Transplant Complications: Noninfectious Diseases



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 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 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


HgbA1c <7%


HgbA1c <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; HgbA1c, hemoglobin A1c; 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:



  • 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 6-413


    • 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.




  • 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:


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 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 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 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: 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 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.




    • 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: 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


          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.


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:

Oct 27, 2018 | Posted by in NURSING | Comments Off on Transplant Complications: Noninfectious Diseases
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