46

Trough blood concentration monitoring plays an important role in the dosing of

sirolimus. Trough concentrations correlate well with sirolimus AUC. Because it has

a longer half-life than the CNI, concentrations are obtained less frequently and only 5

to 7 days after a dose change. The target trough is usually 5 and 15 ng/mL; however,

this continues to be refined with more experience. Early studies achieved

concentrations greater than 15 ng/mL, especially when used without a CNI, which

were associated with a greater immunosuppression and adverse events. Because

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sirolimus is synergistic with CNIs, the target concentrations of the CNIs are also

reduced when these agents are used together. Target tacrolimus trough targets are 5 to

10 ng/mL, and the cyclosporine trough targets are 75 to 100 ng/mL, and in some

patients lower, when used with sirolimus.

46

B.B. could be started on sirolimus at 2 to 5 mg daily. Sirolimus blood trough

concentration should be obtained 5 to 7 days after initiation. B.B.’s cyclosporine may

need to be reduced if concentrations exceed 100 ng/mL. Monitoring parameters

should include a fasting lipid panel, complete blood count, chemistries, and

electrolytes. If everolimus was used, the starting regimen would be 0.5 mg twice

daily. Everolimus blood concentrations should be obtained in 3 to 4 days after

initiation. Target trough goal would be 3 to 8 μg/mL. Monitoring parameters would

be similar to sirolimus.

Post-transplantation Metabolic and Cardiovascular

Complications

CASE 34-5

QUESTION 1: J.F. is a 28-year-old African-American man who received a kidney transplant 8 weeks ago

secondary to focal segmental glomerulosclerosis. His medical history is significant for hypertension. Before the

transplant, he was taking lisinopril 20 mg PO daily and amlodipine 10 mg PO daily. After the transplant,

amlodipine 10 mg PO daily was continued. J.F. was started on tacrolimus 8 mg PO BID and MMF 1 g PO

BID. He also receives 10 mg prednisone PO twice daily and will be tapered down during the next 6 weeks to 5

mg PO daily. J.F.’s tacrolimus trough concentrations have been between 10 ng/L and 14 ng/L. During the next

12 weeks, he will be maintained on a dose of tacrolimus to achieve trough concentrations between 8 ng/L and

12 ng/L. J.F. currently weighs 95 kg and is 6 feet tall. His body mass index (BMI) is 28.5 kg/m

2

. After

transplant, he has required a sliding-scale regular insulin regimen to maintain an appropriate blood glucose level

and was discharged on an insulin regimen that included lispro and glargine insulin. His BP readings during the

past 2 weeks have ranged between 145 and 155/90 and 95. Fasting lipid panel is a total cholesterol, 261 mg/dL;

LDL, 161 mg/dL; HDL, 40 mg/dL; and triglycerides, 200 mg/dL.

Why would J.F. have issues with controlling his blood glucose levels, blood pressure, lipid levels, and

prevention of bone fractures after transplant?

Post-transplantation diabetes mellitus (PTDM) has also been referred to new onset

diabetes after transplant (NODAT) and is another common problem that appears in

transplant recipients. Diabetes significantly affects morbidity and mortality in

transplant recipients. It is often a preexisting condition in renal transplant recipients

and a cause of ESRD. In recipients of other organs, such as livers, diabetes is

common as well, both as a preexisting condition and as a post-transplantation

complication. The definition of PTDM varies among studies. It has been based on

symptoms, plasma glucose and HgbA1c levels, oral glucose challenge results, or the

need for insulin or oral antidiabetic drugs after transplantation. Reported rates are

3% to greater than 40%, with most cases of PTDM occurring within the first year

after transplantation. Risk factors, besides pretransplantation diabetes, include

advanced age, family history, CMV infection, certain HLA phenotypes, race

(African-American or Hispanic), increased BMI, and hepatitis C infection in the

liver transplant population. One of the most critical factors in the development of

PTDM is the immunosuppressive regimen. Cyclosporine, tacrolimus, and prednisone

are all associated with PTDM. The CNIs appear to have a direct toxic effect on the

pancreatic beta cells leading to decreased insulin synthesis and secretion; this effect

seems to be dose-related and generally reversible. Although still debated, the

literature suggests that tacrolimus is more likely to cause PTDM than cyclosporine.

Additionally, conversion from tacrolimus to cyclosporine has been useful in some

patients. Prednisone is a major contributor to PTDM via multiple effects on beta cell

sensitivity to glucose and ability to release insulin and insulin resistance in multiple

tissues. Sirolimus has also been implicated in development of PTDM, although its

role and mechanism is unclear. Other risk factors, such as CNI drug concentrations,

steroid doses, transplant type, and time lapsed after transplantation, must also be

considered.

47 As with diabetes in the general population, a similar intensive

approach in controlling blood glucose should be undertaken. Also, other conditions

(e.g., hypertension and hyperlipidemia) should be managed aggressively to reduce

cardiovascular and kidney damage. Reducing or withdrawing diabetes-inducing

immunosuppression as much as possible without jeopardizing graft function or using

agents that are nondiabetogenic (such as mycophenolate) may be beneficial. One

important aspect of post-transplant diabetes management is to realize the differences

in pharmacologic management in this population, as compared with patients who are

not transplant recipients. Often, in the immediate post-transplant period, because of

the rapidly changing organ function and the dramatic tapering of corticosteroids, a

patient’s antidiabetic medicines may need frequent adjustment. During the first

several weeks post-transplant, insulin is the agent of choice owing to the ability of

the clinician to use sliding scales, the availability of several insulin products, and the

ease in changing doses. Once patients are stabilized on their immunosuppressant

regimen, and their organ function also, the use of oral antidiabetic agents can be

introduced or restarted. Metformin, glitazones, gliptins, and sulfonylureas have been

used in kidney transplants, but the use of oral agents is often dictated by renal

function. Other considerations would be liver function and weight gain.

48

J.F. was not diabetic pretransplant but is now requiring insulin. By some

clinicians’ definitions, he would be classified as having PTDM. Others would wait

to see whether J.F. still required insulin after his immunosuppressant regimen was

tapered to lower levels. In either regard, because J.F. is African-American, he is

considered at high risk for the development of PTDM. At this point, J.F.’s diabetes

should continue to be controlled on an insulin regimen. Once J.F.’s

immunosuppression regimen is stable, he could be switched to oral antidiabetic

agents if needed. J.F. should be counseled on diet and exercise to help control his

blood glucose level. Other pharmacologic interventions that may help prevent longterm diabetes in J.F. is changing his tacrolimus to cyclosporine and reducing or

withdrawing his prednisone. The risks and benefits of changing immunosuppressant

regimens must always be weighed. For instance, changing his tacrolimus to

cyclosporine, or reducing or removing J.F.’s steroids, may reduce his blood glucose

level and may prevent PTDM, but it also will put J.F. at higher risk of developing

acute rejection.

Post-transplant Hypertension

CASE 34-5, QUESTION 2: What pharmacologic options would be used for J.F.’s hypertension?

Cardiovascular disease is very common in patients with ESRD and after kidney

transplantation. These patients with prior ESRD can have CAD, LVH and CHF, and

arrhythmias and valvular heart disease. Cardiovascular disease after transplant is

associated with graft loss and lower patient survival. In those recipients who die

with a functioning graft, 40% die secondary to a cardiovascular event. Some

immunosuppressives, including

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cyclosporine, tacrolimus, and steroids, contribute to the development of

hypertension. Studies have indicated that blood pressure is higher, with high

nighttime systolic blood pressure, and more difficult to manage in patients on

cyclosporine compared with tacrolimus.

49 The appropriate blood pressure goals are

similar to those in the general population, that is, less than 140/90 mm Hg in patients

without proteinuria, as seen in this case. Nonpharmacologic therapies should be

implemented; however, in transplant recipients, pharmacologic management is a key,

often requiring multiple antihypertensives.

Pharmacologic agents used in transplant recipients are the same as those used in

the general population. In the transplant recipient, one must consider the drug

interaction profile and comorbidities. For example, nondihydropyridine calciumchannel blockers (CCBs), such as amlodipine, are less likely to interact with CNIs

than diltiazem or verapamil. CCBs may also ameliorate some of the vasoconstrictive

effects produced by the CNIs. In many programs, CCBs are considered first-line

therapy. β-Blockers such as metoprolol are also frequently used in transplant

recipients. Many recipients have or are at risk for coronary artery disease, and these

agents can be effective in these situations. Angiotensin-converting enzyme (ACE)

inhibitors and angiotensin receptor blockers (ARBs) can be used in transplant

recipients, those with LVH. Historically, these agents were avoided, because of

concern for their association with impaired kidney function. However, these have

significant cardiovascular and renal benefits in patients with comorbidities such as

diabetes, proteinuria, and congestive heart failure. Their use in transplant recipients

has increased and is introduced shortly after transplant to months after transplant

when renal function is more stable. Certainly if an ACE inhibitor or ARB is used,

SCr and potassium levels must be monitored closely. Diuretics are useful in patients

with evidence of fluid overload. In refractory patients, agents such as clonidine,

hydralazine, and minoxidil may be required. In J.F.’s case, because he is already on

amlodipine, a second agent such as lisinopril or metoprolol would be appropriate at

this time with close monitoring and follow-up.

Post-transplant Hyperlipidemia

CASE 34-5, QUESTION 3: What would be an appropriate lipid-lowering therapy for J.F.’s hyperlipidemia?

Hyperlipidemia is another cardiovascular issue that must be addressed in

transplant recipients. As with hypertension, it is fairly common pretransplant and

post-transplant. It is associated with negative cardiac outcomes and reduced graft and

patient survival in transplant recipients. Immunosuppressives including cyclosporine,

tacrolimus, steroids, sirolimus, and everolimus can cause elevations in total

cholesterol, LDL, and triglycerides, and also reduce HDL. Goals of treatment are

primarily based on targeting an LDLof less than 100 mg/dL. Treatment involves diet,

which alone appears to have minimal effect; therefore, pharmacologic treatment is

usually required. Agents utilized in the nontransplant population are effective in

reducing lipids in transplant recipients. Considerations in selecting treatments for

hyperlipidemia include drug interactions with the immunosuppressives and the side

effect profile. Statins are considered first-line treatment and have substantial

evidence to support their use. Cyclosporine can increase concentrations of

simvastatin and rosuvastatin, therefore limiting their doses and increasing potential

for adverse events. Atorvastatin and pravastatin are often used and appear to be safe

and effective in this population. Fibrates, ezetimibe, bile acid binders, and niacin are

considered second-line agents.

49