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Surgery_Schwartz. chills, arthralgias, thrombocytopenia, leukopenia, and an increased incidence of a variety of infections.14,15Nondepleting AntibodiesBasiliximab (Simulect) is an anti-CD25 monoclonal antibody. The alpha subunit of the IL-2 receptor, also known as Tac or CD25, is found exclusively on activated T cells. Blockade of this component by this monoclonal antibody selectively pre-vents IL-2–induced T-cell activation. No lymphocyte depletion occurs with basiliximab; thus, it is not designed to be used to treat acute rejection. Its selectivity in blocking IL-2–mediated responses makes it a powerful induction agent without the added risks of infections, malignancies, or other major side effects. Currently, basiliximab is the only available anti-CD25 mono-clonal antibody approved for clinical use. Usually, it is followed by the use of calcineurin inhibitors, corticosteroids, and MMF as maintenance immunosuppression.16Alemtuzumab (Campath, Lemtrada), another anti-CD52 monoclonal antibody, was


Surgery_Schwartz

Surgery_Schwartz. Usually, it is followed by the use of calcineurin inhibitors, corticosteroids, and MMF as maintenance immunosuppression.16Alemtuzumab (Campath, Lemtrada), another anti-CD52 monoclonal antibody, was initially used to treat chronic lym-phocytic leukemia. The use of alemtuzumab has grown in the field of transplantation, given its profound lymphocyte-depleting effects. It causes cell death by complement-mediated cytoly-sis, antibody-mediated cytotoxicity, and apoptosis. One dose alone (30 mg) depletes 99% of lymphocytes. Monocyte recov-ery can be seen at 3 months posttransplant; B-cell recovery at 12 months; and T-cell recovery, albeit only to 50% of base-line, at 36 months. Alemtuzumab causes a significant cytokine release reaction and often requires premedications (steroids and antihistamines). Because of the long-lasting T-cell depletion, the risks of infection and posttransplant lymphoproliferative dis-order remain. Initially, alemtuzumab was available only through a limited


Surgery_Schwartz

Surgery_Schwartz. Because of the long-lasting T-cell depletion, the risks of infection and posttransplant lymphoproliferative dis-order remain. Initially, alemtuzumab was available only through a limited distribution program, but more recently has been stud-ied in a number of clinical trials.17,18MAINTENANCECorticosteroidsCorticosteroids have had a role in immunosuppression since the beginning of the field of transplantation. Despite numerous Brunicardi_Ch11_p0355-p0396.indd 35901/03/19 6:53 PM 360BASIC CONSIDERATIONSPART ITable 11-3Summary of the main immunosuppressive drugsDRUGMECHANISM OF ACTIONADVERSE EFFECTSCLINICAL USESDOSAGECyclosporine (CSA)Binds to cyclophilinInhibits calcineurin and IL-2 synthesisNephrotoxicityTremorHypertensionHirsutismImproved bioavailability of microemulsion formOral dose 5 mg/kg per day (given in two divided doses)Tacrolimus (FK506)Binds to FKBPInhibits calcineurin and IL-2 synthesisNephrotoxicityHypertensionNeurotoxicityGI toxicity (nausea, diarrhea)Improved patient


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Surgery_Schwartz. 5 mg/kg per day (given in two divided doses)Tacrolimus (FK506)Binds to FKBPInhibits calcineurin and IL-2 synthesisNephrotoxicityHypertensionNeurotoxicityGI toxicity (nausea, diarrhea)Improved patient and graft survival in (liver) primary immunosuppression and rescue therapyUsed as mainstay of maintenance protocolsIV 0.015 mg/kg per day as continuous infusionPO 0.05 mg/kg per day (given every 12 h)Mycophenolate mofetilAntimetaboliteInhibits enzyme necessary for de novo purine synthesisLeukopeniaGI toxicityEffective for primary immunosuppression in combination with tacrolimus1 g bid POSirolimusInhibits lymphocyte effects driven by IL-2 receptorThrombocytopeniaIncreased serum cholesterol/LDLPoor wound healingMay allow early withdrawal of steroids and decreased calcineurin doses2–4 mg/d, adjusted to trough drug levelsCorticosteroidsMultiple actionsAnti-inflammatoryInhibits lymphokine productionCushingoid stateGlucose intoleranceOsteoporosisUsed in induction, maintenance, and treatment of


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Surgery_Schwartz. to trough drug levelsCorticosteroidsMultiple actionsAnti-inflammatoryInhibits lymphokine productionCushingoid stateGlucose intoleranceOsteoporosisUsed in induction, maintenance, and treatment of acute rejectionVaries from milligrams to several grams per dayMaintenance doses, 5–10 mg/dAzathioprineAntimetaboliteInterferes with DNA and RNA synthesisThrombocytopeniaNeutropeniaLiver dysfunctionUsed in maintenance protocols or if intolerance to mycophenolate mofetil1–3 mg/kg per day for maintenanceBelataceptT-cell blockerIncreased risk of bacterial infectionsNew drug for maintenance immunosuppression in renal transplants only5–10 mg/kg per day infusionFKBP = FK506-binding protein; GI = gastrointestinal; IL = interleukin; IV = intravenous; LDL = low-density lipoprotein; PO = oralattempts to limit or discontinue their use, they remain an inte-gral component of most immunosuppressive protocols, for both induction and maintenance. Moreover, they are often the first-line agents in the treatment


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Surgery_Schwartz. or discontinue their use, they remain an inte-gral component of most immunosuppressive protocols, for both induction and maintenance. Moreover, they are often the first-line agents in the treatment of acute rejection. Steroids bind to glucocorticoid-responsive elements in DNA that prevent the transcription of cytokine genes and cytokine receptors. In addition, steroids have an impact on lymphocyte depletion, on decreases in cell-mediated immunity, and on T-cell activation of many phases of rejection.Nonetheless, the numerous adverse effects of steroid therapy contribute significantly to morbidity in transplant recipients.19 Common side effects include acne, increased appetite and asso-ciated weight gain, mood changes, diabetes, hypertension, and impaired wound healing.One of the most common maintenance immunosuppres-sive regimens consists of triple-drug therapy: prednisone, a cal-cineurin inhibitor, and an antimetabolite. Large doses of steroids are usually given perioperatively and


Surgery_Schwartz

Surgery_Schwartz. maintenance immunosuppres-sive regimens consists of triple-drug therapy: prednisone, a cal-cineurin inhibitor, and an antimetabolite. Large doses of steroids are usually given perioperatively and in the immediate postop-erative period. Protocols vary by center, but the steroid dose is usually tapered to an adult dose of roughly 5 to 15 mg daily, or completely stopped at some point. Steroids are substrates for CYP3A4, CYP3A5, and P-glycoprotein pathways where drug interactions might need to be monitored.20,21AzathioprineAn antimetabolite, azathioprine (AZA) is converted to 6-mercaptopurine and inhibits both the de novo purine synthe-sis and salvage purine synthesis. AZA decreases T-lymphocyte activity and decreases antibody production. It has been used as a first-line agent in transplant recipients for more than 40 years, but it became an adjunctive agent after the introduction of cyclospo-rine. With the development of newer agents such as MMF, the use of AZA has decreased


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Surgery_Schwartz. transplant recipients for more than 40 years, but it became an adjunctive agent after the introduction of cyclospo-rine. With the development of newer agents such as MMF, the use of AZA has decreased significantly. However, it is preferred in recipients who are considering conceiving a child because MMF is teratogenic and can cause birth defects. Use of AZA remains an option for recipients who cannot tolerate the gastro-intestinal (GI) side effects of MMF.The most significant side effect of AZA, often dose-related, is bone marrow suppression. Leukopenia is often reversible with dose reduction or temporary cessation of the drug. Other significant side effects include hepatotoxicity, pancreatitis, neoplasia, anemia, and pulmonary fibrosis. Its most significant drug interaction is with allopurinol, which blocks AZA metabolism, increasing the risk of pancytope-nia. Recommendations are to not use AZA and allopurinol together, or if doing so is unavoidable, to decrease the dose of AZA by


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Surgery_Schwartz. which blocks AZA metabolism, increasing the risk of pancytope-nia. Recommendations are to not use AZA and allopurinol together, or if doing so is unavoidable, to decrease the dose of AZA by 75%.22Brunicardi_Ch11_p0355-p0396.indd 36001/03/19 6:53 PM 361TRANSPLANTATIONCHAPTER 11Mycophenolate MofetilApproved in May 1995 by the U.S. Food and Drug Admin-istration (FDA) for preventing acute rejection after kidney transplants, MMF has now been incorporated into routine maintenance regimens after many solid organ transplants. Mycophenolate is the prodrug of mycophenolate acid, derived from Penicillium fungi. Mycophenolate acid is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) involved in the de novo pathway of purine synthesis.23 MMF is available in capsules (250 and 500 mg); the starting dose is 1 g twice daily. In hopes of decreasing the GI side effects, an enteric-coated formulation called Myfortic was developed; its benefits have not been clearly demonstrated in studies,


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Surgery_Schwartz. starting dose is 1 g twice daily. In hopes of decreasing the GI side effects, an enteric-coated formulation called Myfortic was developed; its benefits have not been clearly demonstrated in studies, but in some conversion studies patients did report less GI intolerance. The pharmacoki-netics of MMF are complex; mycophenolic acid (MPA) levels are not routinely performed at most transplant centers. Studies have shown that MPA levels and the incidence of rejection are not significantly correlated.24 The most common side effects of MMF are GI in nature, most commonly diarrhea, nausea, dys-pepsia, and bloating. Esophagitis and gastritis occur in roughly 5% of recipients and may represent a cytomegalovirus (CMV) Table 11-4Side effects and drug interactions of the main immunosuppressive drugs COMMON SIDE EFFECTSOTHER MEDICATIONS THAT INCREASE BLOOD LEVELSOTHER MEDICATIONS THAT DECREASE BLOOD LEVELSOTHER MEDICATIONS THAT POTENTIATE TOXICITYCyclosporine (CSA)Hypertension, nephrotoxicity,


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Surgery_Schwartz. SIDE EFFECTSOTHER MEDICATIONS THAT INCREASE BLOOD LEVELSOTHER MEDICATIONS THAT DECREASE BLOOD LEVELSOTHER MEDICATIONS THAT POTENTIATE TOXICITYCyclosporine (CSA)Hypertension, nephrotoxicity, hirsutism, neurotoxicity, gingival hyperplasia, hypomagnesemia, hyperkalemiaVerapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juiceIsoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wortNephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBsTacrolimus (FK506)Hypertension, nephrotoxicity, alopecia, hyperglycemia, neurotoxicity, hypomagnesemia, hyperkalemiaVerapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juiceIsoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wortNephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBsSirolimusThrombocytopenia and neutropenia, elevated cholesterol, extremity


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Surgery_Schwartz. phenobarbital, phenytoin, rifampin, St. John’s wortNephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBsSirolimusThrombocytopenia and neutropenia, elevated cholesterol, extremity edema, impaired wound healingVerapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juiceIsoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort—Mycophenolate mofetilLeukopenia, thrombocytopenia, GI upset—Cholestyramine, antacidsBone marrow suppression: valganciclovir, ganciclovir, TMP-SMXCorticosteroidsHyperglycemia, osteoporosis, cataracts, myopathy, weight gain———AzathioprineLeukopenia, anemia, thrombocytopenia, neoplasia, hepatitis, cholestasis——Bone marrow suppression: allopurinol, sulfonamidesACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; NSAID = nonsteroidal anti-inflammatory drug; TMP-SMX = trimethoprim-sulfamethoxazoleor herpesvirus family infection. The other


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Surgery_Schwartz. enzyme inhibitor; ARB = angiotensin receptor blocker; NSAID = nonsteroidal anti-inflammatory drug; TMP-SMX = trimethoprim-sulfamethoxazoleor herpesvirus family infection. The other important side effects are leukopenia, anemia, and thrombocytopenia (Table 11-4). Leukopenia can sometimes be reversed by lowering the MMF dose and discontinuing other agents like valganciclovir. MMF does not have any significant drug interactions, but clinicians should be careful to avoid additive toxicities with other medica-tions that might lead to leukopenia and thrombocytopenia.SirolimusThe first mammalian target of rapamycin (mTOR) inhibitors to enter clinical use was sirolimus (Rapamune). A key regulatory kinase, mTOR changes cells from the G1 to S phase in the cell cycle, in response to proliferation signals provided by cytokines like IL-2. The mTOR inhibitors bind to FK506-binding pro-tein (FKBP), and the sirolimus-FKBP complex binds to mTOR. Sirolimus also inhibits proliferation of vascular smooth


Surgery_Schwartz

Surgery_Schwartz. provided by cytokines like IL-2. The mTOR inhibitors bind to FK506-binding pro-tein (FKBP), and the sirolimus-FKBP complex binds to mTOR. Sirolimus also inhibits proliferation of vascular smooth muscle cells, possibly easing the vasculopathy and progressive fibrosis that can affect allografts. Sirolimus is a substrate for CYP3A4/4 and has many significant drug interactions (see Table 11-4).To date, sirolimus has been used in a variety of com-binations for maintenance immunosuppression, alone or in Brunicardi_Ch11_p0355-p0396.indd 36101/03/19 6:53 PM 362BASIC CONSIDERATIONSPART ITable 11-5Drug interactions and side effects associated with calcineurin inhibitorsINTERACTIONSMEDICATIONSInhibition of metabolismClarithromycin, erythromycin, azole antifungals, diltiazem, verapamil, nicardipine, amiodarone, grapefruit juice, ritonavir, azithromycinInduction of metabolismNevirapine, rifampin, St. John’s wort, carbamazepine, phenobarbital, phenytoin, caspofunginHyperkalemiaPotassium-sparing


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Surgery_Schwartz. amiodarone, grapefruit juice, ritonavir, azithromycinInduction of metabolismNevirapine, rifampin, St. John’s wort, carbamazepine, phenobarbital, phenytoin, caspofunginHyperkalemiaPotassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), β-blockers, trimethoprim-sulfamethoxazoleNephrotoxicityNonsteroidal anti-inflammatory drugs, aminoglycosides, amphotericin, ACE-Is, ARBsconjunction with one of the calcineurin inhibitors. In such com-binations, sirolimus usually is used to help withdraw from, or completely avoid, the use of steroids. It also has been used as an alternative to tacrolimus or cyclosporine, in a calcineurin-sparing protocol. One of the most significant side effects of siro-limus is hypertriglyceridemia, a condition that may be resistant to statins and fibrates. Impaired wound healing (immediately posttransplant in particular), thrombocytopenia, leukopenia, and anemia also are associated with sirolimus, and these


Surgery_Schwartz

Surgery_Schwartz. may be resistant to statins and fibrates. Impaired wound healing (immediately posttransplant in particular), thrombocytopenia, leukopenia, and anemia also are associated with sirolimus, and these problems are exacerbated when it is used in combination with MMF.25,26CyclosporineThe introduction of cyclosporine in the early 1980s dramati-cally altered the field of transplantation by significantly improv-ing outcomes after kidney transplantation. Cyclosporine binds with its cytoplasmic receptor protein, cyclophilin, which sub-sequently inhibits the activity of calcineurin, thereby decreas-ing the expression of several critical T-cell activation genes, the most important being for IL-2. As a result, T-cell activation is suppressed.27Many formulations of cyclosporine exist, so it is important to know which one the transplant recipient is taking. Sandim-mune, an older, oil-based formulation, has poor bioavailabil-ity and variable absorption. The newer formulations, Gengraf and Neoral, are


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Surgery_Schwartz. to know which one the transplant recipient is taking. Sandim-mune, an older, oil-based formulation, has poor bioavailabil-ity and variable absorption. The newer formulations, Gengraf and Neoral, are microemulsified with improved bioavailability. Cyclosporine can be given intravenously or orally to maintain trough levels of 250 to 350 ng/mL for the first 3 months post-transplant; then it can be tapered to 150 to 250 ng/mL.28The metabolism of cyclosporine is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4). Calcineurin inhibitors are nephrotoxic and constrict the afferent arteriole in a dose-dependent, reversible manner (Table 11-5). They also can cause hyperkalemia and hypomagnesemia. Several neurologic complications, including headaches, tremor, and seizures, also have been reported.29Cyclosporine has several undesirable cosmetic effects, including hirsutism and gingival hyperplasia. It is associated with a higher incidence of


Surgery_Schwartz

Surgery_Schwartz. tremor, and seizures, also have been reported.29Cyclosporine has several undesirable cosmetic effects, including hirsutism and gingival hyperplasia. It is associated with a higher incidence of hypertension and hyperlipidemia than is tacrolimus.TacrolimusThe calcineurin inhibitor tacrolimus (Prograf) is now the back-bone of most immunosuppressive regimens. Tacrolimus acts by binding FKBPs, causing roughly 10 to 100 times more potent inhibition of IL-2 production than cyclosporine (which acts by binding cyclophilins). It can be given intravenously, orally, or sublingually to maintain trough levels of 8 to 12 ng/mL for the first 3 months posttransplant; then it can be tapered to 6 to 10 ng/mL. The metabolism of tacrolimus is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4).Tacrolimus causes a higher incidence of new-onset dia-betes posttransplant than does cyclosporine. Other side effects include alopecia, nephrotoxicity, neurotoxicity,


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Surgery_Schwartz. interactions (see Table 11-4).Tacrolimus causes a higher incidence of new-onset dia-betes posttransplant than does cyclosporine. Other side effects include alopecia, nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and an increased incidence of certain types of infection.30BelataceptThe best-characterized pathway of T-cell costimulation includes CD28; its homologue, the cytotoxic T-lymphocyte–associated protein 4 (CTLA4); and their ligands, CD80 and CD86. Belatacept (also known as LEA29Y) was developed through two amino acid substitutions to abatacept (also known as CTLA4-Ig), a fusion protein consisting of the extracellular domain of CTLA4 and the Fc domain of immunoglobulin G (IgG). It is a high-avidity molecule with slower dissociation rates.Clinical trials have compared the use of belatacept vs. a standard cyclosporine protocol in recipients of living donor, deceased donor, and extended-criteria donor kidneys. Belata-cept was not inferior to cyclosporine


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Surgery_Schwartz. compared the use of belatacept vs. a standard cyclosporine protocol in recipients of living donor, deceased donor, and extended-criteria donor kidneys. Belata-cept was not inferior to cyclosporine in both patient and allograft survival rates, but was associated with a higher rate of biopsy-proven acute cellular rejection.In terms of adverse effects, belatacept differs from stan-dard calcineurin-based regimens because of an increased risk of posttransplant lymphoproliferative disorder (PTLD); the greatest risk is in recipients who are Epstein-Barr virus (EBV)-seronegative pretransplant. The FDA recommends the use of belatacept only in seropositive recipients. Studies in liver trans-plant recipients were halted early because of increased mortality rates.However, belatacept does have a lower incidence of car-diovascular risk factors including metabolic lipid disorders, hypertension, neurotoxicity, glucose abnormalities, and adverse cosmetic effects. Except for the increased risk of


Surgery_Schwartz

Surgery_Schwartz. lower incidence of car-diovascular risk factors including metabolic lipid disorders, hypertension, neurotoxicity, glucose abnormalities, and adverse cosmetic effects. Except for the increased risk of malignancy, the more favorable adverse effect profile of belatacept and its convenient monthly dosing schedule may make it an attrac-tive option for maintenance of immunosuppression, possibly improving compliance.31,32HUMORAL REJECTIONRituximabA chimeric anti-CD20 (anti-B cell) monoclonal antibody, ritux-imab is currently FDA approved for treating several types of lymphoma. The CD20 antigen is expressed early in the B-cell cycle but is absent on mature plasma cells. The variable region binds to CD20 through three different mechanisms: (a) antibody-dependent cell cytotoxicity, (b) complement-dependent cell killing, and (c) induction of apoptotic cell death. The use of Brunicardi_Ch11_p0355-p0396.indd 36201/03/19 6:53 PM 363TRANSPLANTATIONCHAPTER 11rituximab has grown to include the


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Surgery_Schwartz. cell killing, and (c) induction of apoptotic cell death. The use of Brunicardi_Ch11_p0355-p0396.indd 36201/03/19 6:53 PM 363TRANSPLANTATIONCHAPTER 11rituximab has grown to include the treatment of antibody-mediated rejection and use in desensitization protocols. Studies so far have been small, with rituximab usually used in conjunc-tion with plasmapheresis, steroids, and intravenous immuno-globulin (IVIG).33-35BortezomibA proteasome inhibitor, bortezomib is FDA approved for treat-ing multiple myeloma. It can directly target plasma cells. Tradi-tional treatments have been successful in removing antibodies, inhibiting antibody activity, or lowering antibody production; however, targeting mature antibody production in plasma cells has not met with success. Bortezomib has been shown to cause apoptosis of normal plasma cells, thereby decreasing alloan-tibody production in sensitized patients. Several case reports and series have described the use of bortezomib for the treat-ment of


Surgery_Schwartz

Surgery_Schwartz. cause apoptosis of normal plasma cells, thereby decreasing alloan-tibody production in sensitized patients. Several case reports and series have described the use of bortezomib for the treat-ment of antibody-mediated rejection and in desensitization protocols.34,36,37EculizumabA humanized monoclonal antibody with high affinity for C5, eculizumab is a first-in-class, FDA-approved agent for treat-ing paroxysmal nocturnal hemoglobinuria, hemolytic uremic syndrome, and generalized myasthenia gravis. It blocks the activation of the terminal complement cascade. Most antibody-mediated rejection episodes are associated with early comple-ment activation as evidenced on renal transplant biopsies by the presence of C4d+ staining of the peritubular capillaries. Given its highly selective mechanism of action, this agent is predicted to be useful to treat antibody-mediated rejection and to desensi-tize patients pretransplant. However, its serious adverse effects include an increased risk of


Surgery_Schwartz

Surgery_Schwartz. of action, this agent is predicted to be useful to treat antibody-mediated rejection and to desensi-tize patients pretransplant. However, its serious adverse effects include an increased risk of infections, especially due to encap-sulated bacteria such as Neisseria meningitidis. Patients should be immunized with meningococcal vaccine at least 2 weeks before the administration of eculizumab.34,38,39INFECTIONS AND MALIGNANCIESAdvances in immunosuppression have led to improved graft survival rates. However, the growing population of immuno-suppressed patients, in turn, has led to an increased incidence of opportunistic infections and malignancies. Such posttransplant complications have become important barriers to long-term disease-free survival.InfectionsTransplant recipients are predisposed to a variety of infections. Immunosuppression is the obvious reason. Moreover, such patients have already endured end-stage organ disease pre-transplant and then the stress of an invasive transplant


Surgery_Schwartz

Surgery_Schwartz. to a variety of infections. Immunosuppression is the obvious reason. Moreover, such patients have already endured end-stage organ disease pre-transplant and then the stress of an invasive transplant opera-tion. Posttransplant, they continue to have significant comorbid conditions.Early. Early infections (i.e., infections occurring within 1 month posttransplant) can be due to a wide spectrum of pathogens (bacterial, viral, and fungal). In the immediate postoperative period, recipients are significantly compromised from the stress of the operation, from induction immunosuppression, and often from initially impaired graft function. Infections during this period can be devastating.It is imperative to differentiate between medical and surgical infections. Surgical infections are the most common and require expedient surgical intervention. Typical examples include generalized peritonitis, intra-abdominal abscesses, and wound infections.In liver and pancreas recipients, surgical infections


Surgery_Schwartz

Surgery_Schwartz. and require expedient surgical intervention. Typical examples include generalized peritonitis, intra-abdominal abscesses, and wound infections.In liver and pancreas recipients, surgical infections are most severe. The incidence of intra-abdominal infections is decreasing, but they remain a significant problem: they are the second most common reason (after vascular thrombosis) for graft loss in pancreas recipients.Lengthy operations with significant blood loss, prolonged warm and cold ischemic times, and spillage of contaminated fluid (bile, urine, or bowel contents) predispose patients to intra-abdominal infections. Other prominent risk factors are the high level of induction immunosuppression immediately post-transplant and anastomotic leaks. Furthermore, pretrans-plant infections can reemerge or worsen.The signs and symptoms of intra-abdominal infections are those of peritonitis: fever, hypotension, ileus, and abdominal pain, although the latter can be masked by immunosuppres-sion.


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Surgery_Schwartz. or worsen.The signs and symptoms of intra-abdominal infections are those of peritonitis: fever, hypotension, ileus, and abdominal pain, although the latter can be masked by immunosuppres-sion. Treatment entails a prompt return to the operating room. Intra-abdominal infections are usually polymicrobial, involving several bacterial and fungal species. Common bacterial isolates include Escherichia coli, as well as Enterococcus, Klebsiella, and Pseudomonas species. Common fungal isolates are Candida albicans, Candida krusei, and Candida glabrata. Localized infections or abscesses can be treated with percutaneous drain-age and antibiotics.Medical infections include respiratory, urinary tract, and bloodstream infections. Medical treatment should also be aggressive, often including empiric antibiotics and antifungal medications even before culture results are available. Recipients of organs from infected donors should be treated per the results of donor culture speciation and the antibiotic


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Surgery_Schwartz. and antifungal medications even before culture results are available. Recipients of organs from infected donors should be treated per the results of donor culture speciation and the antibiotic sensitivity profile.Late. Late infections primarily are due to chronic immunosup-pression, specifically the depression of cell-mediated immu-nity that renders recipients susceptible to viruses, fungi, and parasites.Members of the herpesvirus group are the most common etiologic agents of viral infections posttransplantation, with her-pes simplex virus (HSV), CMV, and EBV being the most prom-inent. Pretransplant exposure to viruses may confer immunity. Recipients who are seronegative for HSV, CMV, and/or EBV have a higher incidence of posttransplant infections, especially if they receive donor allografts from seropositive donors.CMV is a latent infection that can be transmitted to sero-naive recipients by donor organs from seropositive individuals, can reactivate during immunosuppression, or both.


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Surgery_Schwartz. from seropositive donors.CMV is a latent infection that can be transmitted to sero-naive recipients by donor organs from seropositive individuals, can reactivate during immunosuppression, or both. Infections usually occur 3 to 6 months posttransplant or during treatment for rejection. The incidence of CMV has been greatly reduced with 12-week acyclovir prophylaxis.40 CMV infections range from an asymptomatic or mild flu-like syndrome to tissue-invasive disease resulting in pneumonitis, hepatitis, and GI ulcerations. Symptomatic infections and all tissue-invasive CMV disease should be treated with intravenous (IV) ganciclovir, a reduction in immunosuppression, or both, although successful treatment of mild to moderate rejection and concurrent mild to moderate CMV disease has been described.EBV infections range from a mild mononucleosis syn-drome to severe hepatitis and highly morbid PTLD. PTLD ranges from a localized tumor to a progressive, diffuse infiltration of various organs


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Surgery_Schwartz. infections range from a mild mononucleosis syn-drome to severe hepatitis and highly morbid PTLD. PTLD ranges from a localized tumor to a progressive, diffuse infiltration of various organs including the brain. It results from the prolifera-tion of EBV-positive B cells in immunosuppressed patients. The main risk factors are a high degree of immunosuppression and 3Brunicardi_Ch11_p0355-p0396.indd 36301/03/19 6:53 PM 364BASIC CONSIDERATIONSPART Ia predisposing EBV serostatus (seronaive recipient, seroposi-tive donor). Among patients with early lesions, the first line of treatment is to reduce immunosuppression. For those with more advanced PTLD, rituximab is used.After 6 months posttransplant, the risk of invasive fungal infections is closely associated with environmental exposures. Blastomyces dermatitidis grows in moist soil in the Midwest and Southeast regions of the United States. Diagnosis is con-firmed by biopsy; the preferred treatment is IV amphotericin B.Coccidioides immitis


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Surgery_Schwartz. dermatitidis grows in moist soil in the Midwest and Southeast regions of the United States. Diagnosis is con-firmed by biopsy; the preferred treatment is IV amphotericin B.Coccidioides immitis can cause invasive coccidioidomy-cosis after inhalation of aerosolized infectious particles. It is endemic in the Southwest, Northern Mexico, and various parts of Central and South America. This infection can be resilient and difficult to treat. The first line of treatment is high-dose amphotericin B.Histoplasma capsulatum is found in chicken, pidgeon, and bat droppings in the Ohio River and Mississippi River val-leys. Dissemination is commonplace; up to a quarter of patients have central nervous system (CNS) involvement. Treatment consists of prolonged (3 to 13 months) administration of oral itraconazole.Opportunistic infections with Aspergillus, Cryptococcus, Mucor, and Rhizopus species are rare but can cause serious infections. Patients with invasive Candida or Aspergillus infec-tions exhibit


Surgery_Schwartz

Surgery_Schwartz. infections with Aspergillus, Cryptococcus, Mucor, and Rhizopus species are rare but can cause serious infections. Patients with invasive Candida or Aspergillus infec-tions exhibit a 20% mortality rate. Prophylaxis with fluconazole has been shown to reduce invasive fungal infections in liver recipients.41Pneumocystis jiroveci (also known as PCP) is ubiqui-tous and can cause pulmonary disease in immunocompromised patients. However, trimethoprim-sulfamethoxazole (TMP-SMX) is effective prophylaxis against PCP, and daily, lifelong administration has virtually eliminated this infection among transplant recipients.MalignanciesChronic immunosuppression increases the risk of develop-ing certain types of malignancies. The most extensive data, from a cohort study involving more than 175,000 solid organ transplant recipients, showed that 10,656 of them developed malignancies. The standardized incidence ratio was 2:10 (as compared with the general population). Recipients had at least a fivefold


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Surgery_Schwartz. organ transplant recipients, showed that 10,656 of them developed malignancies. The standardized incidence ratio was 2:10 (as compared with the general population). Recipients had at least a fivefold increase (as compared with the general population) in these types of malignancies: Kaposi’s sarcoma, nonmelanoma skin cancer, non-Hodgkin’s lymphoma, and cancer of the liver, anus, vulva, and lip. In addition, recipients had a statistically significant increase (as compared with the general population) in melanoma, Hodgkin’s lymphoma, and cancer of the lung, kidney, colon, rectum, and pancreas.42ORGAN PROCUREMENT AND PRESERVATIONOrgan procurement is a key element in organ transplantation. Currently, over 100 organ procurement organizations (OPOs) exist in the United States, all members of the Organ Procure-ment and Transplantation Network (OPTN), which is a feder-ally mandated network created by and overseen by UNOS. Each OPO is responsible for evaluating and procuring deceased donor


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Surgery_Schwartz. the Organ Procure-ment and Transplantation Network (OPTN), which is a feder-ally mandated network created by and overseen by UNOS. Each OPO is responsible for evaluating and procuring deceased donor organs for transplantation in a specific geographic region. Hospitals receiving any type of federal reimbursement for their services (whether transplant-related or not) are required to report all deaths to their OPO in a timely manner. Each OPO then determines the medical suitability of the deceased for organ donation; requests consent for donation from family members; if consent is given, contacts the OPTN to analyze and identify potential recipients whose HLA antigens most closely match those of the donor; and arranges for the recovery and transport of any donated organs.Strategies to increase organ donation and utilization have been successfully implemented in the last 10 to 15 years. The nationwide “Organ Donation Breakthrough Collaborative,” sponsored by the U.S. Department of Health


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Surgery_Schwartz. organ donation and utilization have been successfully implemented in the last 10 to 15 years. The nationwide “Organ Donation Breakthrough Collaborative,” sponsored by the U.S. Department of Health and Human Ser-vices in 2003, brought the OPOs and transplant communities into a single concerted program to develop best practices guide-lines. However, a severe donor shortage remains. The number of living organ donors peaked in 2007 and has declined since.Alternative options include tissue engineering and stem cell research, but those fields are in their infancy in terms of producing fully functional and vascularized human organs. With the development of genetic “knockout” pigs, xenotrans-plantation still shows promise, but two problems in particular—immunologic barriers and xenosis (also known as zoonosis) of endogenous porcine retroviruses—have yet to be satisfactorily addressed.Today, the gap between patients waiting for organ trans-plants and the number of organs available continues to


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Surgery_Schwartz. as zoonosis) of endogenous porcine retroviruses—have yet to be satisfactorily addressed.Today, the gap between patients waiting for organ trans-plants and the number of organs available continues to widen. More than 118,000 patients are on the waiting list for solid organ transplants, but only 33,611 transplants were performed in 2016.Deceased DonorsMost transplants today utilize organs from deceased donors. Formerly, death was determined by the cessation of both cardiac and respiratory function.Donation After Brain Death. In 1968, the concept of “irre-versible coma” was introduced by an ad hoc committee report at Harvard Medical School; that concept was pivotal to the final acceptance, in 1981, of “brain death” as a legal definition in the United States. The legal language states that the declara-tion of brain death should be in accordance with acceptable medical standards but does not specify clinical methodology. It is customary for hospitals to establish their own policies to


Surgery_Schwartz

Surgery_Schwartz. the declara-tion of brain death should be in accordance with acceptable medical standards but does not specify clinical methodology. It is customary for hospitals to establish their own policies to declare brain death, according to their standards of care and local regulations.Typically, brain death is defined as the irreversible cessa-tion of brain function, including the brainstem. The presence of medical conditions that mimic brain death—such as drug over-dose, medication side effects, severe hypothermia, hypoglyce-mia, induced coma, and chronic vegetative state—need to be excluded. The latest evidence-based guideline on determining brain death in adults reaffirmed the validity of current clinical practice.43 Briefly, the clinical diagnosis of brain death consists of four essential steps: (a) establishment of the proximate cause of the neurologic insult; (b) clinical examinations to determine coma, absence of brainstem reflexes, and apnea; (c) utilization of ancillary tests, such


Surgery_Schwartz

Surgery_Schwartz. (a) establishment of the proximate cause of the neurologic insult; (b) clinical examinations to determine coma, absence of brainstem reflexes, and apnea; (c) utilization of ancillary tests, such as electroencephalography (EEG), cere-bral angiography, or nuclear scans, in patients who do not meet clinical criteria; and (d) appropriate documentation. A similar guideline on determining brain death in pediatric patients was recently developed.44Once the diagnosis of brain death has been established, the local OPO assumes the care of the potential donor and initiates the process of donor evaluation and organ donation, and the potential donor is screened for contraindications to donation. The medical history and social history are obtained from the available family members. A battery of tests, including serologic Brunicardi_Ch11_p0355-p0396.indd 36401/03/19 6:53 PM 365TRANSPLANTATIONCHAPTER 11or molecular detection of human immunodeficiency virus (HIV) and viral hepatitis, are


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Surgery_Schwartz. tests, including serologic Brunicardi_Ch11_p0355-p0396.indd 36401/03/19 6:53 PM 365TRANSPLANTATIONCHAPTER 11or molecular detection of human immunodeficiency virus (HIV) and viral hepatitis, are performed. The exact medical conditions that preclude donation vary; nonetheless, in the United States, infections and other medical conditions that determine eligibil-ity are dictated by UNOS bylaws and routinely reviewed and updated.The OPO focuses on preserving organ function and opti-mizing peripheral oxygen delivery until organ procurement commences.45 In all deceased donors, core temperature, sys-temic arterial blood pressure, arterial oxygen saturation, and urine output must be determined routinely and frequently. Arterial blood gases, serum electrolytes, blood urea nitrogen, serum creatinine, liver enzyme, hemoglobin, and coagulation tests need to be monitored regularly. In all brain-dead donors, elevated intracranial pressure triggers a compensatory catechol-amine response to


Surgery_Schwartz

Surgery_Schwartz. creatinine, liver enzyme, hemoglobin, and coagulation tests need to be monitored regularly. In all brain-dead donors, elevated intracranial pressure triggers a compensatory catechol-amine response to maintain cerebral profusion pressure. Isch-emic injury to the spinal cord and the sympathetic system may lead to a profound vasodilation. As a result, brain-dead donors frequently have severe hemodynamic and metabolic derange-ments, so aggressive monitoring and intervention are required to prevent loss of precious organs.Previous studies of deceased donor care focused on organ-specific resuscitation protocols that resulted in only marginal gains in the number of organs transplanted. The latest develop-ments center on multisystem protocols to increase the number of organs transplanted per donor (OTPD).46,47 The goals are to maintain a core temperature between 36.0°C and 37.5°C, a mean arterial pressure >70 mmHg or a systolic pressure >100 mmHg, and a hemoglobin level between 7 and 10


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Surgery_Schwartz. (OTPD).46,47 The goals are to maintain a core temperature between 36.0°C and 37.5°C, a mean arterial pressure >70 mmHg or a systolic pressure >100 mmHg, and a hemoglobin level between 7 and 10 g/dL; hormonal therapy and aggressive treatment of arrhythmias and metabolic derangements are also called for.47Surgical Technique. Procurement of multiple organs (heart, lungs, kidney, liver, pancreas, and/or small bowel), or multivis-ceral procurement, was first described by the Pittsburgh group in 1987.48 Since then, most centers have incorporated changes, especially with regard to the timing and location of dissection and flushing.49,50 The basic steps involve a long incision to provide wide exposure of all thoracic and abdominal organs (Fig. 11-3). A Cattell-Braasch maneuver (complete mobiliza-tion of the distal small bowel, right colon, and duodenum) is performed to allow for identification of the distal aorta, iliac Figure 11-3. Exposure for thoracic and abdominal organ


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Surgery_Schwartz. mobiliza-tion of the distal small bowel, right colon, and duodenum) is performed to allow for identification of the distal aorta, iliac Figure 11-3. Exposure for thoracic and abdominal organ procurement.bifurcation, and distal inferior vena cava (IVC). The infrare-nal aorta is the site for inserting the cannula that will allow for flushing of the organs with cold preservation solution. Some-times, division of the inferior mesenteric artery is necessary to facilitate the exposure of the distal aorta. The third portion of the duodenum is retracted cephalad to expose the root of the supe-rior mesenteric artery (SMA). Limited dissection is performed at the root of the SMA, which is encircled with a vessel loop to enable its temporary occlusion at the time of flushing, thus reducing the incidence of overperfusion injury to the pancreas.A large anomalous or replaced right hepatic artery typi-cally rises from the SMA, and this should be identified and preserved. Lateral to the SMA is the


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Surgery_Schwartz. of overperfusion injury to the pancreas.A large anomalous or replaced right hepatic artery typi-cally rises from the SMA, and this should be identified and preserved. Lateral to the SMA is the inferior mesenteric vein (IMV), which can be cannulated for portal flushing. Dissection of the hepatic hilum and the pancreas should be limited to the common hepatic artery (CHA), and branches of the CHA (e.g., splenic, left gastric, and gastroduodenal arteries) are exposed. The gastrohepatic ligament is carefully examined to preserve a large anomalous or replaced left hepatic artery, if present. The supraceliac aorta can be exposed by dividing the left triangular ligament of the liver and the gastrohepatic ligament.The common bile duct is transected at the superior mar-gin of the head of the pancreas. The gallbladder is incised and flushed with ice-cold saline to clear the bile and sludge. If the pancreas is to be procured, the duodenum is flushed with anti-microbial solution. Before the


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Surgery_Schwartz. pancreas. The gallbladder is incised and flushed with ice-cold saline to clear the bile and sludge. If the pancreas is to be procured, the duodenum is flushed with anti-microbial solution. Before the cannulation of the distal aorta, systemic heparinization (300 units/kg) is administered. The supraceliac aorta is clamped; cold preservation fluid is infused via the aortic (systemic) and IMV (portal) cannulas. The tho-racic organs, liver, pancreas, and kidneys are then removed.Donation After Cardiac Death. Given the severe shortage of donor organs, donation after cardiac death (DCD)—also known as donation by non–heart-beating donors (NHBDs)—was rein-troduced to the transplant community in the 1990s.51 The cat-egory of DCD (Maastricht classification) was initially proposed at an international workshop and is now widely adopted for organ procurement.52 Currently, most NHBDs in the United States meet Maastricht classification III; that is, they have suffered a devastating injury with no


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Surgery_Schwartz. workshop and is now widely adopted for organ procurement.52 Currently, most NHBDs in the United States meet Maastricht classification III; that is, they have suffered a devastating injury with no chance of a meaningful recovery but do not meet the criteria for brain death. After consent for dona-tion is obtained from the next of kin, the donor’s life support is removed. After the cessation of cardiac and respiratory function, organ procurement commences. DCD procurement protocols vary between states; religious and cultural differences need to be taken into consideration. The surgical team must be familiar with, and respect, the local protocol.With cardiac death (as opposed to brain death), warm ischemic injury to organs can occur during the period between circulatory cessation and rapid core cooling through perfusion of preservation solution. However, the difference in long-term outcomes is negligible for recipients of organs from either type of donor. Still, a significant percentage


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Surgery_Schwartz. cooling through perfusion of preservation solution. However, the difference in long-term outcomes is negligible for recipients of organs from either type of donor. Still, a significant percentage of liver grafts procured after cardiac death, especially those with more than 25 minutes of warm ischemic time, develop devastating ischemic cholan-giopathy and fail.53A new development to minimize ischemic injury to organs procured after cardiac death has been the application of extra-corporeal membrane oxygenation (ECMO). With ECMO, DCD differs in two key ways: (a) cannulation occurs before with-drawal of life support and (b) organs are perfused via ECMO with warm oxygenated blood after declaration of cardiac death. Brunicardi_Ch11_p0355-p0396.indd 36501/03/19 6:53 PM 366BASIC CONSIDERATIONSPART IThe initial experience with organs procured using ECMO has been encouraging.Surgical Technique. Surgeons who perform multiple organ retrieval should be familiar and experienced with the


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Surgery_Schwartz. initial experience with organs procured using ECMO has been encouraging.Surgical Technique. Surgeons who perform multiple organ retrieval should be familiar and experienced with the super-rapid technique described by the Pittsburgh group.54 Preferably, NHBDs undergo withdrawal of life support in the operating room after the surgical site is prepped and draped, as soon as the surgical team is ready. Alternatively, the NHBD is transported to the operating room after declaration of cardiac death.A midline incision is used to rapidly gain entry into the abdominal cavity. An assistant retracts the small bowel and the sigmoid colon laterally, so that the bifurcation of the aorta can be easily identified on the left side of the vertebral column. A short segment of the distal aorta is dissected out from the retro-peritoneum. A moist umbilical tape is passed around the aorta, which is used to secure a cannula. The distal aorta is clamped. Next, a cannula is passed cephalad through an aortotomy


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Surgery_Schwartz. from the retro-peritoneum. A moist umbilical tape is passed around the aorta, which is used to secure a cannula. The distal aorta is clamped. Next, a cannula is passed cephalad through an aortotomy and secured. Flushing with cold preservation solution is started at once, followed by cross-clamping the aorta proximally (thoracic aorta) and venting through the vena cava. The portal flush is then instituted.The rest of the procedure is similar to procurement after brain death, with two noticeable differences. First, to avoid injury to a large anomalous or replaced left hepatic artery, the gastrohepatic ligament and the left gastric artery are separated from the stomach at the lesser curvature. Second, to avoid injury to a large anomalous or replaced right hepatic artery, the SMA is examined before it is divided. If the pancreas is not procured, a common aortic patch encompassing both the SMA and the celiac artery can be procured with the liver.Living DonorsThe maxim of medical ethics is


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Surgery_Schwartz. before it is divided. If the pancreas is not procured, a common aortic patch encompassing both the SMA and the celiac artery can be procured with the liver.Living DonorsThe maxim of medical ethics is “primum non nocere” (first, do no harm), and for that reason, living organ donation pres-ents unique ethical and legal challenges. Performing potentially harmful operations to remove organs from healthy individuals seems, at first glance, to contradict that maxim. But in fact, the ethical framework of living organ donation rests on three guid-ing principles respected in all discussions of medical practice: beneficence to the recipient, nonmaleficence to the donor, and the donor’s right to autonomy.55 In order to achieve optimal outcomes (the common good), transplant professionals should focus on maximizing the benefits for the recipient and minimiz-ing the damage to the donor. The Uniform Anatomical Gift Act adopted by all states in the United States (with slight variations) provides the


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Surgery_Schwartz. on maximizing the benefits for the recipient and minimiz-ing the damage to the donor. The Uniform Anatomical Gift Act adopted by all states in the United States (with slight variations) provides the legal framework for competent adult living donors to decide whether or not to donate. It is the fiduciary duty of transplant professionals to explain the risks of organ donation. Any decision to donate should be uncoerced, and no entice-ments should be offered.The use of living donors offers numerous advantages for recipients in need. First and foremost is the availability of lifesaving organs for those who would otherwise succumb to the progression of their end-stage disease. In certain parts of the world, such as East Asia, the concept of brain death and the use of deceased donors conflict with the prevailing culture or religion. Even in countries where the use of deceased donors is accepted, the use of living donors may significantly shorten the waiting time for recipients. A shorter


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Surgery_Schwartz. with the prevailing culture or religion. Even in countries where the use of deceased donors is accepted, the use of living donors may significantly shorten the waiting time for recipients. A shorter waiting time gener-ally implies a healthier recipient—one whose body has not been ravaged by prolonged end-stage organ failure. Moreover, with the use of living donors, transplants are planned (rather than emergency) procedures, allowing for better preoperative preparation of the recipient. Receiving an organ from a closely matched relative may also have immunologic benefits. And long-term results may be superior with the use of living donors, as is certainly the case with kidney transplants.The major disadvantage is the risk to the living donor. Medically, there is no possibility of benefit to the donor, only the potential for harm. The risk of death associated with dona-tion depends on the organ being removed. For a nephrectomy, the estimated mortality risk is less than 0.05%; for a


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Surgery_Schwartz. to the donor, only the potential for harm. The risk of death associated with dona-tion depends on the organ being removed. For a nephrectomy, the estimated mortality risk is less than 0.05%; for a partial hepatectomy, about 0.2%. The risk of surgical and medical complications also depends on the procedure being performed. In addition, long-term complications may be associated with a partial loss of organ function after donation. The guiding prin-ciple should be minimization of risk to the donor. All potential risks must be carefully explained to the potential donor, and written informed consent must be obtained.56Surgical Technique. The kidney, the first organ to be trans-planted from living donors, is still the most common organ donated by these individuals. The donor’s left kidney is usually preferable because of the long vascular pedicle. Use of living donor kidneys with multiple renal arteries should be avoided in order to decrease the complexity of the vascular reconstruction and


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Surgery_Schwartz. preferable because of the long vascular pedicle. Use of living donor kidneys with multiple renal arteries should be avoided in order to decrease the complexity of the vascular reconstruction and to help avoid graft thrombosis. Most donor nephrectomies are now performed via minimally invasive techniques, that is, laparoscopically, whether hand-assisted or not. With laparo-scopic techniques, an intraperitoneal approach is most common: it involves mobilizing the colon, isolating the ureter and renal vessels, mobilizing the kidney, dividing the renal vessels and the distal ureter, and removing the kidney (Fig. 11-4). Extensive dissection around the ureter should be avoided, and the surgeon should strive to preserve as much length of the renal artery and vein as possible.Liver transplants with living donors are not as commonly performed, given the significantly higher rates of donor mor-tality and morbidity. Initially, only adult donors for pediatric recipients were selected, but now,


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Surgery_Schwartz. with living donors are not as commonly performed, given the significantly higher rates of donor mor-tality and morbidity. Initially, only adult donors for pediatric recipients were selected, but now, living donor liver transplants also involve adult donors for adult recipients. In dual graft living donor liver transplants, segmental grafts from two living donors augment the recipient’s graft size.57 The donor hepatectomy is similar to a major lobar hepatectomy, except that it is impor-tant to preserve the integrity of the vascular structure until graft resection (Fig. 11-5).Living donor transplants of organs other than the kidney and liver are fairly uncommon, but certain centers do perform such transplants. Living donor pancreas transplants involve per-forming a distal pancreatectomy, with the graft consisting of the body and tail of the pancreas; vascular inflow and outflow are provided by the splenic artery and splenic vein. Living donor intestinal transplants usually involve


Surgery_Schwartz

Surgery_Schwartz. with the graft consisting of the body and tail of the pancreas; vascular inflow and outflow are provided by the splenic artery and splenic vein. Living donor intestinal transplants usually involve removal of about 200 cm of the donor’s ileum, with inflow and outflow provided by the ileocolic vessels. Living donor lung transplants involve removal of one lobe of one lung from each of two donors; both grafts are then transplanted into the recipient.Organ PreservationThe development and continuing refinement of organ preser-vation methods have completely revolutionized the transplant field. Extending the time that organs can be safely stored after procurement has enabled better organ utilization and better recipient outcomes.58,59 Hypothermia and pharmacologic inhibi-tion are the two most frequent methods. Both slow—yet cannot Brunicardi_Ch11_p0355-p0396.indd 36601/03/19 6:53 PM 367TRANSPLANTATIONCHAPTER 11ABCDEFFigure 11-4. Laparoscopic left donor nephroureterectomy. A. Takedown of


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Surgery_Schwartz. methods. Both slow—yet cannot Brunicardi_Ch11_p0355-p0396.indd 36601/03/19 6:53 PM 367TRANSPLANTATIONCHAPTER 11ABCDEFFigure 11-4. Laparoscopic left donor nephroureterectomy. A. Takedown of splenic flexure of colon to expose the left renal hilum. B. Dissection of left ureter off the psoas muscle. C. Dissection of left renal vein and gonadal vein. Left ureter seen lateral to the dissection. D. Dissection of left renal artery. Lumbar veins clipped and divided. E. Endo-TA stapler transection of the left renal artery. F. Placement of ports and Pfannenstiel incision for the donor kidney extraction.ABFigure 11-5. Donor hepatectomy (right hepatectomy). A. The liver parenchymal transection line (c, the Cantlie line) marked with cautery. Right portal vein (p) and right hepatic artery (a) isolated. b = bile duct. Cystic duct was cannulated for intraoperative cholangiography. B. Exposure of hepatic veins after transection of the parenchyma. IVC = inferior vena cava; L = left hepatic vein; M


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Surgery_Schwartz. b = bile duct. Cystic duct was cannulated for intraoperative cholangiography. B. Exposure of hepatic veins after transection of the parenchyma. IVC = inferior vena cava; L = left hepatic vein; M = middle hepatic vein; R = right hepatic vein.Brunicardi_Ch11_p0355-p0396.indd 36701/03/19 6:54 PM 368BASIC CONSIDERATIONSPART Icompletely shut down—the removed organ’s metabolic activ-ity, so both have adverse effects, such as cellular swelling and degradation. Cold storage solutions were introduced to mitigate some of the adverse effects of hypothermia or pharmacologic inhibition alone. Such solutions help prevent cellular swelling and the loss of cellular potassium.One, and perhaps the most effective, preservation solu-tion was developed at the University of Wisconsin and remains in wide use.60 Its ingredients include lactobionate (which helps prevent cellular swelling and reperfusion injury), raffinose, and hydroxyethyl starch (which helps reduce swelling of endothe-lial cells,


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Surgery_Schwartz. wide use.60 Its ingredients include lactobionate (which helps prevent cellular swelling and reperfusion injury), raffinose, and hydroxyethyl starch (which helps reduce swelling of endothe-lial cells, thereby decreasing edema). Histidine-tryptophan-ketoglutarate solution is also currently in wide use.61Despite enhancements in preservation methods, the amount of time that an organ can be safely stored remains rel-atively short (hours, not days), particularly with organs from marginal donors. Among kidney recipients, delayed graft func-tion becomes significantly more frequent after cold ischemic times of more than 24 hours, necessitating temporary dialysis, which is associated with increased risks of graft loss and higher costs.62 Among liver recipients, primary nonfunction and bili-ary complications ensue after prolonged cold ischemic times. In the case of heart and lung recipients, ischemic times should be under 6 hours. All of those times assume the use of normal donors.There is


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Surgery_Schwartz. complications ensue after prolonged cold ischemic times. In the case of heart and lung recipients, ischemic times should be under 6 hours. All of those times assume the use of normal donors.There is revived interest in the use of the pulsatile perfu-sion pump, a kidney graft preservation method that has been available for more than 40 years.63 With the increasing shortage of available donor organs and the rise in the use of organs after cardiac death, the pulsatile perfusion pump is garnering renewed enthusiasm as an adjunct method of preservation, even for donor organs other than kidneys.64,65KIDNEY TRANSPLANTATIONIntroductionUllman reported the first attempted human kidney transplant in 1902.66 For the next 50 years, sporadic attempts all ended in either technical failure or in graft failure from rejection. Joseph Murray performed the first successful kidney transplant in 1954, an epochal event in the history of organ transplantation. In that first case, the immunologic barrier was


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Surgery_Schwartz. from rejection. Joseph Murray performed the first successful kidney transplant in 1954, an epochal event in the history of organ transplantation. In that first case, the immunologic barrier was circumvented by transplanting a kidney between identical twins.67 For his pivotal contribution, Murray shared the Nobel Prize in Physiology or Medicine in 1990 with E. Donnall Thomas for their discoveries concerning “organ and cell transplantation in the treatment of human disease.”The introduction of AZA (Imuran) in 1960 marked the beginning of a new era in kidney transplantation. With the com-bination of steroids and AZA for maintenance immunosuppres-sion, the 1-year graft survival rate with a living related donor kidney approached 80%; with a deceased donor kidney, the rate was 65%.68 In the ensuing years, major milestones included the introduction of more effective immunosuppressive medications with lower toxicity profiles, such as polyclonal antilymphocyte globulin in the 1970s,


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Surgery_Schwartz. In the ensuing years, major milestones included the introduction of more effective immunosuppressive medications with lower toxicity profiles, such as polyclonal antilymphocyte globulin in the 1970s, cyclosporine in the 1980s, tacrolimus in the 1990s, and biologics in the first decade of the 21st century, as previously mentioned.Parallel to the developments in medical science were the transplant community’s concerted efforts to improve use of healthcare resources. In the United States, the Social Security amendments of 1972 provided Medicare coverage for patients with end-stage renal disease (ESRD). The National Organ Transplant Act of 1984 initiated the process of creating what later became UNOS, an umbrella organization to ensure access to organs by patients in need, to enhance organ procurement and allocation, and to improve posttransplant outcomes. This infrastructure later became the blueprint for other countries to follow. As a result, organ transplantation is the most


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Surgery_Schwartz. organ procurement and allocation, and to improve posttransplant outcomes. This infrastructure later became the blueprint for other countries to follow. As a result, organ transplantation is the most transparent field of medicine. Data such as transplant center performance are readily available on public websites; penalties for violation of regulations and for underperformance often result in trans-plant programs being shut down.Today, a kidney transplant remains the most definitive and durable renal replacement therapy for patients with ESRD. It offers better survival and improved quality of life and is considerably more cost-effective than dialysis.69,70 According to the 2016 Scientific Registry of Transplant Recipients (SRTR) annual report, nearly 100,000 adult patients were on the kidney transplant waiting list, while nearly 20,000 patients underwent renal transplantation. Trends over the past decade indicated that living related transplants remained rela-tively stable, while the


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Surgery_Schwartz. transplant waiting list, while nearly 20,000 patients underwent renal transplantation. Trends over the past decade indicated that living related transplants remained rela-tively stable, while the number of deceased donor transplants rose. Posttransplant outcomes have continued to improve: in 2015, the 1-year graft survival rate with a living donor kidney was nearly 98%; with a deceased donor kidney, the rate was approximately 95.0%.71The advantages of a living donor kidney transplant include better posttransplant outcomes, avoidance of prolonged waiting time and dialysis, and the ability to coordinate the donor and recipient procedures in a timely fashion. Living donor kidney recipients enjoy better long-term outcomes, a low incidence of delayed graft function, and reduced risks of posttransplant complications. Furthermore, the elective nature of living donor kidney transplants provides unique opportunities for recipient desensitization treatment if the donor and recipient are


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Surgery_Schwartz. posttransplant complications. Furthermore, the elective nature of living donor kidney transplants provides unique opportunities for recipient desensitization treatment if the donor and recipient are ABOincompatible or if the HLA cross-match results are positive.Some of the challenges transplant professionals face today are closing the growing gap between supply and demand and thereby reducing the current prolonged waiting times; refining immunosuppressive medications to achieve better outcomes with reduced toxicity; and caring for patients who develop rejection, especially antibody-mediated rejection.Pretransplant EvaluationActive infection or the presence of a malignancy, active substance abuse, and poorly controlled psychiatric illness are the few abso-lute contraindications to a kidney transplant. Studies have demon-strated the overwhelming benefits of kidney transplants in terms of patient survival, quality of life, and cost-effectiveness, so most patients with ESRD are referred


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Surgery_Schwartz. transplant. Studies have demon-strated the overwhelming benefits of kidney transplants in terms of patient survival, quality of life, and cost-effectiveness, so most patients with ESRD are referred for consideration of a kidney transplant. However, to achieve optimal transplant outcomes, the many risks (such as the surgical stress to the cardiovascu-lar system, the development of infections or malignancies with long-term immunosuppression, and the psychosocial and finan-cial impacts on compliance) must be carefully balanced.Any problems detected during the evaluation of transplant candidates are communicated to their referring physician and/or to a specialist if advanced evaluation and treatment are needed, ultimately improving overall care. Essentially, the pretransplant evaluation is a multifaceted approach to patient education and disease management.Before the pretransplant medical evaluation begins, kidney transplant candidates are encouraged to attend a group meeting


Surgery_Schwartz

Surgery_Schwartz. is a multifaceted approach to patient education and disease management.Before the pretransplant medical evaluation begins, kidney transplant candidates are encouraged to attend a group meeting 4Brunicardi_Ch11_p0355-p0396.indd 36801/03/19 6:54 PM 369TRANSPLANTATIONCHAPTER 11focused on patient education. The meeting is coordinated by a transplant physician or surgeon. The intent is to familiarize patients with the pretransplant evaluation process and with per-tinent medical concepts and terms. In an open forum format, important decisions such as type of donor (living vs. deceased) are discussed. The group meeting empowers patients to fully participate in their care and serves as an impetus for a meaning-ful dialogue with healthcare professionals.Medical EvaluationCardiovascular Disease. Diabetes and hypertension are the leading causes of chronic renal disease. Concomitant cardiovas-cular disease (CVD) is a common finding in this population. An estimated 30% to 42% of deaths with a


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Surgery_Schwartz. and hypertension are the leading causes of chronic renal disease. Concomitant cardiovas-cular disease (CVD) is a common finding in this population. An estimated 30% to 42% of deaths with a functioning kidney graft are due to CVD.72,73 Therefore, assessment of the potential kid-ney transplant candidate’s cardiovascular status is an important part of the pretransplant evaluation.In fact, the American Heart Association and the American College of Cardiology Foundation recently published their expert consensus on CVD evaluation and management for solid organ transplant candidates.74 The process should focus on care-ful screening for the presence of significant cardiac conditions (e.g., angina, valvular disease, and arrhythmias) and for a prior history of congestive heart failure, coronary interventions, or valvular surgery. The perioperative risk assessment is based on patient symptoms and exercise tolerance. For all kidney trans-plant candidates, a resting 12-lead electrocardiogram (ECG)


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Surgery_Schwartz. or valvular surgery. The perioperative risk assessment is based on patient symptoms and exercise tolerance. For all kidney trans-plant candidates, a resting 12-lead electrocardiogram (ECG) should be obtained. In addition, in this population, the use of echocardiography to analyze left ventricular function and to assess for pulmonary hypertension is useful.Stress testing may be considered in patients with no active cardiac condition but with risk factors such as diabetes, hemo-dialysis for more than 1 year, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The utility of noninvasive stress testing (as compared with angiographic studies) for evaluating coronary artery disease is controversial; an additional prognostic marker is the troponin T (cTnT) level.Malignancies. Because of the long-term use of immunosup-pressive medications, transplant recipients are at increased risk for development of malignancies. Untreated and/or active


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Surgery_Schwartz. T (cTnT) level.Malignancies. Because of the long-term use of immunosup-pressive medications, transplant recipients are at increased risk for development of malignancies. Untreated and/or active malig-nancies are absolute contraindications to a transplant (with two exceptions: nonmelanocytic skin cancer and incidental renal cell cancer identified at the time of concurrent nephrectomy [i.e., for polycystic kidney disease] and renal transplantation). For most patients who have undergone treatment of low-grade tumors with a low risk of recurrence (e.g., completely locally excised low-grade squamous cell cancer of the skin, colon cancer in a polyp absent stalk invasion), a wait of at least 2 years after suc-cessful treatment is recommended before a kidney transplant can be considered. However, for certain types of tumors, espe-cially at advanced stages or those with a high risk of recurrence (e.g., melanoma, lymphoma, renal cell cancer, breast cancer, colon cancer), a delay of at least 5


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Surgery_Schwartz. for certain types of tumors, espe-cially at advanced stages or those with a high risk of recurrence (e.g., melanoma, lymphoma, renal cell cancer, breast cancer, colon cancer), a delay of at least 5 years is advisable. Accord-ing to the Israel Penn International Transplant Tumor Registry, tumor recurrence posttransplant is not infrequent: the recurrence rate is 67% in patients with multiple myeloma, 53% in nonme-lanocytic skin cancer, 29% in bladder cancer, and 23% in breast cancer.75Infections. A thorough history of infections and immuniza-tions should be obtained from transplant candidates, who need all recommended age-appropriate vaccinations according to the Centers for Disease Control and Prevention (CDC) guidelines. Ideally, vaccinations should be completed at least 4 to 6 weeks before the kidney transplant takes place. Immunosuppressive medications blunt the immune response and reduce the effec-tiveness of vaccinations; even more important, with attenuated vaccines,


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Surgery_Schwartz. 6 weeks before the kidney transplant takes place. Immunosuppressive medications blunt the immune response and reduce the effec-tiveness of vaccinations; even more important, with attenuated vaccines, vaccine-derived infections could occur. If a splenec-tomy is anticipated (e.g., in recipients whose donor is ABO-incompatible or whose HLA cross-match results are positive), then they should be immunized against encapsulated organisms (such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) well in advance of the splenectomy.Transplant candidates should undergo routine tuberculosis (TB) screening. According to the Centers for Disease Control (CDC), in 2016, 9272 TB cases were diagnosed in the United States with 68.5 percent of cases occurring in foreign-born persons.76 Serologic screening combined with a chest roentgenogram for fungal infections such as coccidioidomycosis or histoplasmosis, in patients who either have a history of those infections or are from


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Surgery_Schwartz. Serologic screening combined with a chest roentgenogram for fungal infections such as coccidioidomycosis or histoplasmosis, in patients who either have a history of those infections or are from an endemic area, are recommended. Chronic infections such as osteomyelitis or endocarditis must be fully treated; a suitable waiting period after successful treatment must occur, in order to ensure that relapse does not occur.Hepatitis can be caused by five different type of viruses, hepatitis virus A, B, C, D, and E, with the first three being the most common. Acute viral hepatitis is a contraindication to a kidney transplant; however, chronic viral hepatitis (most com-monly caused by hepatitis B [HBV] or C [HCV]) does not pre-clude a recipient from undergoing a kidney transplant. In such candidates, obtaining a liver biopsy is essential to assess the disease severity. Recipients infected with HBV should undergo antiviral treatment (e.g., lamivudine) to prevent reactivation and progression of


Surgery_Schwartz

Surgery_Schwartz. obtaining a liver biopsy is essential to assess the disease severity. Recipients infected with HBV should undergo antiviral treatment (e.g., lamivudine) to prevent reactivation and progression of liver disease. Note that HBV is a noncytopathic virus; the liver damage is the result of an immune-mediated process.77 Moreover, the presence of normal liver enzymes in patients with HBV antigenemia does not predict the severity of parenchymal damage.Transplant candidates with chronic HCV infection often have HCV-related glomerulonephritis. As with HBV infection, the clinical presentation and biochemical findings with HCV infection are often unreliable in predicting liver damage. In such patients who also exhibit evidence of cirrhosis, a combined liver-kidney transplant should be considered. In appropriate candidates, pretransplant antiviral treatment with interferon-α may be considered. However, after a kidney transplant, inter-feron treatment is not recommended because it is an


Surgery_Schwartz

Surgery_Schwartz. In appropriate candidates, pretransplant antiviral treatment with interferon-α may be considered. However, after a kidney transplant, inter-feron treatment is not recommended because it is an immunos-timulant, and thus HIV may precipitate graft rejection.Thanks to the excellent outcomes of highly active anti-retroviral therapy (HAART), infection with HIV is no longer considered a contraindication to a kidney transplant. Kidney transplant candidates with HIV must have an undetectable HIV viral load and a CD4 lymphocyte count greater than 200/mm3; in addition, they must not have developed any opportunistic infection in the previous year.78Latent viral infections such as CMV and EBV are of par-ticular interest in the field of transplantation, given the risks of reactivation posttransplant and their detrimental effects on graft and patient survival. Knowing the CMV and EBV sero-logic status of the recipient and donor helps transplant pro-fessionals gauge the risk of immunosuppressive


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Surgery_Schwartz. and their detrimental effects on graft and patient survival. Knowing the CMV and EBV sero-logic status of the recipient and donor helps transplant pro-fessionals gauge the risk of immunosuppressive regimens in relation to potential infection, thereby guiding plans for post-transplant antiviral prophylaxis treatment or, as noted earlier, Brunicardi_Ch11_p0355-p0396.indd 36901/03/19 6:54 PM 370BASIC CONSIDERATIONSPART Iavoiding transplants between a seropositive donor and a sero-naive recipient.Kidney Disease. The third most common cause of graft loss in kidney transplant recipients is recurrence of glomerular diseases such as focal segmental glomerulosclerosis (FSGS), immunoglobulin A (IgA) nephropathy, hemolytic uremic syn-drome, systemic lupus erythematosus, and membranoprolifera-tive glomerulonephritis. FSGS deserves special mention due to its frequent occurrence and dramatic presentation of early graft loss. An estimated 30% to 40% of FSGS patients develop recur-rent disease


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Surgery_Schwartz. glomerulonephritis. FSGS deserves special mention due to its frequent occurrence and dramatic presentation of early graft loss. An estimated 30% to 40% of FSGS patients develop recur-rent disease posttransplant; of those, up to half eventually lose their graft.79 In recipients with a history of FSGS, posttrans-plant nephrotic proteinuria should be promptly investigated; if diagnosis is confirmed by transplant kidney biopsy, rescue plas-mapheresis should be instituted at once. Adjuvant therapy with rituximab has been proposed.80Hypercoagulopathy. Kidney transplant candidates with a history of thrombotic events, repeated miscarriages, or a fam-ily history of thrombophilia should be screened for the fol-lowing coagulopathic disorders: activated protein C resistance ratio, factor V Leiden mutation, factor II 20210 gene mutation, antiphospholipid antibody, lupus anticoagulant, protein C or S deficiency, antithrombin III deficiency, and hyperhomocyste-inemia. In recipients at risk for


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Surgery_Schwartz. mutation, factor II 20210 gene mutation, antiphospholipid antibody, lupus anticoagulant, protein C or S deficiency, antithrombin III deficiency, and hyperhomocyste-inemia. In recipients at risk for hypercoagulopathy, pediatric kidney grafts and any kidney allografts with a complex vascular anatomy should be avoided.81 A perioperative anticoagulation protocol is recommended in this population.Surgical EvaluationUrologic Evaluation. Kidney transplant candidates (pediatric patients, in particular) with chronic kidney disease as a result of congenital or genitourinary abnormalities should undergo a thorough urologic evaluation. A voiding cystourethrogram and a complete lower urinary tract evaluation to rule out out-let obstruction are essential. Indications for a native nephrec-tomy include chronic pyelonephritis, large polycystic kidneys with loss of intra-abdominal domain, significant vesicoureteral reflux, or uncontrollable renovascular hypertension.Vascular Evaluation. The potential


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Surgery_Schwartz. chronic pyelonephritis, large polycystic kidneys with loss of intra-abdominal domain, significant vesicoureteral reflux, or uncontrollable renovascular hypertension.Vascular Evaluation. The potential implant sites for a kidney graft include the recipient’s iliac vessels and, less commonly, the aorta and vena cava. Careful physical examination often reveals significant central and/or peripheral vascular disease. Findings such as a pulsatile intra-abdominal mass, diminished or absent peripheral pulse, claudication, rest pain, and tissue loss in lower extremities should be further evaluated by abdomi-nal computed tomography scan or ultrasound, Doppler studies, and/or angiography. With the popularity of endovascular inter-ventions, transplant surgeons also should be familiar with such technology and obtain detailed anatomic studies of patients with vascular stents.Immunologic Evaluation. ABO blood typing and HLA typ-ing (HLA-A, -B, and -DR) are required before a kidney trans-plant. The


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Surgery_Schwartz. and obtain detailed anatomic studies of patients with vascular stents.Immunologic Evaluation. ABO blood typing and HLA typ-ing (HLA-A, -B, and -DR) are required before a kidney trans-plant. The method of screening for preformed antibodies against HLA antigens (because of prior transplants, blood transfusions, or pregnancies) continues to evolve. The panel-reactive anti-body (PRA) assay is a screening test that examines the ability of serum from a kidney transplant candidate to lyse lymphocytes from a panel of HLA-typed donors. A numeric value, expressed as a percentage, indicates the likelihood of a positive cross-match with a donor. A higher PRA level identifies patients at high risk for a positive cross-match and therefore serves as a surrogate marker to measure the difficulty of finding a suitable donor and the subsequent risk of graft rejection.An important development in anti-HLA antibody screen-ing is Luminex technology, using HLA-coated fluorescent microbeads and flow


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Surgery_Schwartz. of finding a suitable donor and the subsequent risk of graft rejection.An important development in anti-HLA antibody screen-ing is Luminex technology, using HLA-coated fluorescent microbeads and flow cytometry, which is considered the “gold standard.” This technology pinpoints donor-specific antibodies (DSAs) in the serum of a kidney transplant candidate with a high PRA level. Since all organ donors must undergo HLA typing, a negative cross-match for recipients with a high PRA level can be ensured by avoiding the selection of donors carrying unac-ceptable antigens (i.e., a virtual cross-match).82 Kidney trans-plant candidate data (including ABO blood types, HLA types, and DSAs) are entered into a nationwide central database to facilitate deceased donor kidney allocation, as described earlier.Psychosocial Evaluation. Psychiatric disorders have been recognized as important contributing factors to poor outcomes posttransplant. Patients with uncontrolled psychiatric disor-ders are at high


Surgery_Schwartz

Surgery_Schwartz. Evaluation. Psychiatric disorders have been recognized as important contributing factors to poor outcomes posttransplant. Patients with uncontrolled psychiatric disor-ders are at high risk for noncompliance with drug treatment, impaired cognitive function, and the development of substance abuse. A robust psychosocial evaluation is essential to ensure that transplant candidates understand the risks and benefits of the procedure and that they adhere to the lifetime immunosup-pressive medication regimen.Recipient OperationKidney allografts usually are transplanted heterotopically. The iliac fossa is recognized as the ideal position because of its prox-imity to the recipient’s bladder and iliac vessels.83,84Retroperitoneal allograft placement also allows easy access for percutaneous biopsies and interventions for ureteral complications. The right iliac fossa is the preferred site because of its easy access to the recipient’s iliac vessels. However, if a pancreas transplant is anticipated


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Surgery_Schwartz. and interventions for ureteral complications. The right iliac fossa is the preferred site because of its easy access to the recipient’s iliac vessels. However, if a pancreas transplant is anticipated in the future or if now failed kidney grafts have been placed at the right iliac fossa, then the left iliac fossa is used for implantation. The current surgical technique for kidney transplants was developed and popularized in the 1950s and 1960s and has changed little since.85A large-bore three-lumen urinary catheter is inserted after the recipient is anesthetized, and it is occluded with a clamp beneath the surgical drapes. Recipients whose native kidneys produce urine will naturally fill up the urinary bladder; those individuals whose kidneys do not will require insufflation of saline prior to creation of the ureteral anastomosis.Exposure of the operative field starts with a curvilinear skin incision, one to two finger widths above the midline pubic bone and the lateral edge of the


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Surgery_Schwartz. to creation of the ureteral anastomosis.Exposure of the operative field starts with a curvilinear skin incision, one to two finger widths above the midline pubic bone and the lateral edge of the rectus sheath. Superiorly, the extension of the incision depends on the recipient’s body habitus and the size of the donor kidney. The anterior rectus sheath is incised, medially to laterally, until the lateral edge of the rectus sheath is exposed. The posterior rectus sheath is missing below the arcuate line, thus providing direct access to the extraperito-neal space. The rectus muscle can be easily mobilized medially without being divided. The remainder of the fascial incision is along the lateral edge of the rectus sheath until the desired expo-sure is achieved (Fig. 11-6).The retroperitoneal space of the iliac fossa is entered by mobilizing the peritoneum medially. The inferior epigastric ves-sels, the round ligament (in females), and the spermatic cord and its vasculature (in males) are


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Surgery_Schwartz. space of the iliac fossa is entered by mobilizing the peritoneum medially. The inferior epigastric ves-sels, the round ligament (in females), and the spermatic cord and its vasculature (in males) are encountered in this space; the former two structures are divided, while the latter is retracted with a vascular loop. A self-retained retractor is used to expose Brunicardi_Ch11_p0355-p0396.indd 37001/03/19 6:54 PM 371TRANSPLANTATIONCHAPTER 11ABCABFigure 11-6. Incision and exposure for kidney transplant. A. Mark for the skin incision. B. Anterior rectus sheath incised obliquely. The abdominal muscle transected lateral to the rectus muscle. C. External iliac artery and vein dissected.Figure 11-7. Vascular anastomoses of kidney transplant. A. Arterial anastomosis: donor renal artery with Carrel patch to recipient external iliac artery, end-to-side. B. Venous anastomosis: donor renal vein with caval extension conduit to recipient external iliac vein, end-to-side.the surgical field. The


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Surgery_Schwartz. patch to recipient external iliac artery, end-to-side. B. Venous anastomosis: donor renal vein with caval extension conduit to recipient external iliac vein, end-to-side.the surgical field. The iliac vessels should be dissected with great care. To minimize the risk of lymphocele development postoperatively, dissection of the iliac artery should be limited; the intertwining lymphatics around the iliac vessels should be ligated. In general, the donor’s renal artery and vein are anasto-mosed to the recipient’s external iliac vessels in an end-to-side fashion (Fig. 11-7). In recipients with a severely calcified iliac artery, the internal iliac artery can be used as an alternative, and in select cases, an endarterectomy must be performed.After restoring the circulation to the donor’s kidney, urinary continuity can be established via several approaches. The approach chosen depends on such factors as the length of the donor ureter and a recipient history of bladder surgery, native


Surgery_Schwartz

Surgery_Schwartz. kidney, urinary continuity can be established via several approaches. The approach chosen depends on such factors as the length of the donor ureter and a recipient history of bladder surgery, native nephrectomy, or pelvic radiation. The two most com-mon procedures to restore urinary continuity are the Leadbetter-Politano and a modification of the Lich (e.g., extravesical) ureteroneocystostomy.During the former procedure, a large cystotomy is cre-ated in the dome of the bladder, and the donor ureter is brought through a lateral and somewhat inferior 1-cm submucosal tunnel into the bladder, the end of which is spatulated and then sewn in place without tension with interrupted absorbable sutures placed through the mucosa and submucosa on the inside of the bladder.An extravesical ureteroneocystostomy is performed by careful dissection of a 1-cm portion of the muscular layers on the anterolateral portion of the bladder until a “bubble” of mucosa is exposed. The donor ureter is spatulated


Surgery_Schwartz

Surgery_Schwartz. is performed by careful dissection of a 1-cm portion of the muscular layers on the anterolateral portion of the bladder until a “bubble” of mucosa is exposed. The donor ureter is spatulated in a diamond-shaped fashion, the bladder mucosa is incised, absorbable interrupted sutures are placed in four quadrants, and a mucosa-to-mucosa anastomosis is created using running absorbable sutures with a temporary ureteral stent in place of the first three-quarters of the anastomosis. The muscular lay-ers of the bladder are then carefully approximated over the anastomosis to prevent reflux.The decision to place a ureteral stent depends on the sur-geon, who must try to balance the risk of infectious compli-cations with the possible technical complications of a ureteral anastomosis, but in general, this is not required except during the rarely performed donor ureter to recipient ureter anastomo-sis or in the case of a pediatric kidney transplant. Fixation of the donor’s kidneys is not necessary,


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Surgery_Schwartz. is not required except during the rarely performed donor ureter to recipient ureter anastomo-sis or in the case of a pediatric kidney transplant. Fixation of the donor’s kidneys is not necessary, except in the case of small kidneys (usually from a pediatric donor) or en bloc kidneys.Brunicardi_Ch11_p0355-p0396.indd 37101/03/19 6:54 PM 372BASIC CONSIDERATIONSPART IFigure 11-8. Arterial and venous reconstruction. A. Two renal arteries combined into a single Carrel patch (arrow). Right renal vein exten-sion conduit constructed with stapled caval patch. IVC = inferior vena cava; R = right renal vein. B. Three renal arteries anastomosed to external iliac artery separately.ABABFigure 11-9. En bloc kidney transplant (3-month-old donor kidneys). A. En bloc kidneys benched. Vascular integrity tested with methylene blue (blue hue look of the kidneys). B. En bloc kidneys transplanted into a 62-year-old woman. Donor aorta anastomosed to recipient’s exter-nal iliac artery; donor cava, to


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Surgery_Schwartz. tested with methylene blue (blue hue look of the kidneys). B. En bloc kidneys transplanted into a 62-year-old woman. Donor aorta anastomosed to recipient’s exter-nal iliac artery; donor cava, to recipient’s external iliac vein.Grafts With Multiple Renal ArteriesIn 10% to 30% of donor kidneys, multiple renal arteries are encountered. Unless kidney transplant candidates have hyper-coagulopathy, grafts with multiple renal arteries fare as well as those with single vessels.86 Vascular reconstruction options include implanting the donor’s arteries separately, reconstruct-ing the multiple arteries into a common channel, or combining multiple arteries into a common Carrel patch (Fig. 11-8).En Bloc GraftsDebate persists about whether to implant kidneys obtained from young donors (<5 years or whose body weight is under 20 kg) as a single en bloc unit into one recipient or separately into two recipients. The underlying issues are the shortage of donor organs, the complexity of the surgical


Surgery_Schwartz

Surgery_Schwartz. whose body weight is under 20 kg) as a single en bloc unit into one recipient or separately into two recipients. The underlying issues are the shortage of donor organs, the complexity of the surgical procedure, the risks of graft thrombosis, ureteral complications, and long-term outcomes.In en bloc kidney transplants, the donor aorta and vena cava are used as the vascular inflow and outflow conduits. Therefore, reconstruction of the en bloc graft pretransplant is key to a successful transplant. The donor’s suprarenal vena cava and aorta are oversewn. The lumbar branches of the cava and aorta are ligated. Dissection around the renal hilum should be avoided. The orientation of the cava and aorta should be clearly marked, in order to avoid torsion of the anastomosis. If the color of the two kidneys looks different after reperfusion, repositioning should be attempted to rule out vascular torsion; fixation of the en bloc kidneys to the retroperitoneum is often necessary. The donor’s


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Surgery_Schwartz. two kidneys looks different after reperfusion, repositioning should be attempted to rule out vascular torsion; fixation of the en bloc kidneys to the retroperitoneum is often necessary. The donor’s ureters are implanted to the recipient’s bladder, either as two separate anastomoses or as a common patch (Fig. 11-9). Only a handful of centers have performed en bloc kidney transplants, but the long-term outcomes are encouraging.87,88Brunicardi_Ch11_p0355-p0396.indd 37201/03/19 6:54 PM 373TRANSPLANTATIONCHAPTER 11Perioperative CarePreoperatively, a thorough history and physical examination should be performed. Any changes in transplant candidates’ recent medical history should be investigated in great detail. In those recipients with a historically negative PRA level who have recently undergone blood transfusions, a prospective tis-sue cross-match is necessary to avoid graft rejection. Electrolyte panels should be checked. Emergency dialysis may be neces-sary for transplant candidates


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Surgery_Schwartz. blood transfusions, a prospective tis-sue cross-match is necessary to avoid graft rejection. Electrolyte panels should be checked. Emergency dialysis may be neces-sary for transplant candidates experiencing hyperkalemia or fluid overload.For dialysis-dependent transplant candidates, the catheter sites should be examined preoperatively to rule out infections. Vascular access for hemodialysis is essential to avoid compli-cations related to posttransplant acute tubular necrosis (ATN). Vascular evaluation is mandatory; any changes in results should be investigated by appropriate imaging studies.As is routine for other major surgical procedures, trans-plant candidates should preoperatively undergo a chest X-ray, a 12-lead ECG, blood typing, cross-match tests, and prophylaxis against surgical site infection (by administration of a nonneph-rotoxic antibiotic with activity against both common skin micro-flora and gram-negative pathogens); candidates should receive nothing to eat or


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Surgery_Schwartz. surgical site infection (by administration of a nonneph-rotoxic antibiotic with activity against both common skin micro-flora and gram-negative pathogens); candidates should receive nothing to eat or drink.Intraoperatively, transplant recipients should be kept well hydrated to avoid ATN and should receive heparin prior to vas-cular occlusion. Before reperfusion of the transplanted kidney, the desired central venous pressure should be maintained at around 10 mmHg, and the systolic blood pressure should be above 120 mmHg. In pediatric recipients of an adult graft, a superphysiologic condition may be necessary to avoid ATN or graft thrombosis. Mannitol often is administered before reper-fusion as a radical scavenger and diuretic agent, and a diuretic such as furosemide is administered as well.Postoperatively, the guiding principles for the care of kidney transplant recipients are the same as for other surgical patients. The crucial elements include hemodynamic stability and fluid and


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Surgery_Schwartz. well.Postoperatively, the guiding principles for the care of kidney transplant recipients are the same as for other surgical patients. The crucial elements include hemodynamic stability and fluid and electrolyte balance. To achieve a euvolemic state, the recipient’s urine output is replaced with either an equal or a reduced volume of IV fluid on an hourly basis, depending on the medical status. In recipients undergoing brisk dieresis, aggressive replacement of electrolytes (including calcium, mag-nesium, and potassium) may be necessary. In recipients expe-riencing ATN, fluid overload, or hyperkalemia, however, fluid restriction, treatment for hyperkalemia, and even hemodialysis may be necessary.Hypotension is an unusual event immediately posttrans-plant. The differential diagnoses include hypovolemia, vasodila-tion, and myocardial infarction with cardiac failure. Immediate action should be taken to avoid life-threatening complications. Posttransplant hypertension can be mediated by


Surgery_Schwartz

Surgery_Schwartz. hypovolemia, vasodila-tion, and myocardial infarction with cardiac failure. Immediate action should be taken to avoid life-threatening complications. Posttransplant hypertension can be mediated by catecholamines, fluid overload, or immunosuppressive agents.Postoperatively, urine output is used as a surrogate marker to monitor graft function. Among recipients whose native kid-neys produce significant amounts of urine, normal or increased urine output can be misleading; for them, serum blood urea nitrogen and creatinine levels are more reliable indicators of kidney graft function.Suddenly decreased or minimal urine output requires immediate attention. A change in volume status is the most common cause, but other culprits include blockage of the uri-nary catheter, urinary leak, vascular thrombosis, hypotension, drug-related nephrotoxicity, ATN, and rejection (all of which must be thoroughly investigated). Diagnostic studies such as Doppler ultrasound, nuclear renograms, or biopsies


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Surgery_Schwartz. thrombosis, hypotension, drug-related nephrotoxicity, ATN, and rejection (all of which must be thoroughly investigated). Diagnostic studies such as Doppler ultrasound, nuclear renograms, or biopsies should be considered.Postoperative bleeding is an uncommon event after a kid-ney transplant. Recipients on anticoagulation or antiplatelet treatments are at increased risk. Signs and symptoms (such as an expanding hematoma over the surgical site, increased pain over the graft, a falling hemoglobin level, hypotension, and tachycardia) should arouse suspicion of hemorrhage. Doppler ultrasound is useful to establish the underlying cause. Surgical exploration seldom is required because the accumulated hema-toma tamponades the bleed. Indications for surgical explora-tion include ongoing transfusion requirement, hemodynamic instability, and graft dysfunction from hematoma compression. For recipients on anticoagulation or antiplatelet treatments, the threshold for surgical exploration is lower.