I. ACUTE CARE
The immediate post-operative period in abdominal
organ transplantation presents multiple therapeutic challenges and potential complications. Among the most
common are: graft dysfunction, electrolyte abnormalities, and infection. Assessment, prevention,
and management differs somewhat between kidney and liver transplant patients as these patients undergo
different surgical procedures, in addition to exhibiting different pathophysiology both before and after
transplantation. Much of the immediate post transplantation care occurs in the intensive care unit (ICU) setting,
particularly following orthotopic liver transplantation, but less so for kidney transplantation.
Time spent in the ICU may vary from less than one day, if at all for kidney transplants to several weeks
for liver transplants.
Monitoring of Graft Function Immediately Post-Transplantation
Within the hours and days immediately following liver and kidney transplantation, monitoring of graft
function plays a significant role in post-operative care. Clinical laboratory tests, appearance and volume
of urine and various surgical drain outputs,
ultrasonography, nuclear medicine tests, and if necessary, biopsy, all aid the clinician's judgement of
the new graft function.
Survival of the liver transplant patient depends upon early graft function, as currently, extracorporeal hepatic
replacement devices are not standard therapy. Assessment of the liver graft function begins shortly following
reperfusion. Once stabilized and in the ICU, the physical examination of a patient with a functioning liver should
reveal recovery of consciousness within approximately 12 hours following surgery. Laboratory evaluation
shows a characteristic elevation of liver function tests with aminotransferases in the 1000's and bilirubin
concentrations also remaining elevated. Steady decline of these values should begin within 2 to 4 days.
As measures of the new liver's synthetic function, prothrombin time (PT) and partial thromboplastin time
(PTT) also should begin to normalize within this time period. Since a functioning liver allograft aids the body
in maintaining blood glucose concentrations through gluconeogenesis, hypoglycemia in the absence of
pharmacologic hypoglycemic agents, also raises concern that the liver is not functioning well.
As the liver continues to improve function, electrolytes such as magnesium and phosphorus may require
Diagnosis of vascular complications from liver transplantation occurs most often through duplex ultrasonography.
Ultrasound depicts blood flow in the hepatic artery, hepatic vein, and portal vein. Fluid collections surrounding
the liver can also be visualized through ultrasound. Although interpretation of these tests is beyond the scope of
this review, their results can influence the patient's pharmacotherapy. If the ultrasound shows decreased blood
flow through these vessels, therapeutic options include pharmcotherapy, return to the operating room for
restoration of blood flow, or retransplantation, in the case of primary graft nonfunction. In a hemodynamically
intensity heparinization is sometimes instituted to theoretically prevent thrombosis around anastomotic sites.
Also nitroglycerin and diltiazem are sometimes employed to improve blood flow. Liver edema due to volume overload
could be another cause of decreased blood flow. Adequate diuresis (furosemide) and conservative fluid administration
should be employed to prevent this occurrence.
In addition, a number of liver transplant patients exhibit renal impairment either before, after, or before and after transplantation.
Complications related to the biliary system are reported to occur in around 10% to 12% of patients.
These complications usually consist of bile leaks or biliary strictures. Bile leaks usually occur early
after transplantation and involve anastomosis sites. Symptoms of a bile leak include fever and right
upper quadrant pain. If a bile collection develops around the leak it can cause obstruction of the bile
duct around this sight.
Laboratory evidence of this includes elevation of bilirubin, GGT, and alkaline phosphatase.
In contrast to the liver transplant patient, delayed graft function is not uncommon in renal transplantation patients,
necessitating reinstitution of hemodialysis. Despite the immediate necessity of hemodialysis, the patient's surgery
usually results in a functioning renal allograft. Patients with a functioning graft should begin having good urine
output within hours of transplantation. A urine output of fifty mililiters per hour within the first two to four
hours following surgery should be expected, with some patients reaching a urine output of 1 liter per hour for
the first 24 hours post-operatively. Appropriate fluid replacement is critical. With such dramatic diuresis,
the patient is also at risk for electrolyte abnormalities. For this reason electrolytes (potassium, calcium,
magnesium, phosphorus) must be monitored frequently. Should repletion be required, administration of
potassium and magnesium should be approached in a conservative manner, as renal function is still not optimal.
In a normally functioning renal allograft, serum creatinine remains elevated for the first 24 hours, then begins
a constant declince to normal or near normal values. Delayed graft function occurs in 8% to 50% of cadaveric
renal transplant patients, and most commonly results from the presence of acute tubular necrosis (ATN).
Delayed graft function is defined as the need for dialysis in the postoperative period or the failure of serum
creatinine to fall below 4 mg/dL or by 30% of the pretransplant value. Pharmacologic strategies to decrease
time the renal allograft undergoes ATN include administration of calcium channel blockers, such as diltiazem,
low dose dopamine (3 mcg/kg/min), and adequate hydration. Tacrolimus and cyclosporine are both associated with
significant renal toxicity,
therefore administration of these agents is sometimes delayed to prevent further damage to the transplanted kidney in ATN.
Stress ulcer prophylaxis is also usually indicated for most
transplant patients. Two definite risk factors are mechanical ventilation and coagulopathy. Hemodialysis is another
potential risk factor for stress ulcer development. At least one and likely more than one of these risk factors
exist in most transplant patients. In addition, transplant patients receive large doses of corticosteroids and other
medications that could precipitate or worsen gastritis.
As a result of this increased risk, patients immediately post operatively should receive pharmacologic stress ulcer prophylaxis.
Within the first 48 hours of tranplantation, patients require intravenous opioids
for pain control. However, as soon as the patient's pain begins to subside (within about 2 to 3 days), medication
should be converted to oral dosage forms, administered on an as needed basis. The use of non steroidal
antiinflammatory drugs (NSAIDS) for pain control is not recommended
in this patient population. Combining NSAIDS with either cyclosporin or tacrolimus may result in synergisitic
Perioperative Antibiotic Prophylaxis and Early Infectious Complications
Although surgery increases the risk of infection in many
otherwise healthy individuals, infection poses even further risk for patients following organ transplantation.
The need for immunosuppressives in addition to the pre-existing functional immunosuppression of end stage
renal and liver disease, places these patients at high risk for life threatening infections. Infectious complications
following abdominal organ transplantation have been estimated to occur in 42% to 83% of patients within 3 months of
liver transplantation and from 10% to 56% in kidney transplant patients. Transplant centers report mortality from
postoperative infections at rates of 4% to 23% in liver transplant patients and 5% to 30% for renal transplant patients.
Although pathogens most commonly associated with infections following these procedures differ, largely because of
differences surgical techniques, the high rate and severity of postoperative
infectious complications solidifies the role of perioperative antibiotic prophylaxis for both liver and kidney transplantation.
Liver transplantation represents one of the most
technically difficult abdominal surgeries with procedure times lasting on average of 8 to 12 hours.
Liver transplantation is classified by the modified National Research Council wound classification criteria
as a clean contaminated procedure. This criteria defines a clean-contaminated procedure as a procedure
involving transection of gastrointestinal, oropharyngeal, GU, biliary or tracheobronchial tracts with
minimal spillage or with minor breaks in technique; clean procedures performed emergently or with major
breaks in technique; reoperation of clean surgery with in 7 days, or procedures following blunt trauma.
Historically, liver transplant patients have received perioperative antibiotics although strong placebo
comparative evidence for this practice does not exist. Despite this lack of evidence for use of perioperative
antibiotics, clinicians recognize that benefits of administering antibiotics seem to outweigh the risks. Appropriate
perioperative antibiotics target potential bacterial infections from pathogens commonly associated with early
(< 2 weeks after procedure) infections. Coagulase negative staph., S. Aureus, Enterocci, and gram negative bacilli,
such as Klebsiella, E coli, Enterbacter sp. and Citrobacter sp. These bacteria, most commonly associated with
intraabdominal and wound infections, originate from the skin and intestinal lumen flora. The most commonly cited
regimen consists of ampicillin plus cefotaxime. This regimen provides activity against common gram negative pathogens,
some anti staphylococcal activity plus activity against enterococcus. Studies have also examined the use of
ampicillin/sulbactam and other third generation cephalosporins. Evidence that 48 hours of perioperative antibiotic
prophylaxis is as effective as other longer duration regimens. Selective bowel decontamination, another strategy
to prevent post-transplantation infections utilizes oral gentamicin, colistin (polymyxin E), and nystatin to clear the
bowel of aerobic gram negative bacilli and yeast, but is controversial.
Since these agents are not well absorbed systemically, they serve to clear the gut of target organisms while avoiding systemic
exposure of the drugs.
During the immediate post-transplant period while in the ICU, the liver transplant patient
acquires infections similar to those nosocomial infections of other surgical ICU patients.
These most commonly include ventilator-associated pneumonia, urinary tract infections,
infections associated with indwelling vascular access devices, surgical wound infections,
and candidal superinfections. Initial empiric antimicrobial therapy should begin with
broad-spectrum antibiotics, later targeted to specific pathogens as culture and
sensitivity results become available. Liver transplant patients may be more susceptible
to candida infections than are other populations, due to surgical manipulation of the
colonized GI tract, time in the ICU. Risk factors include elevated pretransplant serum
creatinine, hemodialysis requirement, duration of ICU stay, antibiotic use
(other than perioperative antibiotics) and immunosuppression. Both fluconazole
and amphotericin B have been studied as candidal prophylactic agents. Several
studies have shown a benefit with the use of fluconazole for antifungal prophylaxis
in patients deemed to be at high risk. Amphotericin B is considered second line therapy
for this indication due to its nephrotoxicity.
Infections within the first two weeks of kidney transplantation usually result from skin flora.
Therefore perioperative antibiotics are targeted toward staph aureus, coagulase negative staphylococci,
Cefazolin is the most common agent utilized for antibiotic surgical prophylaxis in this group.
The most common infectious complication immediately
post renal transplantation is the occurrence of urinary tract infections. Empiric antibiotics are directed towards
the most common pathogens. E coli, Staph aureus, and other gram negative rods are the most commonly cultured.
First line therapy usually consists of sulfamethoxazole/trimethoprim or ciprofloxacin, as the commonly isolated
organisms are usually susceptible to these two agents. Since kidney transplant patients do not usually have extended ICU
stays or receive multiple antibiotic courses, they are less likely to acquire pulmonary infections and candidal superinfections.
II. SUB-ACUTE CARE
As noted in the previous section, recipients may spend a short or extended time in the ICU.
After kidney transplant, most patients spend < 12 hours, if at all, whereas most liver transplants
1-3 days. Besides continued monitoring of hemodynamics, respiratory status, fluid and electrolytes
other issues must be addressed.
This can occur early after transplant and its prevention is most important for long term outcome. Rejection
can present as several different types after transplant. Hyperacute rejection occurs within minutes to hours
after transplant and results in immediate graft loss. Fortunately this is rare and is prevented with appropriate
Accelerated rejection occurs within the first few days after transplant and is also rare and more amenable to
The most common type is acute rejection. The incidence has decreased, particularly with the new
immunosuppressives and can be < 20% in kidney transplants, whereas in liver transplant it occurs
in 30-50% of recipients. Although it can occur at any time, it is most likely to be seen in the first 4-7 days
to first few months after transplant. Finally, the last type of rejection is chronic, which will be discussed
later in this module.
Clinical signs and symptoms of acute rejection can be non-specific and sometimes non-existent in both
types of transplants. These include fever, chills, myalgias, weight gain, edema, pain and tenderness
around the graft site. Kidney transplants may have decreased urine output, along with hypertension.
This must be distinguished from infection, calcineurin toxicity, dehydration and recurrence of disease.
The most likely and often only presentation is an acute rise in serum creatinine.
In liver transplants, besides nonspecific symptoms noted above, ascites may be occur or increase and if available,
a decrease in quantity and quality of bile may be present. The most likely indicators of acute rejection,
are elevations of ALT, AST, AlkPhos and bilirubin. Infection and disease recurrence should be ruled out.
In the case of both kidney and liver transplant, a tissue biopsy must be done to make the diagnosis of acute rejection.
This will dictate appropriate management.
A number of other events take place on the nursing ward. During this inpatient period fine tuning of
immunosuppressives and other medications, addressing any pre-transplant co- mordid conditions
and medications, wound care and removal of catheters and drains. Also focus is placed on the patient
strengthening him or herself, maintaining appropriate dietary intake, fluid intake, ambulation,
bowel function and pain control. These are important so the patient and their family can assume
care outside the hospital. Another important aspect that takes place is patient education and discharge
planning. Many patients are discharged within 5 days after kidney transplant and 10 days after liver transplant.
Knowing their medications, how to monitor and identify any problems and document temperature, blood
pressure, intake and output, weight and how to eat and exercise post transplant are extremely important for long
In order to make a smooth transition from inpatient to outpatient, the inpatient pharmacist should be instrumental
in facilitating this process. The pharmacist should be involved in patient education, should help with identify any
issues that might make discharge and chronic care problematic. The pharmacist should communicate with the
transplant coordinator and make them aware of any outstanding issues and should contact the pharmacy from
which the patient will obtain their medications. If the pharmacist is in an outpatient setting (clinic or community),
besides interacting with the patient, he/she should be in contact
with a member of the team, usually the transplant coordinator or pharmacist involved with the care and discharge
of the patient.
Besides having a good understanding of their care, the patient should leave the hospital with
names and contact information of individuals responsible for their care, a list of current medications
and a diary of
important monitoring parameters that they can carry with them and is accessible to any health care
provider involved in their care.
III. CHRONIC CARE
Although the most crucial time for a transplant patient is during their initial hospital stay, there are a large number
of potential complications a transplant patient may experience upon discharge from the hospital. As we continually
improve immunosuppressive regimens and prevent graft loss, particularly due to acute rejection, it will be
increasingly important to identify, prevent, and treat immunologic and nonimmunologic long-term complications
in transplant patients. As drug therapy experts, we have an important role to help prevent and manage these complications.
LONG-TERM IMMUNOSUPPRESSIVE STRATEGIES
Despite excellent short term results, long-term graft failure and patient death are still a major problem in
kidney and liver transplantation. Graft failure in kidney transplant patients is usually a function of
cardiovascular disease or chronic rejection; whereas, in liver transplant patients, graft loss and patient
death is often related to recurrence of primary disease, renal failure, infections and cardiovascular disease.
For these reasons, long-term immunosuppressive strategies in kidney versus liver transplant patients are
very different. In general, liver transplant recipients usually can tolerate a more rapid and pronounced
withdrawal of immunosuppression. This may include withdrawal of corticosteroids within 3 to 6
months post-transplant and withdrawal of antimetabolites within 6 to 12 months post-transplant.
Long-term, liver transplant recipients often are receiving a calcineurin inhibitor as their sole
immunosuppressant. Kidney transplant recipients, on the other hand, usually require a longer
taper of their immunosuppression. Often, they must be maintained on a 2 or 3 drug regimen.
Each transplant center usually develops protocols which give guidelines on specific immunosuppressive
use and withdrawal strategies. The pharmacist should know these protocols. Table 1
gives some general guidelines concerning long-term monitoring, adverse effects and strategies for specific
Scheduled monitoring of transplant patients is a very important part of their care. Table 2 gives an example of
a specific monitoring schedule for transplant patients. Some patients require more frequent and intense monitoring
if they develop complications such as rejection, infection, or adverse drug events. For more information about
specific immunosuppressant monitoring criteria please refer to Table 1 and Module 5. It is also important to
insure that transplant patients are aware of the importance of self-monitoring. Patients are usually educated
on how to monitor their blood pressures, weights, intakes and outputs, temperatures, calorie intake and blood
glucoses when necessary. This information is recorded in a patient diary for clinicians to review during routine
clinic visits. It is important for transplant patients to understand what signs and symptoms might suggest a problem
that needs further investigation, such as fevers, nausea, vomitting,
diarrhea, pain, decreased urinary output, rapid weight gain or loss, uncontrolled blood pressures or uncontrolled blood glucoses.
Infection is one of the most common life-threatening complications of long-term immunosuppressive therapy.
A patient's risk of developing infection is based upon two factors; the degree of exposure to given pathogens
and the overall level of immunosuppression. Once a patient leaves the hospital, their exposure to virulent
pathogens is decreased and therefore they are at lower risk of developing infections. However, a number
of pathogens are ubiquitous in nature,
and are therefore, more apt to cause infections in immunosuppressed patients. These include bacteria, viruses, and fungus.
Transplant patients are at highest risk for developing certain types of infections based upon time from their
transplant. In the first month post-transplant (usually while in the hospital and shortly thereafter),
the most common occurring infections include nosocomial bacterial and fungal infections of the surgical
wound, lungs, urinary
tract, and vascular access devices. These infections are not unlike the ones seen
in nonimmunosuppressed surgical patients.
During the period between 1 month and 6 months post-transplant, immunomodulating viruses such as
cytomegalovirus (CMV), epstein-barr virus (EBV), herpes simplex virus (HSV), hepatitis B virus (HBV),
hepatitis C virus (HCV), and human immunodeficiency virus (HIV) commonly recur in pre-exposed patients.
CMV is a common and potentially devastating viral infection in transplant recipients and will be discussed
in further detail. Opportunistic infections caused by pathogens such as pneumocystis carinii, asperigillus,
and listeria become more prevalent. It is during this period that prophylactic antimicrobial use is critical
to prevent these potentially fatal infections. Table 3 presents information on specific types of infections,
the causative pathogens, most common symptoms seen, suggested prophylactic regimens for prevention, and
Once a patient is greater than six months from their transplant, infections can be divided into one of three
categories to determine their infection risks. Most patients (>80%) have good graft function and are being
maintained on minimal amounts of immunosuppression. This group of patients has similar infection problems
to those of the general public. These include intestinal and respiratory viruses as well as community bacterial
pneumonias. Opportunistic infections are rare in this group unless the transplant patient has been exposed to
a particularly virulent pathogen. The second group of transplant patients (10%) goes on to develop chronic
infections with certain viruses, such as CMV, EBV, HBV, HCV. These viruses can cause significant morbidity
including end-organ damage. Chronic long-term antiviral therapy is often employed in this setting.
The remaining group of patients develops recurrent acute rejections or chronic rejection, which results
in the patients being exposed to larger amounts of immunosupprression. These are the patients that often
develop chronic viral infections and are at an increased risk for developing chronic opportunistic infections
from pneumocystic carinii, listeria,
nocardia, cryptococcus, and asperigillus. Often, this group of patients requires lifelong antibiotic and/or antifungal prophylaxis.
CMV is the most common and most important post-transplant infection. The disease usually presents within 1 to
6 months after transplantation. It is a ubiquitous virus belonging to the herpes family. The virus can potentiate
the risk for developing both bacterial and fungal infections. CMV is also associated with chronic injury to the
transplanted organ( chronic arteriopathy of the kidney, vanishing bile ducts of the liver). CMV infection in
transplant recipients usually originates from an antibody seropositive donor organ, reactivation of latent
viruses due to immunosuppression, or blood products from seropositive donors. Transmission of CMV
from an antibody positive donor to an antibody negative recipient leads to an 80% to 100% infection rate
and a 40% to 50% clinical disease rate; a positive donor to a positive recipient leads to a 40% to 60%
reactivation rate and a 20% to 30% disease rate; a negative donor to a negative recipient leads to a 0%
to 5% infection rate. Transplant patients at highest risk for developing the disease are ones who have or
Diagnosis of CMV is based upon both clinical and laboratory findings. Serological diagnosis is based upon positive
antibody seroconversion from a previously seronegative person or a greater than, or equal to, fourfold increase
in antibody titers in a previously seropositive person. CMV may be detected by culturing body fluids, such as
bronchoalveolar lavage, urine, blood, and tissue biopsy.
CMV is contained within the host's white blood cells, which appear to have large intranuclear inclusion bodies.
However, identification of virus in the blood (antigenemia) or positive antibody seroconversion is
not diagnostic for active disease without clinical signs and symptoms. Table 3 contains the most common signs
and symptoms seen with CMV disease.
Intravenous ganciclovir is the first-line agent used for the treatment of CMV disease in solid organ transplant
patients. Foscarnet is considered a second-line agent due to the severe toxicities that may develop with its use.
Additionally, CMV hyperimmune globulin, nonspecific immunoglobulins and have been utilized in combination with
antivirals for refractory cases.
Prevention of CMV using antiviral prophylaxis is desirable. The ideal prophylactic regimen has not been determined.
Most transplant centers have protocols specifying which patients should receive prophylaxis and which agent to
use. Commonly used regimens include the use of oral and intravenous ganciclovir, oral acyclovir, and
intravenous CMV hyperimmune globulin. Prophylaxis is usually continued for the
first 3 to 4 months post-transplant. Table 3 contains more specific information regarding the dosing
and monitoring of these agents.
Because prophylactic therapy is not always effective and expensive, preemptive therapy has been used to try
and prevent CMV disease. The technique involves withholding prophylactic therapy and monitoring laboratory
tests to identify presymptomatic CMV viremia. CMV antigenemia may be the best predictor of clinical CMV
disease when compared to polymerase chain reaction (PCR), serology, and shell viral assay. Once a patient
develops viremia, they will usually receive treatment with
intravenous ganciclovir. There is a lack of uniformity on who should receive this therapy and when
treatment should be initiated.
Osteoporosis is a long-term complication associated with organ transplantation. The most critical period of bone
loss appears to be the first 6 months post-transplant. A transplant patient's risks for developing osteoporosis
can be separated into two categories. The first being the risk factors seen in the general population, such as
menopause (women), family history, small frame, smoking, alcohol and caffeine consumption, sedentary lifestyle,
and lack of calcium intake. The second category includes the risk factors that are unique to transplant patients,
which are their pre-transplant underlying disease states (such as end-stage kidney and liver disease) and immunosuppressants.
Glucocorticoids inhibit calcium absorption from the GI tract, induce urinary calcium loss,
inhibit bone formation and accelerate bone resorption. Cyclosporine and tacrolimus increase
bone resorption, leading to bone loss. When a calcineurin inhibitor is used in combination with
glucocorticoids, the effects on bone are more pronounced then when either agent is used alone.
These effects are dose and duration dependent. Therefore, early and rapid taper
of the immunosuppression is an important strategy to help minimize bone loss during the first 3
to 6 months post-transplant.
Preexisting osteomalacia is almost always present in patients undergoing kidney and liver transplantation.
In renal disease, this is usually a function of this kidney's inability to produce 1,25-dihydroxyvitamin D3.
This, in turn, leads to hyperparathyroidism and bone loss. In liver disease, the bone loss is usually more
pronounced and due to factors such as altered vitamin D metabolism, malabsorption of calcium, alcoholism,
poor nutrition, and hypogonadism.
All transplant patients should receive a thorough pre-transplant evaluation to determine their
risk of developing osteoporosis. This should include a complete history to assess and minimize
modifiable risk factors, dual-energy x-ray absorptiometry (DEXA) to assess bone density,
and blood and urine laboratory tests to identify and correct metabolic and secondary causes of bone loss.
these tests should be maintained post-transplant (every 6 months for the first 18 months post-transplant,
then once yearly).
Preventive therapy should be considered in every transplant patient. Similar to the general population,
once a transplant patient develops osteoporosis, effective treatment approaches are difficult to determine.
This is due to the lack of well conducted, prospective controlled trials in the transplant population.
Current treatment options include, but are not limited to the use of calcitonin, bisphosphonates and
hormonal replacement. Alendronate and risedronate are indicated for corticosteroid induced osteoporosis.
The use of agents such as raloxifene and fluoride are controversial. Calcium and vitamin D
supplementation is recommended in all patients receiving corticosteroids and osteopenic and osteoporotic
transplant patients. Table 4 lists more specific information about the prevention and management of
osteoporosis in transplantation.
Post-transplant diabetes mellitus (PTDM) is another complication. There is a growing body of evidence that
links hyperinsulinemia and hyperglycemia with an increased risk of developing atherosclerosis and cardiovascular
disease. Cardiovascular disease, especially in kidney transplant patients, is now the leading
cause of death among long-term transplant recipients. It is therefore extremely important to identify and
effectively treat PTDM.
Currently, there is no consensus on the definition of PTDM. Some clinicians recommend looking solely at fasting
blood sugars (FBS's) on 3 separate occasions, while others advocate the use of oral glucose tolerance tests (OGTT)
in addition to FBS's, while still others suggest the additional use of serial HbA1C concentrations. One recently
proposed definition is a blood glucose of >400 mg/dl at any one point, or >200 mg/dl for more than 2 weeks,
or the need for insulin treatment for at least 2 weeks. This, along with the use of serial measurements of
HbA1C, should form the basis for diagnosing PTDM.
Based on the varying methods of defining and identifying PTDM, the incidence has been reported to be between
4% and 20%.
Recognition, prevention, and treatment of PTDM is a very important aspect of a transplant patient's
long-term care. It is important to insure that every transplant patient is pre-screened for potential
risk factors for developing PTDM. Risk factors that have been identified include impaired OGTT,
impaired C-peptide secretion, and African-American or Saudi Arabian ethnicity. Additionally, any
patients that have risk factors for developing type II diabetes mellitus are at higher risk for
Some of the immunosuppressives utilized in transplantation are a major factor
in developing PTDM. Genetic predisposition may also be important. Corticosteroids
likely decrease the number and affinity of insulin receptors, impair glucose uptake
in the musculature, impair insulin production, and impede the activation of the glucose/FFA cycle.
Corticosteroids also induce insulin resistance. Cyclosporine and tacrolimus are postulated to cause
the inhibition of specific cellular proteins, resulting in the decreased production of insulin from
beta cells in the pancreas. This effect appears to be dose dependent. Although initially this may
be reversible, long-term use of cyclosporine or tacrolimus may cause irreversible damage to the
beta cells. There is a controversy over which agent is more diabetogenic, cyclosporine or
tacrolimus. It appears from clinical trials that the increased potency of tacrolimus may induce
a more pronounced impairment of insulin production and secretion when compared to cyclosporine.
However, this may be offset by steroid sparing effects of tacrolimus based immunosuppressant regimens.
Sirolimus or mycophenolate mofetil are not associated with PTDM.
Since calcineurin inhibitor and corticosteroid dose and duration are significant factors associated with PTDM, most
strategies center around reducing or altering immunosuppressant regimens in patients identified to be at risk for
developing this complication. Commonly, rapid tapering of corticosteroids is suggested. The ultimate goal in this
strategy is early discontinuation of the corticosteroid. Unfortunately, this may not be possible in patients who
have or are at high risk for having acute cellular rejection. By utilizing one of the newer immunosuppressants,
such as mycophenolate mofetil or sirolimus, it may be feasible to remove or reduce the dose of the diabetogenic
immunosuppressants. Regardless, if a patient is known to have, or is at high risk for developing PTDM, close monitoring
of blood glucose and HbA1C is warranted. Additionally, it is especially important in this population to
educate and attempt to reduce other known cardiovascular risk factors, such as hypertension, smoking, dyslipidemia, and obesity.
The treatment of PTDM is similar to the treatment of type II diabetes mellitus, with certain exceptions. Although
some patients can be controlled on oral sulfonylureas, most patients will require exogenous insulin. In theory,
agents such as metformin, rosiglitazone, and pioglitazone would be beneficial in this population due to their
postulated mechanisms of action. However, extreme caution should be used when initiating any of these agents
based upon their relative contraindications (renal dysfunction) and potential side effects (hepatotoxicity).
A PTDM patient should be educated on the same issues as a DM patient, including proper hyper and hypoglycemic monitoring,
diet, foot and eye care, and cardiovascular risk reductions. Be aware
that it may be possible to discontinue antihyperglycemic therapy once a patient's immunosuppressive regimen is altered or reduced.
Although malignancies following transplantation are rare, compared to the general population, a transplant patient
is 20 to 50 times more likely to develop a malignancy. The most common types of cancers that develop in
this population include squamous cell carcinomas of the skin, non-Hodgkin's lymphomas, Kaposi's sarcoma,
in situ carcinomas of the uterine cervix, carcinomas of the vulva and perineum, hepatobiliary carcinomas,
and a variety of sarcomas. The overall incidence of cancer is approximately 6% in this population,
with the average age of these patients being fairly young, at 42 years. The two most common types of
tumors in transplant patients
are cancers of the skin and lips and non-Hodgkin's lymphoma. The scope of this discussion will be limited
to these two cancers.
Skin and lip cancers account for roughly 37% of all cancers seen in transplant patients. There is a 7 to 21-fold
increase in incidence when compared to the general population, depending on the amount of sun exposure.
This risk increases with time after transplant, and is as high as a 54% incidence at 20 years post-transplant.
Unfortunately, when these cancers do develop in transplant patients, they are usually more aggressive and
metastasize earlier. This is why it is extremely important to counsel transplant patients on the avoidance
of sun exposure and the copious use of sunscreens or protective clothing (brimmed hats or sun visors).
This is especially the case in individuals who may be at higher risk due to their characteristical traits
(blond or red hair, fair skin, and blue eyes). All transplant patients should be examined on a regular
basis for identification and removal of any premalignant skin lesions. Treatment options for skin cancers
include surgical excision, topical 5-fluorouracil,
cryosurgery, or radiotherapy. For patients with malignancy, withdrawal or lowering the level of
immunosuppression is important.
The second most common cancer experienced by transplant recipients is non-Hodgkin's lymphoma (NHL),
also referred to as post-transplant lymphoproliferative disease (PTLD). The incidence varies greatly,
but has been reported to be as high as 5%. There is a 28 to 49-fold increase in developing this cancer in
transplant patients compared to the general population. NHL is a morphologically diverse cancer. Timing
of the disease can occur anywhere from 1 to greater than 10 years post-transplant. Polyclonal hyperplasia
usually appears within the first year of transplantation. Patients may present with fever, pharyngitis and
adenopathy. PTLD that presents early post-transplant (within the first year) usually is a less aggressive disease
and responds well to reductions in immunosuppression. Conversely, late presenting PTLD often is difficult to treat
and does not usually respond well to reductions in immunosuppression. The major risk factor for developing PTLD
is the degree of immunosuppression. Additionally, there is a substantially higher incidence of PTLD in pediatric patients
who are epstein-barr virus (EBV) antibody negative at the time of transplantation. There is a close association between
the development of PTLD and EBV. The development of PTLD from EBV infection follows a stepwise process.
This process starts with a primary infection of B-cells by EBV. This progresses into a latent infection. Reactivation of
EBV occurs in transplant patients receiving long-term immunosuppression. This eventually leads to malignant
B-cells developing by mechanisms that are not fully understood. Management of PTLD is often very difficult,
and is complicated by the fact that disease is often diagnosed late and the patients often have poor performance
statuses at the time of diagnosis. Initially, reduction in the degree of immunosuppression is attempted.
This often produces a good response in patients with less aggressive forms of PTLD. PTLD almost universally
responds poorly to chemotherapy. Radiotherapy may increase survival rates in patients with localized disease.
Monoclonal antibodies, such as Rituximab, have shown promising results. Currently, it is believed that acyclovir
and ganciclovir probably plays a minimal role as a therapeutic option in the treatment or prevention of PTLD.
Because treatment options are limited with PTLD, focus should be made on preventing this disease. The rational
use of immunosuppressive regimens is an important part of prevention.
Although there have been significant reductions in the incidence of acute rejection episodes in the past
decade, the incidence of chronic rejection has remained largely unchanged. The definition of chronic
rejection is not universal. Most classifications are based on tissue biopsy results, which include
interstitial fibrosis and tubular atrophy, while others require the presence of artheriosclerosis in
the renal vasculature. Currently, chronic rejection accounts for approximately 15% to 20% of all
graft failures. The time it takes to develop chronic rejection is highly variable. Chronic rejection
can occur as early as 1 year post-transplant, but is more likely to occur 5 to 10 years
post-transplant. Clinical manifestations of chronic rejection include a steady progressive
worsening of renal function indicated by increasing serum creatinine concentrations, proteinuria,
and arterial hypertension. Urinary protein excretion of 1 to 2 grams per day is highly suggestive
of chronic rejection. Early diagnosis is a key to prevention. Diagnosis based on tissue biopsy also helps
differentiate between chronic rejection and other problems that may present with the same clinical and
laboratory findings, such as acute cellular rejection or calcineurin nephrotoxicity.
Many immunologic and nonimmunologic factors have been implicated in increasing the likelihood of developing
chronic rejection. Nonimmunologic factors include race, gender, size and match, hypertension, hyperlipidemia, and
infection. African-Americans have a higher incidence of graft failure due to chronic rejection. It has also been noted
that recipients of organs from non-white male donors have inferior graft survival rates. Hyperlipidemia has been
correlated to proteinuria, hypoalbuminemia, and chronic rejection. The fact that certain immunosuppressive agents
cause dyslipidemias increases the importance of the recognition and proper treatment of this disorder. Please see
Module 3 for more information. Infection with CMV also has been associated with the development of chronic rejection.
The most important immunologic factor implicated in the development of chronic rejection is the number of episodes
and severity of acute cellular rejection. Therefore, the monitoring and treating of acute rejection is an important
preventive measure to reduce the incidence of chronic rejection. Histoincombatibility, insufficient immunosuppression,
and the presence of HLA antibodies also have been implicated with chronic rejection.
Pharmacological management and prevention of chronic rejection has been largely unsuccessful. Strategies
that have been attempted include the use of induction therapy with anti-lymphocyte antibodies, different and
varying degrees of immunosuppressant regimens utilizing cyclosporine, tacrolimus, mycophenolate mofetil,
sirolimus, and leflunomide, control of blood pressure and lipids, and dietary supplementation with fish oils.
Use of ACE inhibitors or angiotensin receptor blockers may be of some benefit to prevent chronic rejection
when used to control blood pressure. The use of statins to control lipids have gained much recognition recently
may be of some use to prevent chronic rejection. Currently, chronic rejection remains a major problem
in renal transplantation.
Chronic rejection in liver transplantation occurs in less than 5% of recipients. The reasons for this are largely
unclear, but a number of hypotheses include the fact that the liver has a large parenchymal cell mass, a large
number of passenger leukocytes, express low number of MHC class I and II cells, and has a regenerative
capability. Because the liver is basically an immunologic organ capable of producing its own leukocytes, it is
theorized that this may cause a mild self-limiting graft-versus-host response, inducing tolerance between the
transplanted liver and the host's immune system. Studies have shown that complete removal of
immunosuppression can be tolerated in a small number of liver transplant recipients without detrimental
consequences. Chronic rejection in liver transplantation can occur early (3 to 6 months post-transplant),
or more commonly later (>12 months). Clinically, it usually presents as a moderately slow progressive
increase in liver function tests (transaminases and bilirubin) coupled with a decline in the liver's synthetic
function capabilities. This can
manifest into coagulopathies, portal hypertension, and ascites. Late-stages of chronic rejection may lead to arterial thrombosis.
If chronic rejection does occur, however, it needs to be diagnosed in similar fashion to renal transplant patients.
A transplant liver tissue biopsy must be performed for definitive diagnosis. On the tissue biopsy, chronic rejection
is diagnosed by the absence of bile ducts in the portal triad. Several studies have shown that conversion
from cyclosporine to tacrolimus might be of some benefit in reversing or halting the progression of chronic liver rejection.
RECURRENCE OF DISEASE
Due to the increase in graft and patient survival accomplished in recent years, the recurrence of pre-transplant
diseases is a major concern. This includes diseases seen in both renal and liver transplantation. As such, it is
very important to develop strategies for early diagnosis and prevention of these recurrences. Recurrence of
disease in renal transplant recipients include metabolic disorders, such as glomerulonephritis, diabetes,
amyloidosis, oxalosis, cystinosis, Fabry's disease, and sickle cell anemia. Recurrence of diseases in liver
transplant recipients is also a major long-term complication. This is especially the case in patients who were
transplanted with end-stage liver disease secondary to viral hepatitis. Liver failure due to viral hepatitis is
now the leading reason for transplantation. Recurrence of HBV has been substantially reduced (from nearly
100% to 30 - 50%) by use of antiviral agents, such as lamivudine, used in combination with long-term
passive immunization with hepatitis B immune globulin. Recurrence of HCV in post-transplant patients is
universal. These patients often are receiving lower amounts of immunosuppression in order to attempt to
prevent unchecked viral replication. Additionally, studies are currently underway looking at the utility of
interferon, ribavirin, and pegylated interferon in the post-transplant hepatitis C positive patient.
Nonetheless, currently, HCV recurrence, and subsequent end-stage liver failure and death is a major
complication. Other diseases
that have been seen to recur in liver transplantation include autoimmune hepatitis, diseases of
the biliary tree, and hepatocellular carcinoma.
Although immunization is an important part of infectious disease prevention in the general population,
its role in transplant patients has not been well studied. Certainly, all patients awaiting transplant should
have their immunizations brought up to date. These include diptheria, tetanus, pertussis, and MMR.
Infants should receive H. influenza b vaccination. Additionally, the use of the hepatitis B, pneumoccocal,
and influenza vaccinations is generally recommended in patients awaiting transplantation.
The use of varicella zoster virus vaccination in pre-transplant pediatric patients is controversial and is not
Most clinicians still recommend using immunizations post-transplant as long as the vaccine does not contain
live viruses. A few small studies have shown the effectiveness of diptheria, tetanus, H. influenza, and
inactive polio vaccines in post-transplant patients. Influenza also appears to be effective in the post-transplant
patient, although response rates are less compared to immunocompetent people. Hepatitis B vaccine produces
lower rates of antibody response in transplant patients, so pre-transplant administration of this vaccine series
should be stressed. Pneumococcal infections are fairly common post-transplant, so booster vaccinations are
recommended. To date, no vaccination study conducted in transplant patients has shown an increase in rejection
rates or any other serious side effects, so use of preventative vaccination in the post-transplant population should be advocated.
As a pharmacist, one of the most important roles in providing pharmaceutical care to transplant recipients is the
recognition and prevention of potential serious drug interactions. Three of the major immunosuppressants
currently prescribed, cyclosporine, tacrolimus, and sirolimus, are primarily metabolized and eliminated via the
cytochrome P450 IIIA4 enzyme system. This means that the transplant patient is at high-risk for being
exposed to numerous drug interactions. Before any new drug is prescribed in these patients, it should be
scrutinized to determine its potential in effecting the drug metabolism of the immunosuppressants or any
other agents the transplant patient is receiving. Use of drugs that inhibit or induce the cytochrome
P450 IIIA4 system are not absolutely contraindicated, as this would eliminate a large number of important
therapeutic options in these patients. One must be diligent in monitoring for organ function and adverse effects
when adding or discontinuing one of these
interacting agents. Table 5 lists some of the most commonly encountered drug interactions that may effect transplant patients.
Potential severe consequences may arise with the use of certain over-the-counter (OTC) medications in transplant
patients. It is important to educate and monitor these patients closely for non-prescription medication use.
In addition to potential drug interactions through the cytochrome P450 IIIA4 enzyme system, non-prescription
medication use can often combine with the immunosuppressants to increase the likelihood of developing severe
adverse drug reactions, such as nephrotoxicity. This includes the use of very common classes of OTC's, such
as NSAIDS, cough and cold products, herbal products, and vitamins. Table 6 lists some of the more common
reasons why people seek
OTC medications, the non-prescription medications that should be avoided, and recommended alternatives for
With the recent explosion in the use of herbal products has come the increased identification of significant
herb-drug interactions. This is a difficult problem to address for a number of reasons. First and most
importantly, the experimental data concerning drug-herb interactions is sparse. There is a lack of clinical
trials, case reports, and case series reviews. To compound this issue, herbs are unregulated products
that can be obtained from a plethora of sources. Additionally, patients often see herbal products not as
drugs, eliciting a pharmaceutical response, but rather as a supplement similar to vitamins. This leads to
the under reporting of herbal use during patient medication histories. It is therefore our responsibility to
review each patient's medication profile to potentially
identify and prevent drug-herb interactions. These interactions can be of a pharmacokinetic or
St. John's Wort has recently been identified to induce hepatic enzymes, and transplant patients taking this herb
have had significant reductions in cyclosporine concentrations, resulting in rejection. The immunostimulating
effects of Echinacea, Astragalus, licorice, alfalfa sprouts, and zinc may offset the immunosuppressive effects
of the calciineurin inhibitors, antimetabolites, and corticosteroids. Feverfew, garlic, ginger, and Ginkgo all
increase the risk of bleeding. Additionally, ginseng should be avoided, as it may increase bleeding and augment
the effects of corticosteroids. Guar gum may inhibit or slow the absorption of many agents, including the
immunosuppressants. Saiboku-to may increase corticosteroid effects, while sho-salko (both Asian herb
may have the reverse effect. The use of chili pepper may increase the likelihood of developing ulcers in this
In general, herbs should be avoided in this population. If a transplant patient is adamant about taking herbal
close therapeutic monitoring is required in order to ensure rapid identification and correction of potential
Another potential dangerous complication that should not be overlooked in these patients is medication
non-adherence. Identifying transplant patients with medication non-adherence difficulties is an important
part of their long-term management. Once a transplant patient is identified as being non-compliant with
prescribed regimens, it is important to identify and alleviate the secondary causes. Commonly encountered
problems include medication cost, complexity of regimen, undesirable side effects, lack of proper education,
and patient apathy or psychological difficulties. All of these problems can and must be overcome to help
prevent patients from developing major complications from non-adherence,
including graft loss and death. For more information about how to educate and alleviate these problems, please refer to Module 7.
DEVELOPMENT OF A PATIENT CARE PLAN
In order for a pharmacist to provide optimal and efficient pharmaceutical care to transplant patients,
the development of a well designed care plan is crucial. A formalized pharmaceutical care plan should
provide a logical, consistent framework that identifies transplant patient's drug-related problems,
develops interventions to resolve or prevent the problems, documents the findings, and measures progress
toward desired pharmacotherapeutic outcomes. Although the basic purpose of the pharmaceutical care plan
is universal, the specific development of a patient care plan should be based upon the most commonly
encountered drug-related problems seen in that particular population. Each pharmacist must develop
an outline for their care plan they feel comfortable using. In order to provide optimal pharmaceutical care,
the pharmacist should be in close contact with the other health providers caring for transplant patients.
The transplant coordinator is usually responsible for maintaining close contact with the patient, and
most of the important therapeutic decisions should ultimately be routed through them. This section
provides demonstrates how to develop a care plan and utilize it in a efficient manner to expose, correct,
document, and bill drug-related transplant issues.
It is up to you, as a practicing clinician, to develop and utilize your own care plan specific for your patients and setting.
STEP ONE: DATA COLLECTION
Data collection is a vital part of the patient care plan and provides the information from which the drug-related
problems are exposed and corrected. Early post-transplant, patients have frequent and intense monitoring of
their vital signs and laboratory values. Much of the therapeutic decision making is based upon accurate collection
and assessment of these monitoring parameters. As such, before any drug-related issues are addressed, it is
important not only to closely review that particular day's monitoring parameters, but to review past values as
well. This will help identify trends in values that may give a better picture of what drug-related problems exist.
Any form that
is used to collect data should have the ability to contain enough information to identify trends in vital signs and laboratory values.
Forms 1 and 2 provide examples of monitoring sheets that can be used to collect data in a transplant patient.
Looking at Form 1, you can see that this is divided into two sections. The top third of the form contains the
demographic and pre-transplant information. This information is important to identify pre-transplant conditions
and medications that need attention post-transplant. In this example patient, we can see that his past medical
history is significant for retinopathy, chronic gastritis, insulin-dependent diabetes mellitus (IDDM),
hypertension, and hypothyroidism. These medical conditions must be closely monitored post-transplant
because a number of them (specifically retinopathy,
hypertension IDDM, and gastritis) may worsen post-transplant due to the long-term side effects of the
The bottom third of the form contains tables that can be used to monitor the long-term complications in
a transplant patient. By recording each complication in the given table, pharmacists can use this data to expose
and correct drug-related issues. For example, by documenting the patient's acute rejection episodes, we will be
able to identify patients at risk for the long-term consequences of multiple acute rejections, such as chronic rejection
and chronic opportunistic infections. This will allow us to recommend appropriate preventive therapy, such as
adjustments in the patient's immunosuppressant regimen and continuation of antibiotic prophylaxis. Another example,
would be documentation and treatment of UTI on 9/4/00.
Form 2 provides an instrument to collect and review data containing vital signs, laboratory values,
immunosuppressant regimens, and cultures.
Each time a patient is seen by a pharmacist, they should thoroughly review all of this data. This will allow us
to identify trends in these values, and make the appropriate interventions. The data on this form represents a
kidney transplant patient who was transplanted on 8/28/00 (see Form 1). Today (9/18/00), you are seeing
this patient on his second clinic visit for a standard follow-up appointment. We can see that there has been a
downward trend in his white blood cells (WBC) and platelets. Notice if we only reviewed this day’s (9/18/00)
values, the WBC and platelets appear to be within normal limits. Only by reviewing the values over the past
several visits can we expose this trend. This information will be important when developing our problem list.
Each time a pharmacist sees a patient, they should obtain a detailed medication list. Form 3 provides
a sheet that can be used by the pharmacist for each patient encounter. At the top of the form, there
is a section to record any subjective data obtained during the patient interview. Referring back to the
example patient, on his first clinic visit (9/12/00), he complains of tremors. On his second visit(9/18/00)
we can see that he is complaining of cramping, bloating, and diarrhea. This information would be important
when assessing the patient's problem list. The pharmacist should obtain an accurate and detailed list of current
medications, including drug, dose, frequency, route and refills. It is important not only to review this with the
patient, but also to review past appointment drug lists as well. This will expose any changes that were made since
the last visit and may additionally identify any inconsistencies between what the patient is listed as taking and what
the patient is actually taking. In transplant patients, this is not an uncommon phenomena due to the relative
complexity of their drug regimens.
Often, simple interventions and corrections of drug regimens can prevent future severe adverse drug reactions.
STEP TWO: DEVELOPMENT OF A DRUG-RELATED PROBLEM LIST
Once you have completed all of the data collection accurately, development of a drug-related problem list is
required. This is similar to the differential list of problems a physician may develop, but is specific to
drug-related issues. Often it is difficult to simply focus only on drug-related problems in the transplant
population because certain diseases may actually cause similar effects as drugs. A problem list should consist
of the observations made while reviewing trends in monitoring parameters and should focus on drug-related
problems. In our kidney transplant example patient, we discovered and documented several problems
(see middle section of form 3). We will use the problem list to develop our
recommendations for changes in current therapies, which will be documented in the assessment
and plan section on the form.
It is important to address all of the drug-related concerns in your problem list and not to focus in only on
the immunosuppression. Often, transplant pharmacists makes important interventions on drugs that may
be overlooked because they are not immunosuppressants or transplant related. For instance, if we return
to our case, we see that the patient is receiving levothyroxine 100 mcg po qd. On his first visit (9/12/00),
he was out of refills, synthroid was renewed and a TSH level was recommended and ordered. On his next
clinic visit (9/18/00) his TSH comes back high and further questioning determines that he has not been
taking his Synthroid.
In addition to this, on 9/12/00 he had an increase in his total cholesterol and HDL for which simvistatin
STEP 3: ASSESSMENT AND PLAN
The assessment and plan is based on the accurate interpretation of the data collection, medications,
and the problem list. Although using monitoring sheets can help in efficient and complete data collection,
the analysis of this data by the pharmacist is based upon their therapeutic knowledge base and experience.
This is something that cannot be conveyed in one or even several modules, but must be learned from
practical hands-on experience and guidance. It is important to develop your knowledge base from the
evidence based medical literature and through practical experiences over time. When developing your
assessments, you should not only list what you believe to be the assessment, but also why you determined
this to be the case.
This will not only help convey your thoughts to your colleagues, but also help when reviewing your previous notes.
If we return to our example case, we see that on 9/18/00 his WBC and platelet counts have fallen over the past week.
This may be a side effect of a number of transplant related medications, most commonly mycophenolate
mofetil and ganciclovir. It also may be a symptom of CMV infection or disease. In order to decide which
is the most likely cause, the use of other information becomes very important. We can see from the patient's
vital signs (see form 2) that he has been afebrile, and from his subjective reports (see top section of form 3),
without complaints of malaise and fatigue. This would suggest CMV as the likely cause. Additionally,
the patient subjectively complains of nausea and diarrhea (see top section of form 3), two frequently
reported side effects of mycophenolate mofetil. However, CMV infection of the gastrointestinal tract may
also produce these symptoms. Often, it is difficult to determine the true cause of a given number of
For this patient, we've recommended decreasing the dose of mycophenolate mofetil (see middle section of form 3).
Your plan should contain the recommended medication changes and future monitoring parameters to
ensure appropriate pharmaceutical care. It should be as specific as possible, including new drugs,
doses, frequencies, and routes. Monitoring recommendations should include which specific parameters
are needed, such as laboratory values, frequency of desired monitoring, and any adjustments that may
be necessary based upon the results of the recommended monitoring parameters. The plan should focus
on the best way to resolve or prevent any identified drug-related problems that were mentioned in the
assessment. New problems should not be addressed here without first being mentioned in the assessment.
In our case example, we've recommended decreasing his mycophenolate dose to 500 mg PO bid based
upon both subjective and objective data indicating that he is having an adverse drug reaction
(see bottom section form 3). In the plan, we have recommended monitoring parameters to insure that
our intervention helps alleviate his complaints. Follow-up is a very important part of the development of a patient
Please see Form 3 for additional examples of how to address drug-related problems in the assessment and plan.
STEP 4: FOLLOW UP and DOCUMENTATION OF OUTCOMES
As the health care system continues to strive for efficient, cost-containing medical care,
it is important, as health care providers, to demonstrate our ability to significantly
contribute to developing better outcomes at reduced costs. This is achieved through
documentation and appropriate follow-up to drug interventions that were previously
addressed and corrected. This can be accomplished by the use of complete pharmaceutical
care plans and well maintained notes. Any interventions that were made on previous visits
should be addressed at the present patient visit for possible documentation of outcome.
For instance, if we again return to our example case, we see a section on the bottom of Form
3 for previous interventions and outcomes. On this patient's first visit (9/12/00),
we recommended reducing his tacrolimus dose based upon an increased blood concentration,
an increased serum potassium and creatinine, and a subjective complaint of mild tremor indicative
of tacrolimus toxicity. On this visit, the patient is no longer complaining of tremor,
and his serum potassium and creatinine concentrations have decreased. It is important to document
the outcomes of your
interventions for several reasons, including the ability to use outcomes for efficient and accurate billing to
third party payers.
Pharmacists continue to be recognized as important providers of health care. This recognition has
occurred primarily on the state and local level with Medicare and some third party payors. This
recognition has occurred in the form of changes in pharmacy practice acts in many states,
recruitment of and contracting with pharmacists into physician practice groups, Medicare
and Medicaid programs which include pharmacists in the care of patients with conditions such
as diabetes, asthma, receiving multiple medications, need for immunization to name a few.
Despite this progress, there are still a number of payors or other participants in health care
delivery system ( physicians and patients) who are unaware of the services that pharmacists
can provide. Even on the national level, pharmacists are not officially recognized as "providers".
A number of national organizations are attempting to change this problem. Therefore,
the pharmacist who seeks reimbursement must have specific plans and goals that can be
communicated to payors, healthcare providers and patients and result in improved patient
This next section will discuss important issues and provide a template for obtaining reimbursement
for pharmaceutical care services for transplant recipients. The attached algorithm ( FIGURE)
illustrates what a pharmacist needs to consider in order to navigate the reimbursement process.
The first step would be to obtain a provider number. This is a number that identifies the specific
healthcare provider and allows for claims processing. This number must be obtained from each payor
that the pharmacist is planning to submit a request for reimbursement. The pharmacist may have to
meet certain requirements in order to obtain this number, depending on the payor. These could
include type of degree, years of experience, special certification. This information, along with
an application should be requested from each payor.
In a hospital setting, the pharmacist would also have to be recognized as a provider. Usually
this consist of applying for credentialing and hospital priviledges. The pharmacist would have to
submit the appropriate application form, evidence of licensure and liability insurance,
a physician letter of support and a list of specific activities and location of where services
will be provided (eg. outpatient clinic, inpatient consults).
Another important step, is to develop a data collection and documentation system as illustrated
in the previous section. This should include reason for patient encounter and intervention
(subjective and objective information), intensity of evaluation (assessment),
services provided (plan, followup and outcome) and patient contact time..
Included in this documentation is a record of the patient's insurance information , along with permission (signed)
from patient to provide these services. In addition, any services provided should have either a request from
the patient's physician or statement indicating that this service is medically neccesary. This must have a
physician's signature on either a prescription or order or form letter depending on setting. Once the patient
is seen by the pharmacist and
a plan is outlined, the pharmacist should provide the physician and patient with a summary of this interaction.
It is important that the pharmacist determine what the overall goals and specific activities will be in
attempting to provide services to transplant recipients. Will they focus on patient education regarding
drug therapy and/or disease management as well as how often they will see patient. One example would
be to spend scheduled time with the patient every 1-3 months depending on outlined plan. The number of
reimbursed interactions may be dictated by the third party payor and/or agreed upon with physician or
patient. These should be discussed with
the patient and their primary healthcare providers( transplant team or primary care physician or specialist).
Once the above steps have been taken, then the process of coding and billing for services should be implemented.
The type and amount of reimbursement is dependent on the practice setting, and its relationship to physician care.
Medicare is the primary payor for health care in transplant recipients and there are several private payors who
administer the Medicare program at the local level. Reimbursement for healthcare providers falls under Medicare
part B. In order to submit a claim is it necessary to complete and submit a HCFA 1500 claim( see attached).
Another form, called the Pharmacist Care Claim Form(PCCF) should also be completed(see attached). The PCCF
was developed by the National Community Pharmacists Association(formerly NARD) and incorporates the coding
system developed by the National Council for Prescription Drug Programs. This form is more easily understandable
language. Which forms are required depends
on the payor. For Medicare claims, the HCFA 1500 is required. For other payors, it may be necessary to complete both forms.
The PCCF is divided in several sections, which use a number of codes. These sections include reasons for
services, professional services, recommendations and result
of services, the level of service, a section to write a brief and specific interaction and billing codes and fees.
The HCFA 1500 claim form requires a much more involved consideration of diagnosis, type of patient
(new or established), where services are provided (office or pharmacy, clinic, hospital, nursing home, etc),
the presence or absence of a physician ("incident to"), what level (degree of complexity) of services
are provided. One need to be aware of Medicare rules and regulations in order to correctly completes
this form. Diagnostic codes are found in the International Classification of Diseases, 9th Revision, and
Clinical Modification (ICD-9-CM) code book. This is available from a number of medical publishers and
the American Medical Association. Keep in mind that only a physician can make a diagnosis. A diagnosis
code is required, but it must be the same diagnosis code used by physician and must be as specific and
as closely related to the reason for encounter as possible. Since there is no room on this form for much
description of encounter the medical necessity document and/or patient encounter form should be submitted
Another key step is determining the level of service provided and the appropriate code. This information
is specifically defined and found in the Physician's Current Procedural Terminology (CPT) code manual.
This can also be obtained from the American Medical Association. This coding is determined by several components,
which are referred to as Evaluation/Management (E/M) services. One is the type of patient. Most patient encounters
fall under either new or established. Second, is the presence or absence of the physician during the encounter.
Third, the history (H) and physical exam (PE). The H & PE are further divided into problem-focused,
expanded problem-focused, detailed, and comprehensive. These are based on specific criteria which
include history of present illness (HPI), review of systems (ROS) and elements of past history (PMH) each
of these categories. Most pharmacist encounters, would generally include a brief HPI, ROS and PMH. (See table for
specific codes) in an established patient without a physician.
Another component that must be utilizied is the level of medical decision making.
This can range from minimal, straight forward, low complexity, moderate complexity and
high complexity. These are based on the number of possible diagnosis and/or management options,
amount and/or complexity of data to be reviewed, risk of complications and/or morbidity or
mortality. Currently, most pharmacists bill and are reimbursed at either the minimal or
Another component that must be utilizied is the level of medical decision making. This can range from minimal, straight forward,
low complexity, moderate complexity and high complexity. These are based on the number of possible diagnosis
and/or management options, amount and/or complexity of data to be reviewed, risk of complications and/or
morbidity or mortality. Currently, most pharmacists bill and are reimbursed at either the minimal or
Once all documents are submitted for reimbursement, it take several weeks before any claim is paid. These are
usually submitted to the medical benefits department, rather than the pharmacy benefits. Follow-up to determine
the status of the claim may be necessary. If claim is rejected, then the pharmacist should determine why and
how this can be corrected. Keep in mind that not all payor may compensate pharmacists, at least initially. This
could be because of its never been done before or lack of understanding of the value of pharmacist services.
a number of organizations( ASHP, AACP, NCPA, NIPCO) may be useful in promoting the value of these services.
In summary, reimbursement for pharmacy services is possible, but requires an understanding of rules and
regulations governing provision and documentation of these services. Keep in mind that these can change and
can be interpreted differently by local administrators for each payor. The pharmacist should contact the
appropriate payors, particulary Medicare, and determine what is needed to become a provider, what are
procedures for submitting a claim and under what circumstances and setting( hospital vs freestanding pharmacy
or clinic), can they submit claims and what types of claims can be submitted. The success which a pharmacist achieves
with this process is not how much compensation is received, generally it is not much, but rather the improvement
in patient outcomes and the recognition that pharmacists play a vital role in the care of these patients.