CASE 34-6, QUESTION 3: During the next 2 weeks, K.T.’s serum creatinine remains unchanged, and his

serum and urine viral loads also remain approximately the same. Are there any additional treatment options for

K.T.’s BK nephritis at this time?

ANTIVIRAL THERAPY

Cidofovir, an antiviral agent indicated for the treatment of CMV retinitis, inhibits

polyomavirus replication in vitro; however, to

p. 734

p. 735

date, no well-conducted clinical trials have proved this agent to be effective in

treating or preventing polyoma-associated nephropathy in the transplant population.

In a small number of case reports and case series, this agent was beneficial, but the

appropriate dose and frequency are still undetermined. Most reports have used very

small doses (0.25–1.0 mg/kg/dose) to minimize nephrotoxicity. It is given IV either

weekly or every other week and usually continued until renal dysfunction is resolved

and a decrease in the viral load occurs.

Cidofovir is associated with a high incidence of nephrotoxicity, especially at much

higher doses; therefore, patients usually receive predose and postdose hydration with

0.9% NaCl boluses. Close clinical monitoring of the patient is advised if this

treatment option is used. Because the doses of cidofovir currently used are

approximately 5% to 10% of the standard dose used to treat CMV (5 mg/kg/dose),

use of probenecid as a premedication to prevent high-dose cidofovir-induced

nephrotoxicity is not advocated. Other therapies that have been tried with mixed

success are IVIG and leflunomide in place of the discontinued antimetabolite, such as

mycophenolate. Retransplantation has also been conducted with some success.

54

LIVER TRANSPLANTATION

Indications

CASE 34-7

QUESTION 1: E.P., a 58-year-old, 78-kg man with an 18-year history of chronic liver disease secondary to

hepatitis C infection, arrives at the emergency room with a 2-day history of confusion, fever up to 102.2°F, and

worsening jaundice, with scleral icterus. Because the patient has severe abdominal distention, a paracentesis is

performed, and 7 L of fluid is drained from his peritoneal cavity. A diagnosis of spontaneous bacterial peritonitis

is made.

E.P.’s clinical status during the next several days gradually worsens, and he is moved to the intensive care

unit for closer monitoring and better supportive care. E.P. continues to be severely jaundiced, with worsening

liver function tests (LFTs). He becomes progressively more confused and eventually comatose requiring

intubation. Within 3 days of admission into the intensive care unit, a suitable liver donor, matched for size and

ABO blood group, is found and E.P. receives an orthotopic liver transplant with a choledocho-choledochostomy

(duct-to-duct anastomosis). CMV serology for E.P. is negative, and the donor liver is CMV positive.

After the transplantation, E.P. is started on fluid maintenance with 0.45% normal saline; tacrolimus 2 mg

NG/PO BID; and high-dose methylprednisolone with a rapid taper: 50 mg IV every 6 hours for four doses, 40

mg IV every 6 hours for four doses, 30 mg IV every 6 hours for four doses, 20 mg IV every 6 hours for four

doses, 20 mg IV every 12 hours for two doses, then 20 mg IV daily; famotidine 20 mg IV every 12 hours; and

ganciclovir 150 mg IV daily. Piperacillin–tazobactam 3.5 g IV every 6 hours for 48 hours was begun in the

operating room. An order also is written to limit all pain medications and sedatives. E.P. returned from surgery

with three abdominal Jackson–Pratt (JP) drains, an NG tube, Foley catheter, and Swan–Ganz central venous

catheter. What was the indication for E.P. to receive a liver transplant?

E.P. was diagnosed with end-stage liver failure (cirrhosis) caused by chronic

hepatitis C infection. Each center varies with respect to the most causes of cirrhosis

leading to liver transplant, but nationwide, hepatitis C and alcohol-induced disease

are the number one and two reasons for liver transplantation; however, in recent

years, nonalcoholic steatohepatitis (NASH) has been increasing in incidence and is

expected to become the most common indication within the next 10 years. Indications

for liver transplantation in adults include cholestatic liver disease (e.g., primary

biliary cirrhosis and primary sclerosing cholangitis), hepatocellular liver disease

(e.g., chronic viral hepatitis B or C, autoimmune, drug-induced, NASH, cryptogenic

cirrhosis), vascular disease (e.g., Budd–Chiari), hepatic malignancy, inherited

metabolic disorders, and fulminant hepatic failure (e.g., viral hepatitis, Wilson

disease, drug-induced or toxin-induced). Controversial indications include alcoholinduced disease and some types of hepatic malignancies. The concern with these

indications is either recurrence of disease, as in the case of hepatic malignancies, or

recidivism in the case of alcoholics.

55,56

Contraindications to transplantation have decreased over the past few years.

Current contraindications to liver transplantation include malignancy outside the

liver, cholangiocarcinoma, active uncontrolled infection outside the biliary system,

patients with alcoholic liver disease who continue to abuse alcohol, psychosocial

instability and noncompliance, severe neurologic disease, and advanced

cardiopulmonary disease. Patients with active infections are considered candidates

after the infection has been eradicated.

56 HIV infection is not considered an absolute

contraindication to transplantation.

57

E.P. was within the age limitations for transplantation (in general, up to age 75

years is considered although exceptions are common); he had severe progressive

disease and was at risk for death if he had not received a liver transplant. Because he

did not have any of the listed contraindications, a liver could be transplanted

emergently. His anticipated survival after transplantation at 1 year is greater than

85%; at 5 years, it is greater than 70%.

56

Patient Monitoring

CASE 34-7, QUESTION 2: How should E.P. be monitored in the initial postoperative period?

Ideally, E.P. should be awake and alert within 12 to 24 hours after the operation,

transferred from the intensive care unit to a regular bed in 1 to 2 days, and discharged

home within 5 to 10 days. Because function of the transplanted liver is essential for

the survival of the patient, extensive clinical, laboratory, and radiologic monitoring

are necessary. E.P. has three JP abdominal drains that must be monitored for output

production. The serum concentrations of BUN, creatinine, LFTs, potassium, sodium,

magnesium, calcium, phosphate, and glucose should be monitored every 6 hours on

the first postoperative day.

58 The surgical transplantation of a liver has been

associated with coagulopathies and bleeding. Therefore, platelets, prothrombin time,

fibrinogen, and factor V levels also should be monitored and deficiencies rapidly

corrected when clinically indicated.

58

Initial LFT results are highly variable; they can either increase for the first day or

two after transplantation because of ischemic and reperfusion injury to the allograft,

or they can decrease because of initial dilution by high-volume blood replacement. If

the liver is functioning well, the LFTs, bilirubin, and prothrombin time all should

begin to trend toward normal within a few days after the transplant.

Magnesium, phosphate, and calcium levels may fall in the early postoperative

period and should be monitored closely. Ionized calcium serum concentrations are

often monitored rather than total calcium because most patients have low serum

albumin concentrations. Hypocalcemia can occur because these patients may receive

large amounts of citrate through blood transfusions, which can lower serum calcium

concentrations. Magnesium deficiency is common in patients with end-stage liver

disease and may be exacerbated in the early post-transplantation period by

tacrolimus or diuretics. Why patients experience hypophosphatemia is not

p. 735

p. 736

fully known, but increased demand for phosphate for incorporation into adenosine

triphosphate is a possible explanation. Hypokalemia or hyperkalemia can occur,

depending on renal function and fluid status. Electrolyte serum concentrations should

be followed and electrolytes replaced if needed (see Chapter 27, Fluid and

Electrolyte Disorders).

Hyperglycemia, which is a good indication of a properly functioning liver due to

its role in glucose homeostasis (gluconeogenesis and glycolysis), may need to be

controlled with a continuous IV infusion of insulin initially, and then subcutaneous

insulin dosed on the basis of periodic glucose measurements. In contrast, persistent

refractory hypoglycemia indicates a poorly functioning liver. Hypertension, which is

multifactorial, also is sometimes seen during this time and usually is treated with

calcium-channel blockers or β-blockers. Renal dysfunction and neurologic

complications also can occur.

58 Neurologic complications, including those that are

drug induced, include oversedation, acute psychosis, depression, tremor, headaches,

peripheral neuropathy, cortical blindness, paresthesias, paresis, and seizures.

59

Additional complications that are common within the first 3 days to 3 months after

liver transplantation include respiratory distress, intra-abdominal hemorrhage,

biliary tract leaks and strictures, hepatic artery thrombosis, and primary graft

nonfunction. Because infection is another early postoperative concern, E.P. should be

monitored for bacterial, fungal, and viral infections.

58

Tacrolimus

PHARMACOKINETICS

CASE 34-7, QUESTION 3: Seven days after his liver transplantation, E.P.’s JP abdominal drains, Foley

catheter, and NG drain have been removed. Current medications include tacrolimus 4 mg PO every 12 hours;

prednisone 20 mg PO daily; TMP–SMX single-strength, one tablet PO daily; and valganciclovir 450 mg PO

daily. E.P.’s current laboratory values include the following:

BUN, 27 mg/dL

SCr, 0.9 mg/dL

Aspartate aminotransferase (AST), 170 IU/L

Alanine aminotransferase (ALT), 154 IU/L

γ-Glutamyl transferase (GGT), 320 IU/L

Total bilirubin, 3.4 mg/dL

Tacrolimus 9.4 ng/dL (whole blood by HPLC mass spectrometry)

What important pharmacokinetic factors should be considered when using tacrolimus after transplantation?

Tacrolimus is a highly lipophilic medication that is absorbed rapidly after oral

administration; peak blood concentrations are achieved in about 0.5 to 1 hour. Oral

bioavailability is usually poor, highly variable, and ranges from 4% to 89% (mean,

25%). Protein binding is approximately 99% and is mainly to erythrocytes and

alpha1-acid glycoprotein. Whole blood concentrations are significantly higher than

serum concentrations for this reason. Tacrolimus has a large volume of distribution

and accumulates in high concentrations in tissues, including the lungs, spleen, heart,

kidney, brain, muscles, and liver. Tacrolimus is predominantly metabolized in the

liver through the cytochrome P-450 3A4/5 isoenzyme system and is primarily

eliminated from the body as several inactive metabolites. Less than 1% of tacrolimus

is eliminated as the parent compound in the urine, and renal dysfunction does not

alter the pharmacokinetics of this agent. The elimination half-life ranges from 5.5 to

16.6 hours, with a mean of 8.7 hours. Varying degrees of liver dysfunction, including

cirrhosis and severe cholestasis, may reduce the metabolism and excretion of

tacrolimus. Pediatric patients have a higher clearance, shorter half-life, and larger

volume of distribution compared with adults.

60 African-American patients may

require higher dosages (0.2–0.4 mg/kg/day orally as opposed to 0.1–0.2 mg/kg/day

orally), such as in E.P.

61

DOSING

CASE 34-7, QUESTION 4: How would you initiate the dosing of tacrolimus for E.P.?

Although tacrolimus can be administered as a continuous IV infusion through a

central or peripheral catheter after transplantation (initial dose 0.025–0.05

mg/kg/day), it is preferable to give it via an NG tube or orally because adverse

effects, such as headache, nausea, vomiting, neurotoxicity, and nephrotoxicity, occur

more commonly with IV administration. If tacrolimus is given IV, patients should be

converted as soon as possible to oral therapy (initial doses of 0.1–0.3 mg/kg/day in

adults and 0.15–0.3 mg/kg/day in children, divided into 12-hour intervals).

62

In E.P., the initial starting dose was approximately 0.1 mg/kg/day given orally or

through the NG tube every 12 hours. Oral tacrolimus should be administered on an

empty stomach or taken consistently in relation to meals. Most institutions

extemporaneously prepare an oral solution for NG tube administration because it is

not commercially available.

61