Transplant Complications: Noninfectious Diseases

Vicki McCalmont, RN, MS, ANP-BC, CNS, CCTC

Kristi Ortiz, RN, MS, ANP-BC, CNS

I. INTRODUCTION

A. Several factors have increased short- and long-term transplant survival rates:

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

B. Survival rates are also influenced by the emergence of long-term medical complications posttransplant.

C. This chapter will provide an overview of the following major (noninfectious, nonrejection) long-term complications following transplantation:

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

D. Monitoring of recipients for posttransplant complications:

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.

II. CARDIOVASCULAR DISEASE (CVD)

A. For the purposes of this discussion, CVD refers to a wide range of vascular and heart-related diseases, disorders, and events that include

Hypertension (HTN)
Arteriosclerosis
Atherosclerosis
Coronary artery disease (CAD)
Myocardial infarction (MI)
Congestive heart failure (CHF)
Peripheral vascular disease (PVD)
Cerebral vascular disease
Stroke

B. A discussion of each of these CVDs is beyond the scope of this chapter. Given, however, that HTN is the most common disorder across all organ types, it will be discussed in detail below.

C. Cardiovascular complications have been emerging as the major cause of late morbidity and mortality in all solid organ transplant groups.²

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

D. There is some evidence that mortality rates due to CVD in transplant recipients are greater than in the general population; for example:

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

E. Risk factors for CVD

Transplant recipients may have CVD risk factors that are common to the general population as well as risk factors that are unique to transplantation.
Risk factors common to the general population⁵^,⁶:
- 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.

F. Given the prevalence of CVD in the transplant population, pre- and posttransplant screening for CVD is imperative. Examples of screening tools include the following:

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

G. Risk factors for coronary heart disease (CHD)¹¹^,¹²:

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)

H. Guidelines for primary and secondary prevention of cardiovascular disease and stroke are shown in Table 6-1.¹²

TABLE 6-1 Guidelines for Primary and Secondary Prevention of Cardiovascular Disease and Stroke

	Goals
Parameter	Primary Prevention				Secondary Prevention
Smoking	Cessation of smoking No exposure to environmental smoke or secondhand smoke Avoid smokeless tobacco				Cessation of smoking No exposure to environmental smoke or secondhand smoke Avoid smokeless tobacco
Blood pressure control	<140/90 mm Hg				<140/90 mm Hg
Diet	Heart-healthy diet Optimize weight—reduce calories if overweight Saturated fat <10% of total calories Cholesterol <300 mg/d Salt intake <6 g/d Limit trans-fatty acids (<5% total calories) Limit alcohol intake				Heart-healthy diet Optimize weight—reduce calories if overweight Saturated fat: <7% of total calories Cholesterol: <200 mg/d Limit trans-fatty acids
Lipid management
Primary goals: (risk factors: HTN, smoking, HDL<40, family Hx of premature) CHD (CHD in male first degree relatives <55, men ≥45; women ≥55)	≤1 risk factor: ≥2 risk factors + 10 y risk <20%: ≥2 risk factors + 10 y risk ≥20% or in setting of DM, CHD		LDL <160 mg/dL LDL <130 mg/dL		LDL <100 mg/dL or <70 mg/dL
			LDL <100 mg/dL
Secondary goals if LDL is at target goal and triglycerides are >200 mg/dL (2.26 mmol/L)	≤1 risk factor ≥2 risk factors + 10 y risk ≤ 20% ≥2 risk factors + 10 y risk ≥20%		Non-HDL <190 mg/dL Non-HDL <160 mg/dL Non-HDL <130 mg/dL
Triglycerides (Tg)	<150 mg/dL—normal 150-199 mg/dL—borderline high 200-499—high >500—very high (risk for pancreatitis if untreated)		For triglycerides ≥200 mg/dL), non-HDL should be <130 mg/dL Non-HDL = total cholesterol minus HDL For triglycerides 200-499 mg/dL ; non-HDL based on risk factors All abnormal Tg need diet, exercise and weight control + meds >200
HDL	Men: >40 mg/dL Women: >50 mg/dL		Men: >40 mg/dL Women: >50 mg/dL
Physical activity	30 min of moderately intense exercise on most, if not all, days of the week		30 min 7 d/wk, minimum: 5 d/wk
Weight	Optimize weight
	BMI: 18.5-24.9 kg/m² Waist circumference:		BMI: 18.5-24.9 kg/m² Waist circumference:
		Men: <40 inches Women: <35 inches		Men: <40 inches Women: <35 inches
	Waist-to-hip ratio:		Waist-to-hip ratio:
		Men >9.0 Women >8.5		Men <9.0 Women <8.5
	Overweight/obese patients: 10% ↓ in weight during first year of therapy		Initial goal: 10% ↓ in weight from baseline
Management of DM	Normal fasting blood glucose: <110 mg/dL HgbA_1c <7%		HgbA_1c <7% Preprandial BG 90-130 Postprandial BG <180 Bedtime glucose 100-140
Anticoagulation/antiplatelet therapy	In setting of chronic AF: anticoagulation with warfarin to goal INR between 2.0 and 3.0 (target: 2.5)		INR 2.0-3.0 for patients with AF or flutter and as indicated in MI patients Aspirin and/or clopidogrel as indicated Newer anticoagulants: rivaroxaban (Xareltro); dabigatran (Pradaxa) will increase cyclosporine drug levels, dose needs adjusted and follow levels; no INR monitoring is needed for the newer drugs.
RAA system blockers (unless otherwise contraindicated)			ACEI		Indefinitely in setting of: EF ≤ 40% Hypertension DM Chronic kidney disease Consider in other settings
			ARBs		In setting of ACEI intolerance and HF or MI with EF ≤ 40%
			Aldosterone blockade		In combination with therapeutic ACEI and β-blocker doses for status post-MI patients with potassium level <5.0 mEq/L and creatinine <2.5 mg/dL (men) or <2.0 mg/dL (women) and with EF ≤40% and DM or HF
β-Blocker therapy (unless otherwise contraindicated)			Indefinitely in patients with MI, ACS, or LV dysfunction with or without HF symptoms Consider for other patients in setting of CHD, DM, or vascular disease		In combination with therapeutic ACEI and β-blocker doses for status post-MI patients with potassium level <5.0 mEq/L and creatinine <2.5 mg/dL (men) or <2.0 mg/dL (women) and with EF ≤ 40% and DM or HF
Influenza vaccine			Recommended for all patients with CVD unless otherwise contraindicated Recommended for all transplant patients unless otherwise contraindicated
ACEI, angiotensin-converting enzyme inhibitors; ACS, acute coronary syndrome; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; DM, diabetes mellitus; HDL, high-density lipoprotein; HF, heart failure; HgbA_1c, hemoglobin A_1c; Hx, history; INR, international normalized ratio; LDL, low-density lipoprotein; LV, left ventricular; MI, myocardial infarction; NSR, normal sinus rhythm; RAA, renin-angiotensin-aldosterone; Rl, renal insufficiency; Tg, triglycerides.
From Kelly SC, Gonzalo R, Petrasko M. A focus on cardiovascular risk modification: clinical significance and implementation of the 2013 ACC/AHA cholesterol guidelines. S D Med. 2014;67(8):320-323.

III. HYPERTENSION

A. Overview:

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.

B. Definition of HTN in the general population:

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

C. There is no evidence that a BP of 130/80 improves outcomes for the general population.¹³ Uncontrolled hypertension, however, can lead to graft loss, MI, HF, and stroke.

D. Definition of HTN—transplant population:

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.
- Current target BP goals include those shown in Table 6-2.¹³

E. Etiology in transplant recipients—general:

Pretransplant HTN
Pretransplant renal disease

Calcineurin inhibitors (CNI)¹⁴^,¹⁵^,¹⁶:

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
High body mass index (BMI), chart listed in Table 6-3.¹⁷
Smoking

F. Etiology in transplant recipients: organ specific:

Renal transplant recipients¹⁸^,¹⁹:

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

G. Clinical signs and symptoms of HTN (note: HTN is often asymptomatic):

Headache
Dizziness
Nosebleeds
Visual disturbances

H. Treatment options¹⁴^,²⁰:

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:

Antihypertensive agents are shown in Table 6-4 ¹³
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
Alpha2 agonists (e.g., clonidine)	↓ 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.

RAS¹^,²¹^,²²:
- 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.

IV. RENAL INSUFFICIENCY (RI)²¹^,²²

A. Overview:

Scope of problem: see Table 6-5 ²³^,²⁴^,²⁵^,²⁶

B. Etiology²²:

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:
- The degree of chronic kidney disease is staged from one to five (Table 6-6).²⁷
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

Kidney²³	Heart²⁴	Lung²⁵	Heart-Lung²⁵	Liver²⁶
According to the US Renal Data System report, renal graft failure carries a 4% annual rate	Cumulative prevalence: Abnormal Cr ≤2.5: 17%, 35%, and 40% at 1, 5, and 10 y posttransplant, respectively Abnormal Cr: >2.5 mg/dL: 6%, 12%, and 17% at 1, 5, and 10 y posttransplant, respectively	Cumulative prevalence: Abnormal Cr ≤2.5: 16%, 36%, and 40% within 1, 5, and 10 y posttransplant, respectively Abnormal Cr >2.5 mg/dL: 4%, 5%, 15%, and 20% within 1, 5, and 10 y posttransplant, respectively	Cumulative prevalence Cr ≤2.5: 12% and 32% within 1 and 5 y posttransplant, respectively	Cumulative prevalence Cr ≤2.5: 22% at 5 y
Cr, creatinine.
Messa P, Ponticelli C, Berardinelli L. Coming back to dialysis after kidney transplant failure. Nephrol Dial Transplant. 2008;23(9):2738-2742; 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; Weber ML, Ibrahim HN, Lake JR. Renal dysfunction in liver transplant recipients: evaluation of the critical issues. Liver Transpl. 2012;18:1290-1301.

TABLE 6-6 Definition and Stages of Chronic Kidney Disease

	Stages of Chronic Kidney Disease
GFR	Stage	Description
>90	1	Normal with ↑ GFR
60-89	2	Mild kidney disease
30-59	3	Moderate kidney disease
15-29	4	Severe kidney disease
<15	5	End-stage renal failure/dialysis
The number represents the stage of kidney disease. Kidney disease is defined as pathologic abnormalities found in tissues, blood, or imaging tests.
Adapted from The National Kidney Foundation. Kidney Disease Improving Global Outcomes Clinical Practice Guidelines For Chronic Kidney Disease: Evaluation, Classification And Stratification. Part 4: Definition And Classification Of Chronic Kidney Disease. Guideline 1: Definition And Stages Of Chronic Kidney Disease. Available at http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm

C. Risk factors for RI/CKD²⁸:

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

D. Posttransplant RI/CKD:

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.

E. Assessment³⁰^,³¹:

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)

F. Interventions:

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.
- Antihypertensive agents (see Table 6-4).¹³
- Screen for secondary causes: sleep apnea, primary aldosteronism, and RAS.
Aggressive treatment of hyperlipidemia

V. HYPERLIPIDEMIA

A. Overview³²:

Hyperlipidemia is a significant posttransplant problem (Table 6-7).²⁴^,²⁵^,³³^,³⁴^,³⁵

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.

B. Etiology: risk factors associated with hypercholesterolemia:

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.
- Effect of posttransplant medications on lipoproteins (Table 6-8)³⁵
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

C. Major consequences of posttransplant hyperlipidemia³⁸:

CVD
Chronic cardiac allograft vasculopathy (CAV)³⁹

D. Screening for posttransplant hyperlipidemia⁴⁰:

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

The underlying causes and secondary risks for ASCVD (Table 6-9)⁴⁰:

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.

E. Treatment: given the multifactorial etiology of hyperlipidemia, a multifaceted and individualized treatment strategy is imperative.⁴²

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
Drugs that affect lipid metabolism (Table 6-11).⁴⁰^,⁴⁴

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.
Additional risk factors associated with rhabdomyolysis include⁴⁵^,⁴⁷
- 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:

Up to 29% of patients who take statins report muscle aches, myalgias, or weakness.⁴⁶^,⁴⁷

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

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

↓ 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.

VI. METABOLIC SYNDROME¹⁰^,³⁷

A. Overeating and the development of obesity may lead to maladaptive cardiovascular and renal disease risk factors that include a cluster of conditions: hypertension, dyslipidemia, abdominal obesity, and insulin resistance.

Metabolic syndrome increases risk for heart disease, renal disease, diabetes, and stroke.⁴⁸

B. Closely related to “insulin resistance”—a condition in which the normal function of insulin is hampered. To rule in for the diagnosis of metabolic syndrome, the patient must have any three of the following risk factors:

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.

C. Definitions of metabolic syndrome (Table 6-12)⁴⁹:

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

D. Management of metabolic syndrome¹²^,⁴⁴:

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

VII. DIABETES MELLITUS

A. Overview:

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
Incidence of DM varies from 2% to 53% of all solid organ transplant recipients⁵²^,⁵³:
- 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 guidelines
  
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Tags: Core Curriculum for Transplant Nurses

Oct 27, 2018 | Posted by drzezo in NURSING | Comments Off

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