23 Transplant

Heart Transplant

Heart transplantation is performed on patients with end-stage heart failure or severe coronary artery disease. Indications for heart transplant include:

• Severe cardiac disability on maximal medical therapy

• Symptomatic ischemia or recurrent ventricular arrhythmia on maximum medical therapy, with left ventricular ejection fraction less than 30%

• Unstable angina and not a candidate for CABG or percutaneous transluminal coronary angioplasty

Donor matching is based on several donor-recipient compatibilities including:

• ABO compatibility

• Body size

• Weight similarity

Contraindications for heart transplantation include:

• Pulmonary hypertension

• Smoking tobacco within six months

• COPD

Acute rejection is the most common form of rejection following heart transplantation.

Rejection is diagnosed and confirmed by endomyocardial biopsy via the right internal jugular vein.

The complications of heart transplantation include:

• Infection

• Pulmonary hypertension

• Graft failure

Lung Transplant

Lung transplantation is performed on patients with end-stage lung disease who are refractory to all other available medical treatments, most commonly secondary to:

• COPD

• Idiopathic pulmonary fibrosis

• Cystic fibrosis

• Primary pulmonary hypertension

• α1-antitrypsin deficiency

Donor-recipient compatibility for lung transplantation is based upon several criteria:

• ABO compatibility

• Pulmonary gas exchange

• No smoking history

• Similar donor-recipient lung volumes

Contraindications for lung transplantation include:

• Smoking within six months

• Cardiac, renal, or hepatic failure

• HIV

• Terminal illness

Chronic rejection is the most common form of rejection following lung transplantation.

Rejection is confirmed by biopsy through bronchoscopy and has several findings including:

• Fever

• Dyspnea

• Decreased PaO2

• Decreased FEV1

• Chest x-ray demonstrating interstitial infiltrate

Complications following lung transplantation include:

• Infection

• Rejection

Immunosuppression

All patients receiving allografts require immunosuppressive therapy. The only exception is recipients of a transplanted organ from an identical monozygotic twin (isograft).

Most immunosuppressive agents covered in this topic are used in maintenance therapy to prevent acute rejection of the graft.

Immunosuppressive agents carry a complex array of morbidities. The most important morbidities to broadly associate with the various immunosuppressive agents are nephrotoxicity, myelosuppression, and metabolic syndrome.

Glucocorticoids suppress B and T cell function and inhibit the release of IL-1 from macrophages. Prednisone is the most commonly used glucocorticoid used in transplantation.

The adverse effects of glucocorticoids include:

• Cushing syndrome

• Cataracts

• Dyspepsia

• Osteonecrosis

• Acne

• Glucose intolerance

Cyclosporine (CsA, Sandimmune, Neoral, Gengraf) is a calcineurin inhibitor that binds cyclophilin and inhibits the secretion and formation of IL-2.

Tacrolimus (FK506, Prograf) is a calcineurin inhibitor that binds FK506 binding protein (FKBP) and inhibits the secretion and formation of IL-2 and other cytokines. It is the most commonly used calcineurin inhibitor in immunosuppressive drug regimens.

In contrast to cyclosporine (another commonly-used calcineurin inhibitor), tacrolimus exhibits less severe androgenic effects.

Azathioprine (Imuran) is an antimetabolite precursor of 6-mercaptopurine, which inhibits nucleotide synthesis. It is being replaced with mycophenolate mofetil (MMF, CellCept).

Sirolimus or rapamycin (Rapamune) exhibits a unique molecular target by inhibiting mTOR (mammalian Target Of Rapamycin) by complexing with FKBP to inhibit T-cell proliferation.

Sirolimus is unique for exhibiting minimal nephrotoxicity.

Muromonab-CD3 (Orthoclone OKT3) is a monoclonal antibody that depletes the T-cell population.

Muromonab-CD3 can induce a one-time cytokine release (fever, bronchospasm) upon use. It can only be used in short-term therapy.

Kidney Transplant

Kidney transplantation is the most common solid organ to be transplanted.

There are multiple causes of end stage renal disease that may warrant transplantation including:

• Diabetes

• Hypertension

• Glomerular nephritis

• Congenital urologic anomalies

• Focal segmental glomerular sclerosis

Existing kidneys are NOT removed due to increased rates of surgical morbidity. The donated kidney is usually placed in the iliac fossa (pelvis).

Left kidney is preferred as a donor because it has a longer renal vein (remember the inferior vena cava is on the right side of the body, so the left kidney needs a longer vein).

Early complications of kidney transplant include oliguria or anuria that may result from graft thrombosis or urine leak.

Late complications of kidney transplant include ureteral stricture (↑ creatinine) and arteriosclerosis of the renal artery.

Pancreas Transplant

Pancreas transplantation is performed on individuals with type 1 diabetes with end-stage renal disease (majority of these are simultaneous pancreas-kidney transplantations).

Type II diabetes is a contraindication to pancreas transplantation.

Liver Transplant

There are multiple causes of liver failure that are indications for transplantation:

• Chronic hepatitis B

• Chronic hepatitis C

• Alcoholic sclerosis

• Biliary disease - primary sclerosing cholangitis, primary biliary cirrhosis, biliary atresia

• Wilson disease

Absolute contraindications for liver transplantation include:

• Active drug or alcohol abuse

• Uncontrolled metastatic cancer outside liver

• Hepatocellular carcinoma with metastases

• Active systemic infection

Individuals with hepatitis B or C may be used as donors for patients with the same infection if there is no organ damage detected in the donor liver.

Transplant Selections

Organ transplant donors are most commonly brain-dead or living voluntary donors without cancer, sepsis, or organ insufficiency. HIV is no longer an absolute contraindication for transplantation; patients with a well-controlled HIV infection are eligible.

Selection of organ transplant donors is based on the following criteria:

• ABO blood group compatibility

• Cross match compatibility (i.e. antidonor antibodies on recipient T cells)

• HLA antigen matching

HLA antigen matching is more significant for pancreas and kidney transplants and less significant for heart and liver.

Organs from individuals with a specific infection (e.g. hepatitis) with no significant organ damage may be transplanted into a recipient with the same infection.

Transplant Rejection

The three types of transplant rejection are:

• Hyperacute

• Acute

• Chronic

Hyperacute transplant rejection occurs immediately or within hours (< 24 hours) of the transplantation.

Preformed recipient antibodies against donor tissue, usually directed toward ABO blood group or HLA antigens, mediate the reaction leading to vascular thrombosis and necrosis. Histologically, the predominant cell infiltrate of hyperacute transplant rejection is polymorphonuclear leukocytes.

Hyperacute transplant rejection is untreatable, but rarely occurs due to cross-matching and blood group matching.

Acute transplant rejection usually occurs 7-10 days after transplantation, but may occur up to a year.

Antidonor T-cells proliferate in the recipient and mediate the reaction leading to mononuclear infiltration into vascular and interstitial spaces. For this reason, histologically, the predominant cell infiltrate of acute transplant rejection is monocyte/macrophage.

Acute transplant rejection is treated with intravenous steroids (e.g. methylprednisolone) and is frequently reversible. If reversed, the graft has a good prognosis.

Chronic transplant rejection occurs years after transplantation.

The pathogenesis of chronic transplant rejection is poorly understood, but is mediated by both cellular and humoral immune reactions. The donor tissue is characterized by vascular intimal hyperplasia and lymphocytic infiltration.

There is no effective treatment for chronic transplant rejection.