Blueprints Surgery, 5th Edition

Part V - Special Topics

Chapter 26

Organ Transplantation

OVERVIEW

Organ transplantation is one of the great achievements of 20th-century medicine. Fueled by technological advances in immunology and surgical technique, transplantation of the liver, kidney, small bowel, heart, and lung is possible with good outcomes. Using various protocols, it is possible to perform transplantation when patient and donor do not have compatible blood types, and even if the recipient is sensitized to the donor. Researchers at various centers are also experiment-ing with hand, face, and uterus transplantation. The decision to perform transplantation must take into account the risk of the surgery as well as long-term immunosuppression.

BASIC SCIENCE

The key to successful organ transplantation, after the technical aspects have been performed successfully, is the ability to prevent the recipient immunologic response from destroying the graft. In most cases, the donor and recipient blood type will be matched, and control of the host's response to the donor's major histocompatibility (MHC) antigens determines the success or failure of organ transplantation. MHC antigens are coded by a single chromosomal complex. In humans, the MHC is named the HLA antigen (human leukocyte antigen), which is located on the short arm of chromosome 6. HLA antigens are classified according to their structure and function. Class I antigens are present on virtually all nucleated cells in the human body and act as targets for cytotoxic T cells. Class II antigens are located on B cells, monocytes, macrophages, activated T cells, and other antigen-presenting cells. The rejection reaction of a transplant recipient directed against mismatched donor HLA antigens is a complex event that involves the actions of cytotoxic T cells, activated helper T cells, B lymphocytes, activated macrophages, and antibodies. The reaction is primarily cellular in nature and is T cell–dependent. Class I antigens stimulate cytotoxic T cells, directly causing donor tissue destruction. Class II antigens activate helper T cells, which, along with activated cytotoxic T cells, elaborate interleukin-1 (IL-1) and IL-2. IL-1 and IL-2, in turn, further activate macrophages and antibody-releasing B cells.

Although most rejections are cell-mediated, humoral rejections are also possible. The exact pathogenesis of humoral rejection is not well understood. When it occurs early after transplantation, it is generally due to preformed antibodies against class I antigens in the recipient. These antibodies are commonly acquired via blood transfusions, pregnancy, or prior transplantations. If this occurs in the period immediately after the transplantation procedure, it is termed "hyperacute rejection." To avoid this, cross-matching of the recipient's serum against the donor's lymphocytes is performed to confirm the absence of preexisting antibodies against donor tissue antigens. Types of rejection are listed in Table 26-1.

Immunosuppressive regimens use a combination of agents among a number of classes. In the past, most patients were treated with three drug regimens, but more and more transplantations are being performed with corticosteroids only in the immediate postoperative period. Generally, patients will receive an antibody as an induction agent for a few days at the time of the transplantation. In general, antibodies bind white blood cells and trigger a destructive immune reaction. The most common agent is rabbit anti-thymocyte

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globulin (Thymoglobulin), which profoundly depletes T cells. Also common are basiliximab and daclizumab, both of which are humanized antibodies to the IL-2 receptor on T cells.

Currently, the foundation of maintenance immunosuppression is a calcineurin inhibitor (either tacrolimus or cyclosporine). This agent binds to immunophilins and inhibits calcineurin activity, which is necessary for the transcription of genes that activate T cells, including IL-2, IL-3, IL-4, and interferon. Unfortunately, nephrotoxicity of these medicines is associated with high rates of renal failure. The major alternative is rapamycin, which does not seem to have nephrotoxicity but can impair wound healing, increase lipid levels, and cause pulmonary toxicity and edema. Most regimens include an antimetabolite, such as mycophenolate mofetil. Mycophenolate mofetil is rapidly converted to the morpholino ethyl ester of mycophenolic acid, which inhibits inosine monophosphate dehydrogenases, blocking proliferation of T and B lymphocytes and inhibiting antibody formation and the generation of cytotoxic T cells. Mycophenolic acid also down regulates the expression of adhesion molecules on lymphocytes. Other drugs in this category include azathioprine, a purine synthesis inhibitor.

Use of corticosteroids, once the mainstay of immunosuppression, is decreasing rapidly. Given the significant long-term complications associated with corticosteroids (e.g., diabetes, heart disease, edema, avascular necrosis of the hip, and easy bruisablity), alternatives have been actively sought. Current data suggest that if an induction agent is included at transplantation, then maintenance corticosteroids are not required. Corticosteroids alter the transcription and translation of several genes responsible for cytokine synthesis; they inhibit T-cell activation by blocking IL-1, IL-2, IL-6, and interferon synthesis; and they have local anti-inflammatory effects.

It is unusual to lose a graft from acute rejection. Antibody therapy that profoundly depletes T cells halts most rejections. The most potent agents are antithymocyte globulin and OKT3, an antibody to CD3 which binds to and depletes T cells.

DONORS

Organs can be used from living people or cadavers. Live donors for kidney transplants are routine, and the majority of kidneys come from this source. The risk of death to the donor is approximately three in 10,000, and complication rates are in the range of 2% to 3%. Live donors can be used for liver transplantation, but donor risk is greater, with a mortality rate of approximately 0.2%, in addition to a biliary complication rate that is much higher. Adult-to-child transplantation procedures usually use the left lateral segment of the liver, which is safer than using the right lobe, as is common in adult-to-adult live-donor liver transplantation.

Other than the kidney and liver, organs are generally not obtained from living people. There are two types of cadaver donors: heart beating or after cardiac death. Heart beating donors are pronounced brain-dead well before the time of donation. In this case, the cadaver is taken to the operating room with full life support, which is withdrawn after the aorta is cannulated. Cold perfusion is instituted immediately after the aorta is clamped, so the organs are preserved immediately. In donation after cardiac death, the decision has been made independent of the transplantation procedure that the patient's condition is terminal and life support will be withdrawn. After this occurs and the heart has stopped by natural causes for 5 minutes, the patient is pronounced dead and the organs are removed. This waiting period when the heart has stopped renders the organs relatively ischemic, and outcomes using livers from these patients may not be as good as from heart-beating donors.

LIVER TRANSPLANTATION

EPIDEMIOLOGY

There are approximately 17,000 patients on the waiting list for liver transplants in the United States, and 2,000 people on the waiting list die each year.

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INDICATIONS

Liver transplantation is indicated for life-threatening or debilitating liver failure or early-stage hepatocellular cancer that is not resectable because of tumor location or underlying liver disease. Disease states leading to end-stage liver disease are listed in Table 26-2.

LIVER ALLOCATION

Assignment of livers to patients depends on the Model for End-Stage Liver Disease (MELD), a formula that uses the patient's creatinine, international normalized ratio (INR) of prothrombin time, and bilirubin.

Values <1.0 are set to 1.0; maximum creatinine level that may be used is 4.0 mg/dL, which is also the score for dialysis patients. "Ln" is the natural logarithm.

This equation produces a number that directly correlates with mortality; livers are offered to the patients with highest mortality. Waiting time is no longer a factor in liver allocation, unless patients have identical MELD scores. This system has been prospectively analyzed and has resulted in fewer deaths on the waiting list. Extra points are offered for certain early-stage tumors in recognition of excellent outcomes with liver transplantation.

PROGNOSIS

Outcome after transplantation depends on a number of factors, including donor quality, recipient health, and indication for operation. Overall, patient survival after liver transplantation is 93% at 3 months, 88% at 1 year, 80% at 3 years, and 74% at 5 years. Graft survival rates are 88% at 3 months, 81% at 1 year, and 66% at 5 years. Fulminant hepatic failure carries poor prognosis after transplantation.

After successful liver transplantation, many patients return to a normal life, including work.

THE OPERATION: LIVER TRANSPLANTATION

Before beginning, it is imperative that adequate blood, platelets, and fresh frozen plasma are available. After the organ is verified to be the correct ABO type, the entire abdomen is prepped, as is the groin in case bypass will be necessary. Intravenous antibiotics are administered, and central monitoring is established. A wide bilateral subcostal incision with midline extension is made. Goals are dissecting the suprahepatic cava, isolating the portal vein in the porta hepatis, and freeing the liver from the diaphragm above the bare area of the liver. The liver can be removed with or without the inferior vena cava. Most commonly, the liver is removed with the retrohepatic cava (straight orthotopic). The new liver is sewn to the supra and infrahepatic portions of the cava. In this case, because the cava is clamped, veno-venous bypass can be useful to preserve venous return to the heart (Fig. 26-1). This also decreases bowel edema. It is also possible to leave the cava intact in the recipient. In this case, the hepatic veins are

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clamped, the liver is cut from the hepatic veins, and the new liver is sewn so it "hangs down" from the hepatic veins (piggyback technique). In both techniques, the portal vein is then reconstructed, followed by the hepatic artery, and finally the bile duct (Fig. 26-2). Drains are placed, and the abdomen is closed.

Complications

Technical complications after liver transplantation include caval stenosis, which can cause lower extremity edema, or outflow problems for the liver, which causes swelling of the graft and dysfunction. A particularly dangerous complication is hepatic arterial stenosis or thrombosis, which often leads to graft loss when acute and intrahepatic abscesses when chronic. Portal vein stenosis or thrombosis can cause portal hypertension and varices, as well as graft dysfunction or graft loss. Bile duct complications include stenosis and leak and may be managed with operative repair, hepaticojejunostomy, or stents.

All patients with hepatitis C will experience recurrence in the graft. This can be a cause of graft loss both early and late. Rejection typically presents with increasing liver function tests.

KIDNEY TRANSPLANTATION

EPIDEMIOLOGY

There are currently >60,000 people in the United States waiting for a kidney transplant, among a group of more than 300,000 patients on dialysis.

INDICATIONS

Kidney transplantation is indicated for end-stage renal disease in patients otherwise healthy enough to tolerate the surgery and subsequent immunosuppression. Common causes are given in Table 26-3.

KIDNEY ALLOCATION

Kidney allocation is based on a formula that incorporates the kidney's degree of match, the waiting time, whether a person has been a kidney donor, the recipient's age, and the recipient's degree of sensitization (Table 26-4).

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PROGNOSIS

The half-life of a cadaver kidney, censoring for patient death, is >10 years, whereas for a live donor kidney, half-life is close to 30 years. Transplantation is superior to dialysis for quality of life and survival, even in older people.

THE OPERATION: KIDNEY TRANSPLANTATION

Before beginning, it is imperative to verify that the proper kidney has been received and is ABO compatible and cross-match negative. Placement of the kidney on the right side is usually easier, as the right iliac vein is more accessible than the left for anastomosis. Incising from the pubis to two fingerbreadths medial to the anterior-superior iliac spine allows exposure of the anterior rectus sheath and the external oblique. Incision through the muscular and fascial layers permits entry into the retroperitoneal space. Care is taken to preserve the spermatic cord in males. Dissection of the retroperitoneal space allows the renal vessels to be anastomosed to the external iliac artery and vein. Anastomosis of the ureter directly to the bladder re-establishes drainage.

Complications

Technical complications after renal transplantation include venous and arterial thrombosis, which generally result in graft loss. Ureteral complications include stricture and leak. Early problems should be fixed with re-operation, either via direct repair or ureteroureterostomy with the recipient's native ureter. For chronic problems, dilation and stenting can be attempted. Rejection typically presents with decreased urine output, increasing creatinine, or edema.

PANCREAS TRANSPLANTATION

Pancreas transplantation is generally reserved for patients with severe type I diabetes who also need a kidney transplant. In this setting, there is no additional risk of immunosuppression. In patients with hypoglycemic unawareness, who can lose consciousness from low blood sugars, and other patients with severe complications, pancreas transplantation alone is indicated. Transplantation will generally arrest the development, but not reverse, diabetic complications. One- and 3-year graft survival of the pancreas in kidney plus pancreas recipients is 85% and 71%, respectively. One- and 3-year graft survival of the pancreas with pancreas transplantation alone is 73%, and 53%, respectively.

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The pancreas is prepared with the donor duodenum intact to allow control of exocrine secretions. A bifurcated arterial graft is placed to connect the splenic artery and superior mesenteric artery of the pancreas so that the entire gland receives blood. The gland is drained via its portal vein. The graft is placed either in the right iliac fossa or in the middle of the abdomen. Right iliac placement requires inflow from the right common iliac artery and drainage via the right common iliac vein, although the aorta and vena cava can both be used. The pancreas can also be placed in the middle of the abdomen and have venous drainage through the superior mesenteric vein (portal drainage). The duodenum may be anastomosed to the bowel or bladder to control exocrine secretions.

Major complications include arterial or venous thrombosis, leak of the duodenal anastomosis, and pancreatitis. Bladder drainage can lead to hematuria from bladder irritation and metabolic acidosis owing to loss of bicarbonate secretions.

SMALL BOWEL TRANSPLANTATION

Small bowel transplantation is indicated for short bowel syndrome or intestinal failure, commonly resulting from surgical resection. It is commonly performed in combination with liver transplantation. One- and 3-year graft survival is 78% and 40%, respectively.

HEART TRANSPLANTATION

Heart transplantation is indicated for patients with end-stage heart failure whose symptoms cannot be controlled with medications. The most common causes are coronary artery disease (45%) and congestive heart failure (40%). Valvular disease, congenital, and other causes account for fewer than 10% of all transplant recipients. One- and 3-year graft survival is 88% and 79%, respectively. Allograft vasculopathy is a major cause of late graft loss.

LUNG TRANSPLANTATION

Lung transplantation is indicated for symptomatic end-stage lung disease. Chronic obstructive pulmonary disease/emphysema accounts for >50% of transplants, and idiopathic pulmonary fibrosis another 26%. Less common causes include alpha-1 antitrypsin deficiency, cystic fibrosis, sarcoidosis, and re-transplantation. One- and 3-year graft survival is 83% and 64%, respec-tively. Because the lung is in direct contact with the environment, infection is a major problem, and there is a constant struggle between overimmunosuppression and rejection. Bronchiolitis obliterans syndrome is a poorly understood entity that is a major source of morbidity and mortality in these patients.

Heart and lung transplantation are often performed together, and the operation is depicted in Figures 26-3, 26-4, 26-5, and 26-6.

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KEY POINTS

• Control of the host response to donor major histocompatibility antigens is necessary for successful organ transplantation.
• Most current immunosuppressive regimens have moved away from long-term use of corticosteroids.
• Cadaver donors can be divided into heart-beating and non–heart-beating donors.
• Liver transplantation is indicated for end-stage liver disease or unresectable early-stage hepatocellular cancer and can be performed with removal or preservation of the recipient vena cava.
• Kidney transplantation is superior to dialysis for long-term patient survival and quality of life.
• Pancreas transplantation is indicated for patients with type I diabetes receiving a kidney, but transplantation will generally not reverse diabetic complications.
• Small bowel transplantation is indicated for patients with small bowel syndrome or irreversible bowel failure.
• Heart transplantation is a successful therapy for end-stage heart disease.
• Allograft vasculopathy is a major source of morbidity in heart transplantation.
• Bronchiolitis obliterans syndrome is an important cause of morbidity after lung transplant.