.

A study done a few years ago compared survival of obese patients (those with a BMI > 30 kg/m2) on dialysis and after receiving a transplant, which showed a survival benefit of transplantation over dialysis. However, multiple studies have shown increased complications after kidney transplants in obese patients. This has led to increased waiting periods for obese individuals on the transplant list, which itself leads to increasing obesity and more complications. Multiple transplant centers have developed strict protocols and restrictions on how they will mange obese patients on the transplant waiting list. Most centers will not accept patients whose BMI is more than 40 kg/m2 and some even going down to 35 kg/m2 as their upper limit.

Adverse effects due to obesity after a kidney transplant include increased incidence of acute rejection, delayed graft function (defined as the need for dialysis in the first week after a transplant) and eventual failure of the transplant. Increased BMI is associated with a shorter time to graft failure, eventually causing the patient to be put back on dialysis. There is also an increased incidence of wound complications such as wound infections and hernias in obese individuals.

It is estimated that approximately 20 percent of kidney transplant recipients become obese after they receive the transplant. This usually happens in the first two years after the procedure. Most recipients are put on corticosteroids as part of their maintenance immunosuppression to prevent rejection. However, a major side effect of the corticosteroid is weight gain and obesity. Another factor that may contribute to this phenomenon is the hormone leptin. This hormone tapers off after kidney transplantation which contributes to the obesity as well.

CAN A PERSON WITH HEPATITIS C BE AN ORGAN DONOR?

In the US today, there is a huge demand for organs for the approximately 120,000 patients waiting for a life-saving transplant. Approximately, 100,000 patients are in need of a kidney and there are numerous efforts under way to increase the donor pool so that a life could be saved. One of the ways is the utilization of kidneys from donors who are infected with the hepatitis C virus (HCV).

Currently, it is estimated that between 7 to 10 percent of all end stage renal disease (ESRD) patients have HCV infection. They have been shown to have a higher mortality rate compared to the patients who do not have HCV.

Multiple questions loom large when deciding whether or not to transplant a patient with HCV. On the positive side, there is a huge survival advantage of transplantation compared to dialysis. However, there are certain disadvantages of having HCV and having a kidney transplant. There is an increased incidence of progression of liver disease after transplant. This can be monitored by assessing the condition of the liver by doing a liver biopsy during the work-up phase and then doing further biopsies should liver dysfunction occur after the transplant. It has also been demonstrated that the incidence of new onset diabetes mellitus after transplant (NODAT) goes up and so does the risk of cardiovascular disease. In summary, short-term survival is comparable to a non-HCV infected recipient but longer survival is definitely inferior.

Using a deceased donor’s kidneys who is infected with HCV was considered a contraindication for transplantation not too long ago. This resulted in a lot of kidneys that were potentially usable but were being discarded at a higher rate. With a growing shortage of available donors, transplant centers revised their policies and HCV positive donor kidneys are being used for ESRD patients with HCV. Recent studies show that although the outcomes of using HCV kidneys for HCV recipients are inferior to using non-HCV kidneys, there is a significant reduction in the wait time, which itself translates into longer survival compared to being on dialysis. If it is shown that the donor is viremic, (actively replicationg HCV, based on the HCV RNA), then those kidneys are usually discarded.

ESRD patients with HCV need to be actively worked up to rule out progressive liver disease, including performing a liver biopsy, especially those with positive HCV RNA. Recent data has shown that approximately 25 percent of ESRD HCV positive patients have liver fibrosis. Monitoring liver enzymes alone is not accurate as it has been shown that the enzyme levels are lower when a patient is on dialysis. Sometimes, based on the severity of liver disease on the biopsy, a decision to proceed with a combined liver-kidney transplant could be made.

Treatment of HCV after renal transplant is complicated and involves many newer drugs on the market and some older medications such as pegylated interferon (PEG-IFN) and ribavirin. Caution is necessary as the PEG-IFN and ribavirin can cause morbidity and may have side effects, especially when immunosuppression is involved for the prevention of rejection

BASIC IMMUNOLOGY IN TRANSPLANTATION -OR IMMUNOLOGY FOR DUMMIES

Immunology is the study of immune system of the body. The immune system is responsible for the protection of the body against “foreign invaders” such as bacteria or viruses. It also is responsible for the process of rejection of an organ after transplantation. This is because the immune system does not recognize the organ as “self” and therefore wants to destroy it. The long term success of any organ transplant is dependent on adequately decreasing the effectiveness of the immune system so that the transplant can co-exist within the recipient and perform its function and keep the person alive.

The immune system has a series of immune cells that work together to protect the body from “foreign invaders”. There are two main types of immune cells-

a) T cells – that recognize the “foreign invader” with the help of a receptor on its surface, which then starts off a series of chemical reactions that stimulate other T cells to destroy the invader.
b) B cells – that produce a protein called an antibody that then destroys the invading cells.

Multiple other cells, such as the platelets work in tandem with the cells in the immune system to help in the fight as well.

There are pre-formed antibodies such as those associated with the different blood groups that also can cause severe rejection if the blood groups are not adequately matched prior to the transplant procedure. There are four major blood types:

Type A
Type B
Type AB
Type O

The recipient with type A can accept an organ from a donor who is type A or type O. This is because the type A blood group person has antibodies to type B, called anti-B antibodies.
Similarly, type B recipient can accept an organ from type B or type O, since he has anti-A antibodies
Type O can receive an organ from type O only, since he has antibodies to both type A and type B.
Type AB is also called the universal recipient, can receive organs from types A, B, O or AB.

HEPATITIS C

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV). This disease primarily infects the liver and in its early stages, it has very few symptoms. Patients may present with a fever, abdominal pain and mild jaundice (yellowish tinge in the skin). In the majority of the patients with the acute infection, the virus will persist in the liver and over many years, progress to cirrhosis of the liver.

HCV is spread by blood-to-blood contact, caused by intravenous drug use, poorly sterilized medical equipment, needlestick injuries in healthcare workers and blood transfusions. It can also spread during childbirth, from an infected mother to her baby.

HCV is a global health problem, with approximately 143 million people (2%) infected with this disease. It is most common in Africa and Central and East Asia. In 2015, approximately 167,000 deaths due to HCV related liver cancer and 326,000 deaths from HCV related cirrhosis occurred worldwide.

In the US, HCV is prevalent in approximately 2 % of the population, almost 3.5 million people. Approximately, 15,800 deaths in 2008 were due to HCV. According to the CDC, almost 30,500 newly infected patients were found in 2014. 70 % of the HCV patients in the US are caused by genotype 1 and 40 to 70 % patients who are infected are unaware of their HCV status.

Diagnosis of HCV is by detecting antibodies to HCV. If this is positive, a confirmatory test with an immunoassay as well as the viral load is determined. The viral load is determined by checking the HCV RNA. Liver enzymes initially run a variable course but gradually begin to rise at seven weeks after infection. The degree of liver damage can be assessed by doing a liver biopsy.

Routine screening is currently not recommended by the CDC except for those born between 1945 to 1965. Screening is recommended in those with higher risk for HCV such as injection drug users, those who received blood transfusions prior to 1992, those on hemodialysis, incarcerated individuals or those with tattoos.

Treatment consists of antiviral medications, recommended especially for patients at risk for complications, based on the degree of liver scarring. The regimen recommended depends on the type of HCV, known as the genotype, with which a person is infected. Prior to 2011, there were only two drugs that were available, pegylated interferon (PEG-IFN) and ribavirin. These drugs are now less commonly used because of their side effects and also because the newer medications are more effective with less side effects, albeit more expensive.

Boceprevir (victrelis)and telaprevir (incivek)were introduced in 2011 as protease inhibitors. They act by stopping viral reproduction and were approved for patients infected with HCV genotype 1, given mainly in combination with PEG-IFN and ribavirin.
Simeprevir (olysio) was introduced in 2013 as a once daily protease inhibitor. It is used in combination with sofosbuvir (sovaldi) and approved for HCV genotype 1.
Sofosbuvir can also be used for genotypes 1, 2, 3 and 4. This is a once daily medication and is a polymerase inhibitor, blocking a specific protein in the virus that it needs o grow.

Ledipasvir and sofosbuvir combination drug (harvoni) was introduced in 2014 for patients with genotype 1 and was found to cure 94 % patients in 12 weeks. It has now been approved for genotypes 4, 5, 6 and in patients co-infected with HIV. With ribavirin, it has been approved for use in patients who have undergone liver transplantation.

Multiple other combinations of newer drugs have been introduced and continue to be developed.

Liver transplantation is the treatment option for patients who have chronic HCV and have decompensated cirrhosis. The virus does recur after transplantation and causes cirrhosis in almost 30 % patients within 5 years.

Alternative treatment options include milk thistle, ginseng and colloidal silver have not shown to be effective in the treatment of HCV.

PANCREATIC ISLET TRANSPLANTATION

The pancreas is a complex organ located behind the stomach in the upper abdomen. It has two main functions:

1)   To secrete enzymes that aid in digesting food, known as exocrine function

2)   To secrete hormones like insulin and glucagon, which aid in the metabolism of blood glucose, known as endocrine function

Pancreatic islets consist of a cluster of different cells. One of the types is the beta cell that secretes the hormone insulin. The function of insulin is to help the cells throughout the body to absorb the glucose and use it for energy or store it for use later in the form of glycogen. A lack of insulin will cause the glucose to remain in the blood stream and increase the blood glucose level, a condition called diabetes mellitus. Diabetes is a serious illness that can lead to life threatening medical problems if not treated adequately and on time.

Type 1 diabetes is an autoimmune disorder, where the beta cells are destroyed by the body’s immune system. Type 2 diabetes usually begins with insulin resistance where the body is unable to use insulin effectively. Over a period of time, the insulin production slows down and therefore, many type 2 diabetics will also need insulin.

Pancreatic islet transplantation consists of separating and removing islets from a donor pancreas, purifying them and then transplanting them in a patient with diabetes. This procedure is still considered experimental in the US and is suitable for patients whose blood sugar is difficult to control with insulin given to them exogenously. Approximately, 450,000 to 500,000 islets are isolated from a single donor. Most patients will require two infusions of islets, approximately 1 million in total in order to get an adequate amount of insulin for them to be cured of diabetes.

After an adequate number of islets have been purified, they are transplanted in the recipient by placing a catheter into the portal vein of the liver and then infusing them. Once these islets are lodged in the liver, they begin to produce insulin. It will take a few days for new blood vessels to grow around these islets and therefore, insulin injections are still required initially after the procedure. Gradually, the transplanted islets will take over and the need for insulin injections will lessen over time. New research has identified the omentum, the apron of fat in the abdomen as a potential area for placing the islets and has shown encouraging initial results.

Benefits of islet transplants include better blood sugar control, especially in those patients who diabetes is difficult to control because of erratic blood sugar levels (brittle diabetes) and in patients who have hypoglycemic unawareness. An alternative to islet transplantation is whole organ pancreas transplantation. This is a major surgical procedure with a greater risk of complications and even death. Risks associated with islet transplantation include bleeding and blood clots. After the procedure, anti-rejection medications are required to be taken for life in order to prevent rejection. Risks of taking anti-rejection medications include infections, high blood pressure and increased risks of certain cancers, to name a few.

Long term results of islet transplantation remain unclear at the present time. While most islet cell recipients achieve better blood sugar control, very few patients have remained euglycemic without the use of external insulin beyond the four year mark. More research is needed in order to make islet transplantation a better alternative for long term cure of this dreaded disease.