Kidney transplantation

Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease. Kidney transplantation is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantation depending on the source of the donor organ. Living-donor renal transplants are further characterized as genetically related (living-related) or non-related (living-unrelated) transplants, depending on whether a biological relationship exists between the donor and recipient.

History
The first cadaveric kidney transplantation in the United States was performed June 17, 1950, on Ruth Tucker, a 44-year-old woman with polycystic kidney disease, at Little Company of Mary Hospital in Evergreen Park, Illinois. Although the donated kidney was rejected ten months later because no immunosuppressive therapy was available at the time—the development of effective antirejection drugs was years away—the intervening time gave Tucker's remaining kidney time to recover and she lived another five years.

The first kidney transplants between living patients were undertaken in 1954 in Boston and Paris. The Boston transplantation, performed on December 23, 1954, at Brigham Hospital was performed by Joseph Murray, J. Hartwell Harrison, John P. Merrill and others. The procedure was done between identical twins to eliminate any problems of an immune reaction. For this and later work, Dr. Murray received the Nobel Prize for Medicine in 1990. The recipient died eight years after the transplantation.

The first kidney transplantation in the United Kingdom did not occur until 1960, when Michael Woodruff performed one between identical twins in Edinburgh. Until the routine use of medications to prevent and treat acute rejection, introduced in 1964, deceased donor transplantation was not performed. The kidney was the easiest organ to transplant: tissue typing was simple, the organ was relatively easy to remove and implant, live donors could be used without difficulty, and in the event of failure, kidney dialysis was available from the 1940s. Tissue typing was essential to the success: early attempts in the 1950s on sufferers from Bright's disease had been very unsuccessful.

The major barrier to organ transplantation between genetically non-identical patients lay in the recipient's immune system, which would treat a transplanted kidney as a "non-self" and immediately or chronically, reject it. Thus, having medications to suppress the immune system was essential. However, suppressing an individual's immune system places that individual at greater risk of infection and cancer (particularly skin cancer and lymphoma), in addition to the side effects of the medications.

The basis for most immunosuppressive regimens is prednisolone, a corticosteroid. Prednisolone suppresses the immune system, but its long-term use at high doses causes a multitude of side effects, including glucose intolerance and diabetes, weight gain, osteoporosis, muscle weakness, hypercholesterolemia, and cataract formation. Prednisolone alone is usually inadequate to prevent rejection of a transplanted kidney. Thus other, non-steroid immunosuppressive agents are needed, which also allow lower doses of prednisolone.

Indications
The indication for kidney transplantation is end-stage renal disease (ESRD), regardless of the primary cause. This is defined as a glomerular filtration rate <15ml/min/1.73 sq.m. Common diseases leading to ESRD include malignant hypertension, infections, diabetes mellitus, and focal segmental glomerulosclerosis; genetic causes include polycystic kidney disease, a number of inborn errors of metabolism, and autoimmune conditions such as lupus and Goodpasture's syndrome. Diabetes is the most common cause of kidney transplantation, accounting for approximately 25% of those in the US. The majority of renal transplant recipients are on some form of peritoneal dialysis, or the similar process of hemofiltration—at the time of transplantation. However, individuals with chronic renal failure who have a living donor available may undergo pre-emptive transplantation before dialysis is needed.

Contraindications and requirements
Contraindications include both cardiac and pulmonary insufficiency, as well as hepatic disease. Concurrent tobacco use and morbid obesity are also among the indicators putting a patient at a higher risk for surgical complications.

Kidney transplant requirements vary from program to program and country to country. Many programs place limits on age (e.g. the person must be under a certain age to enter the waiting list) and require that one must be in good health (aside from the kidney disease). Significant cardiovascular disease, incurable terminal infectious diseases and cancer often are transplant exclusion criteria. In addition, candidates are typically screened to determine if they will be compliant with their medications, which is essential for survival of the transplant. People with mental illness and/or significant on-going substance abuse issues may be excluded.

HIV was at one point considered to be a complete contraindication to transplantation. There was fear that immunosuppressing someone with a depleted immune system would result in the progression of the disease. However, some research seem to suggest that immunosuppressive drugs and antiretrovirals may work synergistically to help both HIV viral loads/CD4 cell counts and prevent active rejection.

Sources of kidneys
Since medication to prevent rejection is so effective, donors do not need to be genetically similar to their recipient. Most donated kidneys come from deceased donors; however, the utilization of living donors in the United States is on the rise. In 2006, 47% of donated kidneys were from living donors. This varies by country: for example, only 3% of kidneys transplanted during 2006 in Spain came from living donors.

Living donors
More than one in three donations in the UK is now from a live donor and almost one in three in Israel. The percentage of transplants from living donors is increasing. Potential donors are carefully evaluated on medical and psychological grounds. This ensures that the donor is fit for surgery and has no disease which brings undue risk or likelihood of a poor outcome for either the donor or recipient. The psychological assessment is to ensure the donor gives informed consent and is not coerced. In countries where paying for organs is illegal, the authorities may also seek to ensure that a donation has not resulted from a financial transaction. In the UK, the Human Tissue Act 2004 (HTA) dictated that donors must prove a familial or long-term relationship or enduring friendship, for instance by providing photographs of themselves together spread over a period of time or a birth or wedding certificate. Purely altruistic donation to strangers has recently been accepted by the Human Tissue Authority in the United Kingdom, but as of December 2007 only four people had been given permission to do this under the HTA. The decision must be approved by a panel, whereas the typical donation based on relationship is required only to go through an executive. There is good evidence that kidney donation is not associated with long-term harm to the donor. In some cases of male living donors a hydrocele may occur in the scrotum related to the side of the nephrectomy. As an example, a living donor who had a left side laproscopic nephrectomy, the left side of the scrotum can develop a hydrocele that envelopes the left testicle and enlargens the left side of the scrotum. This condition is typically non threatening and can disappear over time. So called "daisy chain" transplants in the US involve one altruistic donor who donates a kidney to someone who has a family member willing to donate, who isn't a match. That family member then donates to a recipient who is a match. This "chain" can be continued with several more pairs of donors/recipients.

Traditionally, the donor procedure has been through a single incision of 4 –, but live donation is being increasingly performed by laparoscopic surgery. This reduces pain and accelerates recovery for the donor. Operative time and complications decreased significantly after a surgeon performed 150 cases. Live donor kidney grafts tend to perform better than those from deceased donors. Since the increase in the use of laparoscopic surgery, the number of live donors has increased. Any advance which leads to a decrease in pain and scarring and swifter recovery has the potential to boost donor numbers. In January 2009, the first all-robotic kidney transplant was performed at Saint Barnabas Medical Center through a two-inch incision. In the following six months, the same team performed eight more robotic-assisted transplants.

In 2004 the FDA approved the Cedars-Sinai High Dose IVIG therapy which reduces the need for the living donor to be the same blood type (ABO compatible) or even a tissue match. The therapy reduced the incidence of the recipient's immune system rejecting the donated kidney in highly sensitized patients.

In 2009 at the Johns Hopkins Medical Center, a healthy kidney was removed through the donor's vagina. Vaginal donations promise to speed recovery and reduce scarring. The first donor was chosen as she had previously had a hysterectomy. The extraction was performed using natural orifice transluminal endoscopic surgery, where an endoscope is inserted through an orifice, then through an internal incision, so that there is no external scar. The recent advance of single port laparoscopy requiring only one entry point at the navel is another advance with potential for more frequent use.

Organ trade
In the developing world some people sell their organs. Such people are often in grave poverty or are exploited by salespersons. People traveling to make use of such kidneys, sometimes known as "transplant tourists," are not looked upon favorably by organizations such as the U.S. National Kidney Foundation. These patients may have increased complications owing to poor infection control and lower medical and surgical standards. One surgeon has said that organ trade could be legalized in the UK to prevent such tourism, but this is not seen by the National Kidney Research Fund as the answer to a deficit in donors.

Deceased donors
Deceased donors can be divided in two groups: Although brain-dead (or "beating heart") donors are considered dead, the donor's heart continues to pump and maintain the circulation. This makes it possible for surgeons to start operating while the organs are still being perfused. During the operation, the aorta will be cannulated, after which the donor's blood will be replaced by an ice-cold storage solution, such as UW (Viaspan), HTK, or Perfadex. Depending on which organs are transplanted, more than one solution may be used simultaneously. Due to the temperature of the solution, and since large amounts of cold NaCl-solution are poured over the organs for a rapid cooling, the heart will stop pumping.
 * Brain-dead (BD) donors
 * Donation after Cardiac Death (DCD) donors

"Donation after Cardiac Death" donors are patients who do not meet the brain-dead criteria but, due to the small chance of recovery, have elected via a living will or through family to withdraw support. In this procedure, treatment is discontinued (mechanical ventilation is shut off). After a time of death has been pronounced, the patient is rushed to the operating room where the organs are recovered. Storage solution is flushed through the organs. Since the blood is no longer being circulated, coagulation must be prevented with large amounts of anti-coagulation agents such as heparin. Several ethical and procedural guidelines must be followed; most importantly, the organ recovery team should not participate in the patient's care in any manner until after death has been declared.

Compatibility
If plasmapheresis or IVIG is not performed, the donor and recipient have to be ABO blood group compatible. Also, they should ideally share as many HLA and "minor antigens" as possible. This decreases the risk of transplant rejection and the need for another transplant. The risk of rejection may be further reduced if the recipient is not already sensitized to potential donor HLA antigens, and if immunosuppressant levels are kept in an appropriate range. The level of sensitization to donor HLA antigens is determined by performing a panel reactive antibody test on the potential recipient. In the United States, up to 17% of all deceased donor kidney transplants have no HLA mismatch. However, HLA matching is a relatively minor predictor of transplant outcomes. In fact, living non-related donors are now almost as common as living (genetically)-related donors.

In the 1980s, experimental protocols were developed for ABO-incompatible transplants using increased immunosuppression and plasmapheresis. Through the 1990s these techniques were improved and an important study of long-term outcomes in Japan was published. Now, a number of programs around the world are routinely performing ABO-incompatible transplants.

Procedure
In most cases the barely functioning existing kidneys are not removed, as this has been shown to increase the rates of surgical morbidities. Therefore, the kidney is usually placed in a location different from the original kidney, often in the iliac fossa, so it is often necessary to use a different blood supply: There is disagreement in surgical textbooks regarding which side of the recipient’s pelvis to use in receiving the transplant. Campbell's Urology (2002) recommends placing the donor kidney in the recipient’s contralateral side (i.e. a left sided kidney would be transplanted  in the recipient's right side) to ensure the renal pelvis and ureter are anterior in the event that future surgeries are required. In an instance where there is doubt over whether there is enough space in the recipient’s pelvis for the donor's kidney the textbook recommends using the right side because the right side has a wider choice of arteries and veins for reconstruction. Smith's Urology (2004) states that either side of the recipient's pelvis is acceptable, however the right vessels are “more horizontal” with respect to each other and therefore easier to use in the anastomoses. It is unclear what is meant by the words “more horizontal”. Glen's Urological Surgery (2004) recommends putting the kidney in the contralateral side in all circumstances. No reason is explicitly put forth; however, one can assume the rationale is similar to that of Campbell's&mdash;to ensure that the renal pelvis and ureter are most anterior in the event that future surgical correction becomes necessary.
 * The renal artery of the kidney, previously branching from the abdominal aorta in the donor, is often connected to the external iliac artery in the recipient.
 * The renal vein of the new kidney, previously draining to the inferior vena cava in the donor, is often connected to the external iliac vein in the recipient.

Kidney-pancreas transplant
Occasionally, the kidney is transplanted together with the pancreas. This is done in patients with diabetes mellitus type 1, in whom the diabetes is due to destruction of the beta cells of the pancreas and in whom the diabetes has caused renal failure (diabetic nephropathy). This is almost always a deceased donor transplant. Only a few living donor (partial) pancreas transplants have been done. For individuals with diabetes and renal failure, the advantages of earlier transplant from a living donor (if available) are far superior to the risks of continued dialysis until a combined kidney and pancreas are available from a deceased donor. A patient can either receive a living kidney followed by a donor pancreas at a later date (PAK, or pancreas-after-kidney) or a combined kidney-pancreas from a donor (SKP, simultaneous kidney-pancreas).

Transplanting just the islet cells from the pancreas is still in the experimental stage, but shows promise. This involves taking a deceased donor pancreas, breaking it down, and extracting the islet cells that make insulin. The cells are then injected through a catheter into the recipient and they generally lodge in the liver. The recipient still needs to take immunosuppressants to avoid rejection, but no surgery is required. Most people need two or three such injections, and many are not completely insulin-free.

Post operation
The transplant surgery takes about three hours. The donor kidney will be placed in the lower abdomen and its blood vessels connected to arteries and veins in the recipient's body. When this is complete, blood will be allowed to flow through the kidney again. The final step is connecting the ureter from the donor kidney to the bladder. In most cases, the kidney will soon start producing urine.

Depending on its quality, the new kidney usually begins functioning immediately. Living donor kidneys normally require 3–5 days to reach normal functioning levels, while cadaveric donations stretch that interval to 7–15 days. Hospital stay is typically for 4–7 days. If complications arise, additional medications (diuretics) may be administered to help the kidney produce urine.

Immunosuppressant drugs are used to suppress the immune system from rejecting the donor kidney. These medicines must be taken for the rest of the patient's life. The most common medication regimen today is a cocktail of tacrolimus, mycophenolate, and prednisone. Some patients may instead take cyclosporine, sirolimus, or azathioprine. Cyclosporine, considered a breakthrough immunosuppressive when first discovered in the 1980s, ironically causes nephrotoxicity and can result in iatrogenic damage to the newly transplanted kidney. Blood levels must be monitored closely and if the patient seems to have declining renal function, a biopsy may be necessary to determine whether this is due to rejection or cyclosporine intoxication.

Postoperative diet
Kidney transplant recipients are discouraged from consuming grapefruit, pomegranate and green tea products. These food products are known to interact with the transplant medications, specifically tacrolimus, ciclosporin and sirolimus; the blood levels of these drugs may be lowered, potentially leading to a rejection episode.

Acute rejection occurs in 10–25% of people after transplant during the first 60 days. Rejection does not necessarily mean loss of the organ, but it may necessitate additional treatment and medication adjustments.

Complications
Problems after a transplant may include:
 * Transplant rejection (hyperacute, acute or chronic)
 * Infections and sepsis due to the immunosuppressant drugs that are required to decrease risk of rejection
 * Post-transplant lymphoproliferative disorder (a form of lymphoma due to the immune suppressants)
 * Imbalances in electrolytes including calcium and phosphate which can lead to bone problems amongst other things
 * Other side effects of medications including gastrointestinal inflammation and ulceration of the stomach and esophagus, hirsutism (excessive hair growth in a male-pattern distribution), hair loss, obesity, acne, diabetes mellitus type 2, hypercholesterolemia.

A patient's age and health condition before transplantation affect the risk of complications. Different transplant centers have different success at managing complications and therefore, complication rates are different from center to center.

The average lifetime for a donated kidney is ten to fifteen years. When a transplant fails, a patient may opt for a second transplant, and may have to return to dialysis for some intermediary time.

Prognosis
Kidney transplantation is a life-extending procedure. The typical patient will live 10 to 15 years longer with a kidney transplant than if kept on dialysis. The increase in longevity is greater for younger patients, but even 75-year-old recipients (the oldest group for which there is data) gain an average four more years of life. People generally have more energy, a less restricted diet, and fewer complications with a kidney transplant than if they stay on conventional dialysis.

Some studies seem to suggest that the longer a patient is on dialysis before the transplant, the less time the kidney will last. It is not clear why this occurs, but it underscores the need for rapid referral to a transplant program. Ideally, a kidney transplant should be preemptive, i.e., take place before the patient begins dialysis.

At least four professional athletes have made a comeback to their sport after receiving a transplant: New Zealand rugby union player Jonah Lomu, German-Croatian Soccer Player Ivan Klasnić, and NBA basketballers Sean Elliott and Alonzo Mourning.

Statistics

 * Bill Thompson is the longest-surviving American kidney recipient, having received his kidney in 1966 at age 15; it has survived over 40 years.
 * Denice Lombard of Washington, D.C., received her father's kidney on August 30, 1967, at age 13 and is still alive and healthy forty years later.
 * John Dan of Nairobi, Kenya, is the known longest-surviving kidney recipient in East Africa. He received a kidney from his brother in 1984 and is still alive 26 years later.
 * Chakravarthy from chennai, India, received kidney from his brother on 2nd May 1983 at the age of 29, is still alive and healthy 27 years later.

In addition to nationality, transplantation rates differ based on race, sex, and income. A study done with patients beginning long-term dialysis showed that the sociodemographic barriers to renal transplantation present themselves even before patients are on the transplant list. For example, different groups express definite interest and complete pretransplant workup at different rates. Previous efforts to create fair transplantation policies had focused on patients currently on the transplantation waiting list.

In the US health system
Transplant recipients must take immunosuppressive anti-rejection drugs for as long as the transplanted kidney functions. For the routine immunosuppressives Prograf, Cellcept and prednisone, these drugs cost US$1,500 per month. In 1999 Congress passed a law that restricts Medicare from paying for more than three years for these drugs, unless the patient is otherwise Medicare eligible. Transplant programs may not transplant a patient unless the patient has a reasonable plan to pay for medication after the medicare expires, however, patients are almost never turned down for financial reasons alone. 50% of patients with end-stage renal disease only have Medicare coverage.

In March 2009 a bill was introduced in the Senate, 565 and in the House, H.R. 1458 that will extend Medicare coverage of the drugs for as long as the patient has a functioning transplant. This means that patients who have lost their jobs and insurance will not also lose their kidney and be forced back on dialysis. Dialysis is currently using up $17 billion yearly of Medicare funds and total care of these patients amounts to over 10% of the entire Medicare budget.