The development of potent immunosuppression regimens that have reduced graft loss and death from acute rejection
Individualized immunosuppressive therapies
Earlier detection and treatment of infection
Cardiovascular disease
Renal insufficiency (RI)
Hyperlipidemia
Metabolic syndrome
Diabetes mellitus (DM)
Obesity
Malignancy
Bone disease
Gastrointestinal (GI) dysfunction
Gout
Gingival hyperplasia
Sexual dysfunction
Neurocognitive impairment
While each transplant organ group may have unique posttransplant complications, the amount of evidence for posttransplant complications is highest in the renal transplantation population.
The American Society for Transplantation (AST) has developed guidelines for routine surveillance of kidney transplant recipients in the outpatient setting.1
These detection and prevention guidelines, which include specific recommendations, strength of evidence, and pertinent reviews of the scientific literature, are designed to be used as a reference by health care professionals.
Given the similarities across organ transplant groups, many of the AST renal transplant guidelines are applicable to other types of solid organ transplant recipients.
Hypertension (HTN)
Arteriosclerosis
Atherosclerosis
Coronary artery disease (CAD)
Myocardial infarction (MI)
Congestive heart failure (CHF)
Peripheral vascular disease (PVD)
Cerebral vascular disease
Stroke
For example, from 2007 to 2011, CVD was the leading cause of death in renal transplant recipients and accounted for 31% of all deaths.3
Approximately 40% of renal transplant recipients have a cardiovascular event within the first 3 years posttransplant.4
The annual risk of a fatal or nonfatal CVD event is 3.5% to 5% in kidney transplant recipients; this is 50-fold higher than the general population.5
Transplant recipients may have CVD risk factors that are common to the general population as well as risk factors that are unique to transplantation.
Male gender
Older age
Family history of premature CVD
Elevated serum lipid concentrations
Obesity
Diet high in fat and cholesterol content
Sedentary lifestyle
Cigarette smoking
Excessive alcohol consumption
Prothrombic factors
Left ventricular hypertrophy
Transplant-specific risk factors:
Maintenance immunosuppressive therapy—particularly calcineurin inhibitors (CNI), mammalian target of rapamycin (mTOR) inhibitors, and corticosteroids.7
Treatment of acute rejection episodes requiring increased dosing of immunosuppression.
Chronic rejection.
CKD with or without proteinuria.
Anemia.
Please refer to organ-specific chapters for additional information on risk factors.
Framingham Heart Study Risk Assessment Tool: estimates 10-year risk of myocardial infarction or coronary death in adults who do not have heart disease or diabetes8 (available at http://cvdrisk.nhlbi.nih.gov/calculator.asp)
German Prospective Cardiovascular Munster (PROCAM) study score: considers sex, age, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, systolic blood pressure (BP), smoking, diabetes mellitus (DM), and family history9 (PROCAM is available at http://www.chd-taskforce.com/coronary_risk_assessment.html)
Systematic Coronary Risk Evaluation Project (SCORE) risk chart: estimates 10-year risk of fatal CVD; considers age, gender, smoking status, systolic blood pressure, and total cholesterol.10
Nonmodifiable risk factors:
Age:
Males: ≥45 years
Females: ≥55 years
Male gender
Family history of premature CHD:
MI or sudden death before age 55 in father or other male first-degree relative
MI or sudden death before age 65 in mother or other female first-degree relative
Modifiable risk factors:
Hypertension
Elevated LDL cholesterol
Cigarette smoking
Thrombogenic/hemostatic state
DM
Obesity
Sedentary lifestyle
Atherogenic diet
Negative (protective) risk factor: HDL cholesterol >60 mg/dL (>1.5 mmol/L)
Emerging risk factors:
Lipid risk factors:
Triglycerides
Lipoprotein remnants
Elevated lipoprotein(a)
Small LDL particles
HDL subspecies
Apolipoprotein B
Total cholesterol/HDL cholesterol ratio
Nonlipid risk factors:
Elevated homocysteine level
Thrombogenic/hemostatic factors
Inflammatory markers (e.g., elevated high-sensitivity C-reactive protein)
Homocysteine (if elevated, may indicate a lack of folic acid, vitamin B6, and vitamin B12).
Prothrombotic factors (fibrinogen)
Subclinical atherosclerotic disease
Impaired fasting glucose (110 to 125 mg/dL) (2.85 to 3.24 mmol/L)
TABLE 6-1 Guidelines for Primary and Secondary Prevention of Cardiovascular Disease and Stroke | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Common complication of all types of solid organ transplantation
May develop as early as the first few days and weeks after transplantation and increase over time or may develop later in the posttransplant course.
Hypertension is the most common complication seen posttransplant (affecting >70% of transplant patients)11 and can lead to graft loss, MI, heart failure (HF), stroke, renal failure, and death if not treated.
National Institutes for Health (NIH) commissioned a medical committee (the Joint National Committee [JNC]) to develop evidence-based consensus guidelines for the treatment of HTN (Table 6-2).13
Per JNC-8 guidelines published in December 201313:
Hypertension is defined as repeated BP readings >140/90 mm Hg on two separate readings.
Blood pressure goals:
Adults under age 60 with no comorbidities: <150/90
Adults over age 60 with comorbidities (e.g., DM, renal disease): <140/90
To date, there is no standard definition of HTN for transplant recipients. The AST advocates following the 2013 NIH JNC-8 consensus guidelines for treatment:
These guidelines are updated by the JNC every 5 to 10 years.
Pretransplant HTN
Pretransplant renal disease
Produce afferent arteriolar vasoconstriction through enhanced sympathetic nervous system activity and up-regulation of renin-angiotensin-aldosterone system.
Cause sodium and water retention.
Reduce nitric oxide (a vasodilating prostaglandin).
Mediate elaboration of vasoconstrictor cytokines (e.g., adenosine, platelet-derived growth factor, endothelin 1).
Note: Cyclosporine (Neoral, Gengraf) typically causes more HTN than tacrolimus (Prograf, Astagraf XL).
Use caution when using CNIs in combination with other CYP3A inhibitors or inducers as this will alter the drug metabolism; a dose adjustment is strongly advised, and a trough level should be monitored to avoid an adverse reaction.
TABLE 6-2 Hypertension in the General Population
No Comorbidities
Comorbidities: DM, CKD
Age
BP Goal
Age
BP Goal
Age ≥60
<150/90 mm Hg
Age ≥60
<140/90 mm Hg
Age <60
<140/90 mm Hg
Age <60
<140/90 mm Hg
DM, diabetes mellitus; CKD, chronic kidney disease.
Adapted from JNC-8 Guidelines, 2013.
From James, PA, Oparil S, Carter BL, et al. 2014 evidenced-based guidelines for the management of high blood pressure in adults: reports from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
Drugs that are CYP pathway inhibitors (will cause an increase in transplant drug levels when used together) include, but are not limited to, the following:
Cyclosporine (Neoral, Gengraf)
Tacrolimus (Prograf, Astagraf XL)
Alprazolam (Xanax)
Quetiapine (Seroquel)
Amlodipine (Norvasc)
Amiodarone (Cordarone)
Diltiazem (Cardizem)
Atorvastatin (Lipitor)
Hydrocortisone (Prednisone)
Erythromycin (E-mycin)
Fluconazole (Diflucan)
Levofloxacin (Levaquin)
Glyburide (Diabeta)
Fluoxetine (Zoloft)
Drugs that are CYP pathway inducers (will cause a decrease in transplant drug levels when used together) include, but are not limited to
Tobacco
Rifampin (Rifadin)
Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Omeprazole (Prilosec)
If a patient taking tacrolimus is prescribed Diflucan for a fungal infection, the drug-drug interaction (DDI) may increase the tacrolimus level, and therefore, the tacrolimus dose may need to be decreased to avoid any drug toxicities.
If a patient is taking tacrolimus and is placed on antiseizure medications like phenytoin, the tacrolimus level will decrease, and the tacrolimus dose may need to be increased to avoid rejection.
Corticosteroid therapy increases sodium and water retention
Smoking
HTN in donor
TABLE 6-3 Body Mass Index Values
BMI
Interpretation
<18.5
Underweight
18.5-24.7
Normal
25 ≤ 30
Overweight
≥30
Obesity
≥40
Extreme obesity
From American Heart Association. Body Composition Tests. Available at http://www.heart.org/HEARTORG/GettingHealthy/WeightManagement/BodyMassIndex/Body-Mass-Index-BMI-Calculator_UCM_307849_Article.jsp. Accessed March 5, 2015.
Uncontrolled renin secretion from the remaining kidney
Renal artery stenosis (RAS)
Chronic allograft nephropathy
Recurrence of intrinsic renal disease
Heart transplant recipients:
Abnormal regulation of sodium balance associated with cardiac denervation and renal impairment
Structural changes in resistance arteries
Liver transplant recipients:
Cirrhosis
Portopulmonary hypertension
Headache
Dizziness
Nosebleeds
Visual disturbances
Goals:
Prevent damage to the kidneys and heart
Prevent cerebral vascular events
Prevent graft dysfunction or graft loss
Nonpharmacologic therapy:
Used alone, may be successful only if patient’s systolic blood pressure (SBP) is within 10 mm Hg of target SBP
Strategies:
Smoking cessation
Weight reduction
Salt restriction
Fluid restriction (as indicated)
Regular exercise
Pharmacologic therapy:
Substitution of another immunosuppressive agent for cyclosporine
TABLE 6-4 Antihypertensive Agents/Cardiac Medications
Medication
Advantages
Disadvantages
Specific β1-blockers (e.g., atenolol, metoprolol)
Agents of choice in patients with coronary artery disease (CAD) and good left ventricular function
↓ Cardiac output
May ↓ renal blood flow
Reflex tachycardia if abruptly stopped
Alpha 1-blocker + nonspecific β-blocker (e.g., labetalol, carvedilol)
May be effective for patients who need both vasodilatation and heart rate control
Bronchospasm
Avoid with peripheral vascular disease
Possible ↑ risk of cerebrovascular events
May exacerbate cyclosporine-induced hyperkalemia
↓ Cardiac output
Erectile dysfunction
Alpha1-blockers (e.g., terazosin)
May help in patients with benign prostatic hyperplasia;
May ↑ renal blood flow
Orthostatic hypotension
Syncope
Calcium channel blockers: dihydropyridines (e.g., nifedipine)
Best agents to prevent cyclosporine A-induced vasoconstriction
Does not affect cardiac conduction
Edema (nonsodium retentive)
Reflex tachycardia
Avoid with active CAD, CHF
May exacerbate cyclosporine-induced gingival hyperplasia
Calcium channel blocker: diltiazem
Can prevent cyclosporine A-induced vasoconstriction
Effects cardiac conduction (less than verapamil)
↑ Cyclosporine levels
↑ Tacrolimus levels
Bradycardia
Calcium channel blocker: verapamil
Can prevent cyclosporine A-induced vasoconstriction
Effects cardiac conduction and negative inotrope effect
↑ Cyclosporine levels
↑ Tacrolimus levels
↓ Cardiac output
Bradycardia
Constipation
Angiotensin-converting enzyme inhibitors (ACEI) (e.g., enalapril)
May be best agents for patient with ↓ left ventricular function or left ventricular dilatation
Hyperkalemia
↓ Renal perfusion (stop if creatinine ↑ 30% over baseline)
Dry cough
Neutropenia
Angioedema (lips)
Angiotensin II blockers (e.g., losartan)
May be best agents to ↓ proteinuria experimentally. May ↓ cyclosporine-mediated renal fibrosis
Deterioration in renal function (particularly in patients with renal artery stenosis)
Hyperkalemia
Angioedema to lips
Alpha2 agonists (e.g., clonidine)
Effective in many people
Drowsiness
↓ Central sympathetic discharge
Dry mouth
Direct vasodilators (e.g., hydralazine, minoxidil)
Hydralazine often used with patients intolerant to ACEI or alpha II blockers with congestive heart failure
Minoxidil effective in refractory patients
Reflex tachycardia
Sodium retention
Headache
Lupus syndrome at high doses
Diuretics (e.g., furosemide, bumetanide)
Often necessary in volume overloaded patients
Electrolyte disorders (Na, K, Mag, Ca, Mag)
Volume depletion may activate renin-angiotensin II system
May exacerbate cyclosporine-induced fibrosis
Contraindicated if sulfa allergy
Data from JNC-8 guidelines and Epocrates online.
From James, PA, Oparil S, Carter BL, et al. 2014 evidenced-based guidelines for the management of high blood pressure in adults: reports from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
Risk factors for RAS include
Procurement and operative techniques postrenal transplant (such as suturing or trauma)
Atherosclerotic disease
Cytomegalovirus (CMV) infection
Delayed graft function
Administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) to the patient with RAS can lead to a rise in creatinine and reversible decline in glomerular filtration rate (GFR). This will aid in the diagnosis of RAS.
Treatment options for RAS include correcting the stenosis with angioplasty, stent, or bypass surgery.
Nonrenal transplant recipients: pretransplant RI (also known as chronic kidney disease [CKD]) is associated with end-stage heart or liver disease related to low perfusion states and chronic high-dose diuretic use:
Posttransplant nephrotoxicity may be associated with the use of
CNIs (cyclosporine, tacrolimus)
Antibiotics
Certain nonmaintenance immunosuppressants used to treat acute rejection
TABLE 6-5 Scope of the Problem of Renal Insufficiency | ||||||||||||||||||||
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TABLE 6-6 Definition and Stages of Chronic Kidney Disease | |||||||||||||||||||||||||||
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|
Pretransplant RI/CKD:
Preexisting renal dysfunction
DM
HTN
Older age
Generalized atherosclerosis
Perioperative events:
Hypotension
Use of pressor agents
Sepsis
CMV infection
HTN
Hyperlipidemia
Proteinuria
Types of cyclosporine-induced injury:
Acute29:
Severe, rapid, and intense vasoconstriction of preglomerular (afferent) arterioles leads to decrease in renal blood flow and GFR; this vasoconstriction is presumably mediated by an increase in sympathetic tone and is activated by the renin-angiotensin system, thereby decreasing production of vasodilator molecules resulting in vasoconstriction.
Effects are dose related and are often reversed with withdrawal of cyclosporine.
Chronic29:
Characterized by structural changes in renal architecture, which cause sustained functional nephrotoxicity and induce:
Glomerular ischemia
Tubular atrophy
Tubulointerstitial fibrosis
Glomerulosclerosis
Injury worsens over time and results in permanent renal dysfunction.
Potential clinical manifestations:
Elevated serum creatinine >2 mg/dL:
Calcium channel blockers (CCB) have been used to reduce cyclosporine-induced nephrotoxicity by reducing afferent arteriolar tone. Administering a CCB with cyclosporine may reduce the accumulation of cyclosporine within the renal tubule cells.
Renal-sparing protocols involve substituting sirolimus for the calcineurin inhibitor.
Decreased creatinine clearance/GFR
Proteinuria
Increased serum potassium level
Increased serum uric acid level
Decreased sodium excretion
HTN
Fluid retention
Anemia
Hypomagnesemia:
Common after transplant due to calcineurin-induced down-regulation of renal expression of magnesium channel TRPM6.
Signs and symptoms include weakness, muscle spasms, nausea, vomiting, diarrhea, and cardiac arrhythmias.
Monitor trough levels of cyclosporine (Sandimmune, Neoral, Gengraf) or tacrolimus (Prograf, Astagraf XL).
Nephrotoxicity typically occurs with high trough levels but may occur at low trough levels.29
Assess patient’s volume status to determine if dehydration is contributing to RI.
Review patient’s medication profile to identify other medications that may be contributing to nephrotoxicity, such as:
Antibiotics
Antihypertensive medications
Diuretics
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Target patients who have a significant increase in serum creatinine during the first 6 months posttransplant28
Immunosuppression management:
If possible, reduce dose of CNI: cyclosporine or tacrolimus.
Consider changing patient’s CNI from cyclosporine to tacrolimus.
BP control:
Diastolic HTN has been linked to severe RI.
Screen for secondary causes: sleep apnea, primary aldosteronism, and RAS.
Aggressive treatment of hyperlipidemia
The terms “hyperlipidemia” and “dyslipidemia” are used interchangeably. This disease process involves abnormally elevated levels of any or all lipid proteins.
TABLE 6-7 Hyperlipidemia
Type of Transplant
Scope of Problem
Kidney
Hyperlipidemia and hypertriglyceridemia have been reported in 50%-90% of kidney transplant recipients.33,35
Heart
Cumulative prevalence in survivors at 1 and 5 posttransplant: 60%, 88%, respectively24
Total cholesterol, LDL, apolipoprotein B, and triglyceride levels may increase during the first 3 mo posttransplant
Lung
Cumulative prevalence in survivors during first posttransplant year: 27% cumulative prevalence in survivors within five posttransplant: 59%25
Heart-lung
Cumulative prevalence in survivors within 1 and 5 y: 26.7% and 70%, respectively (per ISHLT 2014 database)25
Liver
May affect up to 45% of recipients34
From Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report—2014. J Heart Lung Transplant. 2014;33(10):996-1008; International Society for Heart and Lung Transplantation. The Registry Of The International Society For Heart And Lung Transplantation: Thirty-First Adult Lung And Heart-Lung Transplant Report. Available at http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry. Accessed August 8, 2015; Razeghi E, Shafipour M, Ashraf H, et al. Lipid disturbances before and after renal transplant. Exp Clin Transplant. 2011;9(4):230-235; Charlton M. Obesity, hyperlipidemia and metabolic syndrome. Liver Transpl. 2009;15(suppl 2):S83-S89; Gosmanova EO, Tangpricha V, Gosmanov AR. Endocrine-metabolic pathophysiologic conditions and treatment approaches after kidney transplantation. Endocr Pract. 2012;18(4):579-589.
Hypercholesterolemia is referencing cholesterol levels that are higher than normal.
Hypertriglyceridemia is referencing triglyceride levels that are higher than normal.
Hyperlipidemia in the transplant patient may be related to high fat diets, genetic predisposition and immunosuppressive medications.
History of pretransplant hyperlipidemia and/or obesity
Genetic factors
Male gender
Older age
Posttransplant medications36:
Immunosuppressive agents:
Cyclosporine: decreases bile acid synthesis from cholesterol, thus increasing serum cholesterol, LDL cholesterol levels and triglyceride levels.
Corticosteroids can cause hyperlipidemia. They increase in LDL, total cholesterol, and triglycerides and a decrease in HDL levels by:
Increasing acetyl coenzyme A (CoA) carboxylase activity and free fatty acid synthesis.
Increasing hepatic synthesis of very-low-density lipoproteins.
Increasing the 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase enzyme that is used for “statin therapy.” Of note, statins are used to inhibit this enzyme and normalize the lipid profile.
There is a risk for myopathy or rhabdomyolysis when both cyclosporine (Neoral, Gengraf) and pravastatin (Pravachol) are taken concurrently. Tacrolimus (Prograf) and sirolimus (Rapamune) are not metabolized the same as cyclosporine and do not carry a drug-drug interaction risk for rhabdomyolysis.
Any patient taking a “statin” medication is at risk for myopathy.
Inhibiting LDL.
Tacrolimus is similar to cyclosporine but has less pronounced effects on lipid metabolism.
Mammalian target of rapamycin (mTOR) inhibitors (everolimus [Zortress] and sirolimus [Rapamune]) are used as potent immunosuppressive agents in solid organ transplant recipients.
mTOR inhibitors reduce the catabolism of circulating lipoproteins by inhibiting the activity of lipases, resulting in an increased prevalence of dyslipidemia up to 75% of patients.
The risk/benefit ratio should be carefully considered before starting an mTOR inhibitor in patients with preexisting hyperlipidemia.18
Everolimus (Zortress) carries a 21% to 24% increase in hyperlipidemia.
Sirolimus (Rapamune) carries a 30% to 64% increase in hyperlipidemia.
Antihypertensive agents:
Beta-blockers (atenolol [Tenormin]) and diuretics (hydrochlorothiazide [HCTZ]) can elevate LDL and triglycerides.
Comorbid conditions:
DM: associated with hypertriglyceridemia and hypercholesterolemia
Proteinuria: associated with elevated LDL and lipoprotein A
Renal dysfunction
Obesity37:
Causes excessive production of very-low-density lipoprotein (VLDL) particles
Increases triglyceride levels
Increases LDL levels
Decreases HDL levels
Diet high in saturated fat and/or cholesterol
CVD
Chronic cardiac allograft vasculopathy (CAV)39
Fasting (8 to -12 hours) total cholesterol, LDL, HDL, and triglyceride levels at least twice during the first posttransplant year.
Use of fasting lipids may change in the future as the American College of Cardiology (ACC) and American Heart Association (AHA) have recommended moving away from lowering LDL-C to specific target levels and treating with moderate to high-intensity statins in patients with atherosclerotic heart disease. This intensity will reduce LDL-C by 40% to 50% and can be assessed using nonfasting blood samples.41
TABLE 6-8 Relative Risk of Adverse Effects of Immunosuppressants Agents on Lipid Metabolism
Cyclosporine
Tacrolimus
Mycophenolate Mofetil
Sirolimus
Everolimus
Corticosteroids
Azathioprine
↑↑
↔
↔
↑↑
↑↑
↑↑
Unknown
↑↑, substantially increased; ↔, unchanged.
Adapted from Gosmanova EO, Tangpricha V, Gosmanov AR. Endocrine-metabolic pathophysiologic conditions and treatment approaches after kidney transplantation. Endocr Pract. 2012;18(4):579-589.
More frequent screening for recipients with history of pretransplant hyperlipidemia and those at high risk for hyperlipidemia (e.g., patients on rapamycin [Sirolimus]).
Using data from the National Health and Nutrition Survey III (NHANES III) elevated LDL or non-HDL levels were linked to higher risk of death.41
Regular screening throughout the posttransplant course, particularly for recipients with risk factors for CVD.
Download the 2013 Prevention Guidelines Tools: Cardiovascular Risk Calculator: http://my.americanheart.org/cvriskcalculator:
This risk calculator estimates 10-year and lifetime risks for atherosclerotic cardiovascular disease (ASCVD) events based upon age, sex, race, total cholesterol, HDL cholesterol, SBP, any BP-lowering medications, DM, and smoking status.
Presence or absence of CHD or other forms of ASCVD:
Acute coronary syndrome
Prior history of MI
Stable or unstable angina
Coronary or other arterial revascularization procedure
Transient ischemic attack (TIA) or stroke
Peripheral arterial disease
Very high LDL cholesterol ≥190 mg/dL (≥4.92 mmol/L)
Age 40 to 75 with DM + LDL 70 to 189
LDL 70 to 189 + 10-year risk of ASVD >7.5% (use risk calculator above in section IV-C)
TABLE 6-9 Risk Category for Atherosclerotic Cardiovascular Disease and Therapy
Risk Category
Type of Dyslipidemia
Goal
Treatment
HIGH Low-density lipoprotein (LDL)
Very high LDL cholesterol ≥190 mg/dL (≥4.92 mmol/L)
Age 40-75 with DM + LDL 70-189
LDL 70-189 + 10-y risk of ASCVD >7.5%
First line: high-intensity dose statin to achieve LDL reduction 50% or more
Atorvastatin 40-80 mg daily
Rosuvastatin 20-40 mg daily
MODERATE LDL
LDL 70-189 with 10-y risk of 5%-7.5%
LDL >160 + genetic risks (CV disease in first-degree male < age 55)
Moderate-dose intensity statin (average LDL reduction about 30% to <50%):
Atorvastatin 10-20 mg daily.
Fluvastatin 80 mg (XL) daily
Lovastatin 40 mg daily.
Pitavastatin 2-4 mg daily
Pravastatin 40-80 mg daily.
Rosuvastatin 5-10 mg daily
PREVENTION/LOW LDL
Daily dose lowers low-density lipoprotein-cholesterol (LDL-C) on average, by <30%
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40
NONSTATINS
Encourage statin use, lifestyle modification
Do not add Gemfibrozil (Lopid) to any statin
ELEVATED TRIGLYCERIDES (Tg)
Elevated serum triglycerides:
Normal: <150 mg/dL
Borderline-high: 150-199 mg/dL
High: 200-499 mg/dL
Very high: ≥500 mg/dL
SI units:
Normal: <1.69 mmol/L
Borderline high: 1.69-2.24 mmol/L
High: 2.26-5.63 mmol/L
Very high: ≥5.65 mmol/L
Borderline-high:
Weight reduction
↑ physical activity
Drug therapy for high Tg
Contributing factors:
High:
Intensify therapy to lower LDL or
Add nicotinic acid or fibrate
Very high:
Prevent acute pancreatitis with very low-fat diet (≤15% of total intake), weight reduction, ↑ physical activity, and omega-3 fatty acids, fibrate or nicotinic acid
No evidence that adding a nonstatin to a statin will ↓ CV risk
Overweight
Obesity
Physical inactivity
Smoking
Excess alcohol intake
High carbohydrate diet
Certain disease states (e.g., type 2 DM)
Certain drugs (e.g., corticosteroids)
Genetic disorders
High-density lipoprotein (HDL)
Low HDL cholesterol: <40 mg/dL (<1.03 mmol/L)
Achieve target LDL goal:
When LDL goal is reached:
Strong predictor of coronary heart disease
Weight reduction
Physical activity
Physical inactivity
Isolated low HDL:
Type 2 DM/insulin resistance
Smoking
High carbohydrate intake
Certain drugs (e.g., beta-blockers)
Nicotinic acid
Fibrates
New lipid guidelines focus on reducing CV risk using the 10-year risk calculator http://my.americanheart.org/cvriskcalculator.
Dyslipidemia is a risk factor for ASCVD. First recommendation is lifestyle modification (diet and exercise). If unsuccessful, then drug therapy. Current guidelines do not recommend titrating statins to an LDL number, they titrate to lower LDL by a set percentage.
Drugs are selected to achieve high intensity, moderate intensity, or prevention in the low-risk group for ASCVD events.
Patients at risk for atherosclerotic cardiovascular disease (ASCVD) include primary LDL-C >160 mg/dL or evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years in a first-degree male relative or <65 years in a first-degree female relative, and high sensitivity C-reactive protein >2 mg/L.
Patients with clinical ASCVD (defined as acute coronary syndromes; prior MI, stable or unstable angina, coronary revascularization, stroke, or TIA believed to be of atherosclerotic origin, and peripheral arterial disease or past revascularization) are at increased risk for recurrent ASCVD and death. These patients should take high-intensity statin therapy to ↓ risk for future ASCVD events and/or death. DM, diabetes mellitus; MI, myocardial infarction; CV, cardiovascular.
From Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129(25 suppl 2):S1-S45.
Once risks have been assessed, the patient’s risk category is determined and therapy is individualized (Table 6-10).40
The CV Risk Calculator (Section IV-C) can be used for all transplant recipients.
If the 10-year risk calculator score exceeds 7.5, follow treatment guidelines per the ACC/AHA recommendations to reduce ASCVD risks.
Similar to treatment of hyperlipidemia in the general population
TABLE 6-10 Secondary Causes of Dyslipidemia
Secondary Cause
Elevated LDL-C
Elevated Triglycerides
Diet
Saturated or trans fats
Weight gain
Anorexia
Weight gain, very low-fat diets, ↑intake of refined carbohydrates, excessive alcohol intake
Drugs
Diuretics, cyclosporine, glucocorticoids, amiodarone
Sirolimus, beta-blockers (not carvedilol), thiazide diuretics, steroids (glucocorticoid or anabolic), estrogens, raloxifene, tamoxifen. bile acid sequestrants, protease inhibitors, retinoic acid
Diseases
Transplant (d/t meds and organ function), biliary obstruction, nephrotic syndrome
Transplant (d/t meds and organ function). Nephrotic syndrome, chronic renal failure, lipodystrophies, diabetes
Disorders and altered states of metabolism
Hypothyroidism, obesity, pregnancy
Disorders and altered states of metabolism
Diabetes (poorly controlled), hypothyroid, obesity, pregnancy
Adapted from Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129(25 suppl 2):S1-S45 (2013 ACC/AHA Blood Cholesterol Guideline).
Nonpharmacologic interventions:
Optimization of weight
Exercise
Smoking cessation
Diet low in saturated fat and cholesterol
Pharmacologic interventions:
Indications for drug therapy vary among transplant populations and transplant centers.
Some heart transplant centers prescribe HMG-CoA reductase inhibitors, also known as statins, for all recipients, even those with normal cholesterol profiles.
There is evidence that pravastatin (Pravachol), in addition to lowering cholesterol levels in heart transplant recipients, may have additional beneficial effects.
For example, Kobashigawa and colleagues demonstrated that pravastatin also decreased the incidence of rejection associated with hemodynamic compromise, increased 1-year survival, and decreased the development of CAV.42
Heart transplant recipients: ISHLT guidelines for adults43:
Begin statins 1 to 2 weeks following heart transplantation (regardless of cholesterol levels).
Initial dose should be lower than typical dose due the potential drug-drug interactions between statins and cyclosporine for myopathy and rhabdomyolysis.
In patients with high risk for ASCVD, new guidelines were developed in 2013. The ACC and AHA convened an expert panel to formulate evidence-based medical practice guidelines.40
This group discontinued the use of LDL targets and recommended appropriate statin intensity (based on risk) to reduce risk of ASCVD complications in patients most likely to benefit.
The four high-risk groups that could benefit from statin therapy are
Patients with known ASCVD
Patients with LDL-C ≥190 mg/dL (4.9 mmol/L)
Patients age 40 to 75 with DM
Patients age 40 to 75 with ≥7.5% risk of developing ASCVD in the next 10 years using the Global Risk Assessment for Primary Prevention: http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp
Moderate to high intensity statins are recommended in patients with atherosclerotic heart disease. This intensity will reduce LDL-C by 40% to 50%.
The use of nonstatins was not advised, unless the patient had a statin allergy. Nonstatin therapy did not significantly lower the ASVCD risk upon review.
The 2013 ACC/AHA Cholesterol Guidelines can be accessed online: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.full.pdf
Drug interactions:
Interactions may occur between cyclosporine and statins such that both serum concentrations (statins and cyclosporine levels) are increased.
Recommendations to follow cyclosporine levels closely and assess for toxicities.
Recommendations to limit pravastatin to 20 mg/d when also receiving cyclosporine due to potential risk for increased statin serum levels and toxic side effects: myalgia, myopathy, and rhabdomyolysis.
Increased serum levels of statins can lead to the development of rhabdomyolysis45:
Rhabdomyolysis is a potentially fatal disease that is characterized by the destruction of striated muscle.
As the muscle breaks down and becomes necrotic, intracellular muscle contents leak into the circulation and extracellular fluid.
Rhabdomyolysis may be asymptomatic; however, symptoms typically include the classic triad of muscle pain, weakness, and dark urine:
Muscle pain may be generalized or may involve specific muscle groups such as the thighs, calves, and lower back.46
Symptoms may develop acutely upon initiation of statin therapy or many months or years later.
Older age
Female gender
DM
Concurrent renal or liver disease
Concurrent use of fibrate-type agents14
Instruct patients to promptly report muscle pain, weakness, or any other untoward symptoms:
Approximately 10% of patients have a “true statin intolerance” based upon adverse reactions assessed after taking two different statins.47
TABLE 6-11 Drugs that Affect Lipid Metabolism
Drug Class
Dose Range
Effect
Potential Side Effects
Contraindications
Follow-up Monitoring
HMG CoA reductase inhibitors
↓ LDL 18%-55%
↓ Triglycerides 7%-30%
↑ HDL 5%-15%
Myopathy
Rhabdomyolysis
↑ liver enzymes
Absolute:
Liver disease (acute or chronic)
Advise patient to reports: jaundice, abdominal pain, muscle aches
Lovastatin
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Rosuvastatin
20-80 mg
20-40 mg
20-80 mg
20-80 mg
10-80 mg
5-40 mg
LDL ↓ 21%—42%
LDL ↓ 22%-37%
LDL ↓ 26%-47%
LDL ↓ 22%-35%
LDL ↓ 35%-60%
LDL ↓ 45%-63%
Relative:
Certain medications that are metabolized through the cytochrome p450 system:
Cyclosporine, macrolide antibiotics, some antifungal agents
Monitor patient for:
Muscle pain, tenderness, soreness
Onset of therapy: evaluate patient for muscle symptoms; check CK (if ↑ 3× baseline, DC)
Subsequent visit:
Evaluate patient for muscle symptoms
If patient develops muscle pain, tenderness, or soreness: check CK
Onset of therapy: monitor ALT and AST
Monitor ALT and AST immediately after onset of therapy, 4-12 wk after onset of therapy, and annually thereafter or as indicated
Consider statin dose reduction if LDL <40 on two consecutive lab draws.
Bile acid sequestrants
Cholestyramine
Colestipol
Colesevelam
4-24 g
5-30 g
2.6-4.4 g
↓ LDL 15%-30%
↑ HDL 3%-5%
Triglycerides:
↑ or no change
Mainly GI:
Indigestion
Bloating
Constipation
Abdominal pain
Flatulence
Nausea
↓ Absorption of other medications
Side effects may preclude long-term compliance
Absolute:
Dysbeta-lipoproteinemia
Triglycerides >400 mg/dL (4.52 mmol/L)
Relative:
Triglycerides >200 mg/dL (2.26 mmol/L)
Monitor patient for side effects at onset of therapy and at each follow-up visit
May interfere with absorption of cyclosporine; check cyclosporine levels
Cyclosporine and other medications should not be taken 1 h before or 4 to 6 h after bile acid sequestrant is taken
Nicotinic acid
Immediate-release
Extended-release
Sustained-release
Flushing
Itching
Tingling
Headache
Nausea
Flatulence
Heartburn
Fatigue
Rash
Hyperglycemia
Hyperuricemia
Gout
Hepatotoxicity
Absolute:
Chronic liver disease
Severe gout
Relative:
Diabetes
Hyperuricemia
Peptic ulcer disease
New onset atrial fibrillation
Monitor patient for side effects at onset of therapy and at each follow-up visit
FBS and uric acid:
At onset of therapy,
6-8 wk later;
Annually or as indicated thereafter
AST and ALT:
At onset of therapy; start dose low and advance slow
6-8 wk later;
At dose of 1,500 mg;
6-8 wk after reaching maximum dose;
Annually or as indicated thereafter
For patients on cyclosporine: may ↑ LFTs and uric acid
1.5-3 g
1-2 g
1-2 g
↓ LDL 5%-25%
↓ Triglycerides 20%-50%
↑ HDL 15%-35%
Fibric acid derivatives
Gemfibrozil
Fenobibrate
Clofibrate
600 mg BID
200 mg BID
1,000 mg BID
↓ LDL 5%-20%
↓ Triglycerides 20%-50%
↑ HDL 10%-20%
Abdominal pain
Dyspepsia
Headache
Drowsiness
Cholelithiasis
Myopathy
Absolute:
Severe renal disease
Severe liver disease
Monitor patient for side effects at onset of therapy and at each follow-up visit
Monitor PT/INR
May potentiate effects of warfarin
Use with caution in diabetic patients: interacts with insulin and sulfonylureas
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; GI, gastrointestinal; HDL, high-density lipoprotein; FBS, fasting blood glucose; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; LFT, liver function test; PT, prothrombin time; INR, international normalized ratio.
Cyclosporine, macrolide antibiotics, various antifungal agents, and other cytochrome P-450 inhibitors (fibric acid derivatives and nicotinic acid should be used with caution).
From Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129(25 suppl 2):S1-S45; National Cholesterol Education Program. National Cholesterol Education Program (NECP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. Circulation. 2002;106:3143-3421.
If rhabdomyolysis is suspected, obtain hepatic function tests and a serum creatine kinase (CK).
CK may be within normal range, but it typically begins to rise within 12 hours of development of rhabdomyolysis, peaks after 1 to 3 days, and then declines over a period of 3 to 5 days after the muscle injury ceases.
Monitor lipid profile, CK, and hepatic function tests:
When a statin is started.
Anytime a statin dose is increased.
Stop the statin:
If the patient is symptomatic with myalgias or other adverse effects
If the CK is 10 or more times the upper limit of normal
If hepatic function is three or more times the upper limit of normal.
Some patients may not tolerate any statins. Others may tolerate one statin; but, not another.
It is recommended that patients be given a trial of at least two different statins before they are labeled with a statin allergy.
Metabolic syndrome increases risk for heart disease, renal disease, diabetes, and stroke.48
Excess body fat, particularly in the abdominal area (commonly seen in patients with insulin resistance).
Physical inactivity/obesity: exercise and weight loss are keys to improving this syndrome and reducing heart disease and diabetes risks.
Genetic predisposition (in certain individuals).
Hypertriglyceridemia: diet and drug therapy.
Low HDL: encourage exercise to increase HDL.
Hypertension: 40% of patients with hypertension have metabolic syndrome.
World Health Organization (WHO) clinical definition
National Cholesterol Education Program Adult Treatment Panel III
American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI)
International Diabetes Federation (IDF)
Consensus definition: AHA/NHLBI and IDF
Control LDL cholesterol.
Weight reduction (WHO estimates 1.6 billion people worldwide are overweight defined as a BMI >25).12,17
TABLE 6-12 Definitions of Metabolic Syndrome
World Health Organization (1998)
NCEP ATP III (2001)
AHA/NHLBI (2004)
International Diabetes Federation (2005)
Consensus Definition: AHA/NHLBI and IDF
Criteria
Insulin resistance (defined as Type 2 DM or IFG (↑ 100 mg/dL) or IGT) plus two of the following:
Any three of the following
Any three of the following
BMI ↑ 30 kg/m2 plus two of the following:
Any three of the following:
Abdominal obesity
Waist-to-hip ratio:
Men: ↑ 0.9
Women: ↑ 0.85
or
BMI ↑ 30 kg/m2
Waist circumference:
Men: ↑ than 102 cm
Women: ↑ than 88 cm
Waist circumference:
Men: 102 cm or ↑
Women: 88 cm or ↑
↑ Waist circumference (according to population and country-specific definitions)
Triglycerides
150 mg/dL or ↑
and/or
HDL cholesterol in:
Men ↓40 mg/dL
Women: ↓ 50 mg/dL
150 mg/dL or ↑
150 mg/dL or ↑
150 mg/dL or ↑
150 mg/dL or ↑
HDL cholesterol
Men: ↓ 40 mg/dL
Women: ↓ 50 mg/dL
Men: ↓ 40 mg/dL
Women: ↓ 50 mg/dL
HDL cholesterol in:
Men: ↓ 40 mg/dL
Women: ↓ 50 mg/dL
HDL cholesterol in:
Men: ↓ 40 mg/dL
Women: ↓ 50 mg/dL
Blood pressure
140/90 mm Hg or ↑
130/85 mm Hg or ↑
130/85 mm Hg or ↑
130/85 mm Hg or ↑
130/85 mm Hg or ↑
Fasting glucose
110 mg/dL or ↑
100 mg/dL or ↑
100 mg/dL or ↑
100 mg/dL or ↑
Microalbuminuria
Urinary albumin secretion rate 20 µg/min or ↑, or albumin-to-creatinine ratio 30 mg/g or ↑
AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; IDF, International Diabetes Federation; DM, diabetes mellitus; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; HDL, high-density lipoprotein; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III.
Adapted from Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: definitions and controversies. BMC Med. 2011;9:48-60.
Increase physical activity to
Lower very-low-density lipoprotein (VLDL) levels
Lower LDL levels (in certain patients)
Increase HDL cholesterol
Lower BP
Decrease insulin resistance
DM that develops de novo after transplantation is also referred to as new onset diabetes after transplantation (NODAT).50
Metabolic syndrome was found in 57% of pretransplant recipients. Recipients with preexisting metabolic syndrome were more likely to develop NODAT compared to recipients without metabolic syndrome (34.4% vs. 27.4%, p = 0.057).51
Kidney: 30%
Heart: 18.5% of recipients within 1 to 5 years posttransplant
Lung: 18.5% of recipients within 1 to 5 years posttransplant
Liver: 15%
Onset53:
Typically occurs early in the posttransplant period or when corticosteroid therapy is augmented to treat rejection.
Carries the same short- and long-term risks as DM in the general population.
Typically diagnosed as per general population guidelinesStay updated, free articles. Join our Telegram channel
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