Transplantation, Immunology, and Cell Biology

Transplantation, Immunology, and Cell Biology

Jarrett Santorelli, MD and Leslie Kobayashi, MD

Division of Trauma, Acute Care Surgery, Surgical Critical Care and Burns, University of California San Diego, San Diego, CA, USA

  1. A 57‐year‐old woman is admitted to the intensive care unit (ICU) with hepatic encephalopathy requiring intubation and management of cerebral edema. Her body mass index (BMI) is 41 kg/m, her albumin is 1.9 g/dL, and prealbumin is 9 mg/dL. A feeding tube is placed for enteral nutrition. Regarding nutrition in cirrhotic and pretransplant patients, which of the following is true?

    1. A preoperative BMI < 20 is associated with improved outcomes following transplant.
    2. A preoperative BMI > 40 is associated with improved outcomes following transplant.
    3. Preoperative energy intake should target a goal of 30–35 kcal/kg/day.
    4. Immuno‐enhanced nutrition has been associated with improved outcomes following transplant.
    5. Percutaneous gastrostomy (PEG) tube is the preferred route for long‐term enteral access in cirrhotic patients.

    It is well known that nutrition has a central prognostic and therapeutic role in the management of patients with liver disease. Based on available published data, patients should have an energy intake of 30–35 kcal/kg/d and a protein intake of 1.2–1.5 g/kg/d. In a well‐conducted prospective trial measuring total body nitrogen, the nocturnal administration of oral nutritional supplements has been shown to be more effective in improving total body protein status than daytime oral nutritional supplements. Patients undergoing liver transplantation who are underweight or severely obese experience significantly higher rates of morbidity and mortality in comparison with patients in the middle BMI categories. Across different eras of liver transplantation, underweight and severe obesity are independent predictors of death in a multivariable analysis. Despite some promising small studies of immuno‐enhanced nutritional supplementation particularly in the burn ICU population, there is no good evidence to support their use in patients with end‐stage liver disease (ESLD) either pre‐ or post‐transplant. Anti‐inflammatory oils have also not been demonstrated to have any substantial benefit when compared to standard enteral nutrition. While there is definite evidence that enteral nutrition is superior to parenteral nutrition, PEG tubes are not recommended in patients with ESLD. The presence of ascites, abdominal wall, gastric and esophageal varices, as well as the coagulopathy present in many ESLD patients, makes the risks of placement and infection/dislodgement after placement prohibitive.

    Answer: C

    Dick AAS, Spitzer AL, Seifert CF, et al. Liver transplantation at the extremes of the body mass index. Liver Transplantation 2009; 15(8): 968–977.

    Plauth M, Bernal W, Dasarathy S, et al. ESPEN guidelines on clinical nutrition in liver disease. Clinical Nutrition 2019; 38(2): 485–521.

  2. A 37‐year‐old male is postoperative day (POD) 3 from orthotopic liver transplant (OLT) and his postoperative course has been unremarkable after successful extubation on POD 1. Today was his first day working with physical therapy and getting out of bed. He reports to you after the session that he noticed some weakness and moderate swelling and pain with movement in his right calf. Ultrasound of the bilateral lower extremities reveals a deep venous thrombosis (DVT) of the right popliteal vein. Regarding venous thromboembolic (VTE) complications in live transplant patients, which of the following is true?

    1. Rates of VTE are higher after liver transplant than after other major abdominal procedures.
    2. Chemoprophylaxis is associated with reduced rates of VTE after OLT.
    3. Comorbid conditions such as end‐stage renal disease and diabetes are associated with lower risk of VTE following OLT.
    4. Treatment factors such as veno‐venous bypass and central venous catheters have not been shown to increase risk of VTE in OLT patients.
    5. Conventional laboratory measures of coagulation are good measures of VTE risk and can be relied upon to guide timing of VTE chemoprophylaxis.

    Venous thromboembolism (VTE), with deep vein thrombosis (DVT) and pulmonary embolism (PE) as the most common manifestations, is a serious and potentially fatal complication of major abdominal surgery and is estimated to occur in 5–10% of patients. The most common risk factors for VTE are hospitalization (52%), cancer (48%), and surgery (42%). Numerous risk factors for VTE exist in patients who undergo orthotopic liver transplantation (OLT) including critical illness, prolonged periods of bedrest, indwelling central venous catheters, and veno‐venous bypass. Recent studies have also demonstrated an increased risk of VTE in transplant recipients with diabetes, previous history of VTE, end‐stage renal disease (ESRD), patients discharged to rehabilitation centers, receiving factor VII during surgery, or having postoperative pneumonia. A marked reduction of both procoagulant factors (II, V, VII, IX, X, XI, XII), anticoagulant factors (anti‐thrombin III, protein C, and protein S), an increase in von Willebrand factor (vWF), and a reduced level of ADAMTS13 are the specific features of cirrhosis and bring the patient to a new hemostatic balance. Elevated tissue plasminogen activator and a deficiency of thrombin‐activatable fibrinolysis inhibitor have been associated with laboratory changes typical of hyperfibrinolysis and an increased risk of bleeding. However, cirrhosis has also been associated with reduced fibrinolysis, as shown by the decreased plasminogen and increased plasminogen activator inhibitor. The contrasting results explain the ongoing debate regarding the absence or presence of a hyperfibrinolytic state in patients with liver disease, even if the balance of fibrinolysis is probably restored by the parallel changes in profibrinolytic and antifibrinolytic drivers. In addition, patients may also suffer from microvascular consumption causing further decreases in AT‐III levels. Despite this balanced hemostatic condition, cirrhosis results in the prolongation of standard coagulation tests, which usually do not analyze the complex interplay between pro‐ and anticoagulants and thus do not provide an accurate evaluation of the alteration in the in vivo hemostatic balance. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and International Normalized Ratio (INR) provide only a measure of procoagulant factors and are insensitive to the plasma levels of anticoagulant factors, so they are unreliable to depict the hemostatic status of patients with end‐stage liver disease.

    Compared to patients undergoing other major abdominal surgeries, OLT patients have comparable to somewhat lower rates of VTE. Chemoprophylaxis, when utilized, has been associated with reduced risk of VTE after OLT. Chemoprophylaxis has also been associated with lower rates of portal vein thrombosis. Chemoprophylaxis has not been associated with higher mortality or complications.

    Answer: B

    Feltracco P, Barbieri S, Cillo U, et al. Perioperative thrombotic complications in liver transplantation. World Journal of Gastroenterology 2015; 21(26): 8004–8013.

    Nachal R, Subramanian R, Karvellas CJ, et al. Guidelines for the management of adult acute and acute‐on‐chronic liver failure in the ICU: cardiovascular, endocrine, hematologic, pulmonary and renal considerations: executive summary. Critical Care Medicine 2020; 48(3): 415–419.

    Salami A, Qureshi W, Kuriakose P, et al. Frequency and predictors of venous thromboembolism in orthotopic liver transplant recipients: a single‐center retrospective review. Transplantation Proceedings 2013; 45(1): 315–319.

    Yip J, Bruno DA, Burmeister C, et al. Deep vein thrombosis and pulmonary embolism in liver transplant patients: risks and prevention. Transplantation Direct 2016; 2(4):e68.

  3. A 73‐year‐old man with a medical history significant for hypertension, diabetes, and gastroparesis previously requiring total parenteral nutrition (TPN), and end‐stage renal disease (ESRD) is now POD 10 from renal transplant. The patient has had increasing work of breathing and required intubation; his post‐intubation x‐ray is seen below. Further workup including bronchoscopy with bronchoalveolar lavage and CT scan of the chest demonstrated an invasive fungal disease (IFD). The patient was started on caspofungin. Regarding IFD following solid organ transplant, which of the following is true?
    Photo depicts a chest X-ray.

    1. IFD are common complications following solid organ transplant.
    2. IFD do not impact mortality following transplant.
    3. Of all solid organ transplant recipients, IFD are most common following renal transplant.
    4. Candida and Aspergillus are the most common causes of IFD.
    5. IFD most often occur early following transplant, with the majority of infections occurring <90 days after surgery.

    Invasive fungal disease (IFD) is one of the critical opportunistic infections afflicting solid organ transplant (SOT) recipients. IFD contributes to relatively high morbidity and mortality compared to its low incidence, due to multiple causes, which include fungal virulence and delayed diagnosis in SOT patients. While still uncommon, incidence of IFD is increasing slightly over time. The incidence of IFD among kidney transplant recipients is commonly known to be the lowest among all SOT recipients, reported as 1–10%. The patients with highest risk for IFD are small bowel, lung, and liver recipients. The period of the highest risk for the development of IFD is known to be the period of intense immunosuppression, from one to six months after SOT. Recent studies reported that the majority of IFD cases developed later than six months after kidney transplantation (KT). Candida and Aspergillus species are the most common organisms, with non‐albicans species increasing in frequency.

    Answer: D

    Lum L, Lee A, Vu M, Strasser S, Davis R . Epidemiology and risk factors for invasive fungal disease in liver transplant recipients in a tertiary transplant center. Transplant Infectious Disease 2020; e13361.

    Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant‐Associated Infection Surveillance Network (TRANSNET). Clinical Infectious Diseases 2010: 50(8): 1101–1111.

    Seok H, Huh K, Cho SY, et al. Invasive fungal diseases in kidney transplant recipients: risk factors for mortality. Journal of Clinical Medicine 2020; 9(6):1824.

  4. A 45‐year‐old woman is POD 11 from combined OLT and kidney transplant and is doing well on the floor when she develops a fungal urinary tract infection and is started on fluconazole. Over the next several days, the patient’s urine output drops and the patient’s creatinine begins to rise. She also appears sleepy on rounds and when asked how she feels complains of a headache. The patient’s vital signs have remained stable except for mild hypertension. Lab abnormalities also include worsening hyperglycemia and new hyperkalemia. Which of the following agents is the most likely cause of these signs and symptoms? (Table 22.1).

    1. Prednisone
    2. Mycophenalate mofetil
    3. Tacrolimus
    4. Gabapentin
    5. Oxycodone

    This patient is demonstrating the most worrisome toxicity of tacrolimus, which is nephrotoxicity. Other typical symptoms of calcineurin inhibitor (CNI) toxicity include altered mental status, hypertension, hyperglycemia, and hyperlipidemia. CNIs are both the savior and Achilles heel of kidney transplantation. Though CNI have significantly reduce rates of acute rejection, their numerous toxicities can plague kidney transplant recipients. CNIs function as immunosuppressants by blocking T‐cell activation by binding to specific receptors and blocking calcineurin, a calcium‐dependent phosphatase within T‐cells. Though CNIs have been successful in preventing acute kidney transplant rejection, their use has been described as a significant contributing factor in acute and chronic allograft injury and ultimately allograft loss – with virtually universal presence of CNI nephrotoxicity on allograft biopsy by 10 years after kidney transplant. CNIs are metabolized by cytochrome P450 3A4 (CYP3A4) in both the liver and small intestine, and clearance is primarily from biliary excretion and fecal elimination. Any medications that inhibit CYP3A4 will increase drug concentrations, and in contrast, medications that induce CYP3A4 will decrease drug concentrations. Azole antifungals like fluconazole are commonly encountered inhibitors of CYP3A4 and will result in increased levels of tacrolimus and increased toxicity. While steroids, narcotics, and gabapentin may all contribute to altered mental status and increased somnolence, they are unlikely to affect renal function and both narcotics and gabapentin are more likely to result in decreased blood pressure than hypertension. Mycophenolate mofetil (MMF) is a first‐line drug in the maintenance of immunosuppression after solid organ transplant and has the benefit of low toxicity and minimal side effect profile. Side effects of MMF include gastrointestinal distress and pancytopenia. In contrast to CNIs, nephrotoxicity and neurotoxicity are rare with MMF.

    Table 22.1 Common pharmacologic CYP3A4 inhibitors and inducers.

    Inhibitors Inducers
    Cannabidiol Carbamazepine
    Diltiazem Phenytoin
    Verapamil Phenobarbital
    Erythromycin Rifampin
    Ketoconazole Rifabutin
    Fluconazole Efavirenz
    Clotrimazole Dexamethasone

    Answer: C

    Farouk SS, Rein JL . The many faces of calcineurin inhibitor toxicity‐ What the FK? Advances in Chronic Kidney Disease 2020; 27(1): 56–66.

    Vanhove T, Annaert P, Kuypers DR . Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metabolism Reviews 2016; 48(1):88–112.

  5. A 47‐year‐old woman with medical history significant for hypertension, diabetes, and ESLD secondary to alcoholic cirrhosis is now POD 0 from OLT. Regarding immunosuppression regimens in liver transplant recipients, which of the following is TRUE?

    1. Tacrolimus results in improved graft survival and mortality compared to cyclosporine when used for maintenance immunosuppression.
    2. Steroids have improved mortality and graft failure compared to basiliximab when used for induction immunosuppression.
    3. Tacrolimus causes fewer adverse events compared to cyclosporine.
    4. Tacrolimus has reduced risk of post‐transplant diabetes compared to cyclosporine when used for maintenance immunosuppression.
    5. Tacrolimus plus sirolimus reduces mortality and graft loss compared to tacrolimus alone when used for maintenance immunosuppression.

    Both tacrolimus and cyclosporine are classified as calcineurin inhibitors (CNIs) and are often used in maintenance immunosuppression following SOT. Tacrolimus binds to FK binding protein‐12 and blocks proliferation of calcineurin, preventing interleukin‐2 (IL‐2) expression/production, thus preventing an immune response from lymphocytes. Tacrolimus is superior to cyclosporine in increasing patient and graft survival. Fewer episodes of acute cellular rejection and steroid‐resistant rejection have also been seen with tacrolimus use in the first‐year post‐transplant compared to cyclosporine. Tacrolimus is preferred at most transplant centers because of its greater potency and improved cardiovascular side‐effect profile. While cyclosporine and tacrolimus have similar nephrotoxicity, tacrolimus has a greater diabetogenic effect than cyclosporine. Based on low‐quality evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroid induction in people undergoing liver transplantation. Based on low‐quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increase mortality and graft loss at maximal follow‐up compared with tacrolimus.

    Answer: A

    Best LMJ, Leung J, Freeman SC, et al. Induction immunosuppression in adults undergoing liver transplation: a network meta‐analysis. Cochrane Database of Systematic Reviews 2020; 1(1): CD013203.

    Haddad EM, McAlister VC, Renouf E, et al. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database of Systematic Reviews 2006; 18(4):CD005161.

    Rodrique‐Peralvarez M, Guerrero‐Misas M, thorburn D, et al. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta‐analysis. Cochrane Database of Systematic Reviews 2017; 3(3):CD011639.

  6. A 67‐year‐old female with Childs C cirrhosis secondary to hepatitis B has been in the ICU for several weeks with acute‐on‐chronic liver failure, requiring intubation for respiratory failure and hepatic encephalopathy, and hepatorenal syndrome requiring continuous renal replacement therapy. She is currently on the wait list to receive a liver transplant. Which of the following are risk factors for poor outcomes following transplantation?

    1. Hypernatremia
    2. Mechanical ventilation
    3. High Sequential Organ Failure Assessment (SOFA) score
    4. High Model of End‐stage Liver Disease (MELD) score
    5. Occurrence of acute‐on‐chronic liver failure

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Dec 15, 2022 | Posted by in CRITICAL CARE | Comments Off on Transplantation, Immunology, and Cell Biology

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