Posttransplantation Cardiovascular Disease

Posttransplantation Cardiovascular Disease

Phuong-Thu T. Pham

Phuong-Mai T. Pham

Phuong-Anh T. Pham

Hai V. Pham

Phuong-Chi T. Pham

Son V. Pham

Cardiovascular disease (CVD) is the most frequent cause of death with a functioning graft. Although kidney transplantation ameliorates cardiovascular (CV) risk by restoring renal function, it introduces new CV risks, including impaired glucose tolerance or diabetes mellitus, hypertension, and dyslipidemia due in part to immunosuppressive medication-related adverse effects. CV risk factors in kidney transplant recipients encompass both conventional and unconventional risk factors (summarized in Table 14-1). Treatment and management of selected CV risk factors are discussed.


  • Posttransplantation hypertension is common and is present in 50% to 90% of kidney transplant recipients. In one single-center study, ambulatory blood pressure (BP) measurements demonstrated that only 5% of kidney transplant recipients were normotensive (defined as BP <130/80 mm Hg).1

  • Hypertension is a risk factor for both CVD and kidney graft failure.

  • Risk factors for posttransplantation hypertension

    • Recipient-related factors

      • Preexisting hypertension

      • High body mass index or excess weight gain

      • Sodium intake after transplantation

      • Excess renin output from the native kidneys may play a contributory role in some patients. In kidney transplant recipients with severe hypertension refractory to medical therapy, bilateral native nephrectomy has been reported to ameliorate BP control.2

      • Note: In the immediate postoperative period, elevated BP may be due to hypervolemia, postoperative pain, high-dose corticosteroid, discontinuation of home antihypertensive medications, and/or anxiety. Overly aggressive BP lowering may increase the risk for acute tubular necrosis or delayed graft function and should be avoided. In the acute setting, a systolic BP <180 mm Hg is acceptable because blood flow to the newly transplanted kidney is dependent on an adequate mean systemic BP.3

      TABLE 14-1 Posttransplantation Conventional and Unconventional Cardiac Risk Factors



      Modifiable or potentially modifiable


      Modifiable or potentially modifiable





      Obesity or metabolic syndrome



      Family history

      Pretransplant diabetes

      Male gender

      History of pretransplant and posttransplant cardiovascular disease


      Posttransplant diabetes mellitus

      Left ventricular hypertrophy



      Vitamin D deficiency

      Cytomegalovirus infection

      Delayed graft function


      Dialysis vintage

      Recipient factors

      Prior acute rejection episodes

      Chronic kidney injury from any cause

      Preexisting coronary calcification

      Cardiac troponin T

      Posttransplant chronic kidney disease

      Donor factors (donor quality)

      Low albumin level

      Obstructive sleep apnea

      Prothrombotic state

      Low physical activity

      Increased inflammatory markers such as inflammatory cytokines, C-reactive protein

      Donor age

      Donor hypertension

      Donor recipient size mismatch

      Donor APOL1 gene polymorphism

      (may be associated with early graft dysfunction)

      Abbreviation: APOL1, apolipoprotein L1.

    • Immunosuppressive agents

      • Corticosteroids

      • Cyclosporine and, to a lesser degree, tacrolimus

    • Donor-related factors

      • Donor age, hypertension, and donor family history of hypertension

      • Donor factors associated with reduced graft function may indirectly increase posttransplantation hypertension risk (eg, donor apolipoprotein L1 [APOL-1] or CYP3A5 gene variants; the former is associated with early graft failure and the latter with calcineurin inhibitor [CNI] nephrotoxicity).4

    • Kidney allograft-related factors

      • Delayed graft function

      • Chronic allograft injury

      • Acute rejection episodes

      • Recurrent or de novo glomerulonephritis

      • Transplant renal artery stenosis

  • Management of posttransplantation hypertension should include

    • Identification and treatment of the underlying cause.

    • Lifestyle modifications and treatment of associated CV risk factors. Dietary approach is discussed in chapter 17.

    • Home BP monitoring may be invaluable in guiding therapy.

  • BP goal

    • The Kidney Disease Improving Global Outcome (KDIGO) guidelines suggest a BP goal of <130/80 mm Hg for kidney transplant recipients irrespective of the level of albuminuria (recommendations based solely on epidemiologic data).5

    • A BP goal <125/75 mm Hg for patients with proteinuria is of uncertain benefit.

  • Selection of antihypertensive agents

    • Currently available literature shows no conclusive evidence to suggest that one class of antihypertensive agent is superior to another in the transplant setting. Treatment should be individualized based on efficacy, tolerability, concomitant comorbidity, and drug-drug interactions with immunosuppressive agents. Examples6

      • β-Blockers

        • image Should be considered in patients with ischemic heart disease or atrial fibrillation with rapid ventricular rate

        • image Perioperative β-blocker use reduces coronary heart disease events in transplant candidates with history of coronary artery disease.

      • Nondihydropyridine calcium channel blockers

        • image Increase CNI blood levels and permit CNI dose reduction

        • image At the authors’ center, unless contraindicated, diltiazem is used in all kidney transplant recipients to boost CNI drug levels.

      • Diuretics

        • image Use in the early posttransplant period is beneficial in patients who are volume expanded.

        • image Thiazides may improve both hypertension and hyperkalemia commonly seen in CNI-treated kidney transplant recipients (CNIs have been shown to induce a Gordon-like syndrome via activation of thiazide sensitive channels at the distal convoluted tubules).

      • Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)

        • image May cause acute changes in renal function as well as hyperkalemia

        • image These agents are generally not started until allograft function is stable.

    • Randomized controlled trials in the general population demonstrated that ACE inhibitors, ARBs, β-blockers, and aldosterone receptor antagonists improve symptoms, reduce hospitalization, and/or provide survival benefit in chronic heart failure with reduced ejection fraction (HFrEF with ejection fraction ≤40%).7 Similar studies in the transplant settings are lacking. Limited studies in kidney transplant recipients demonstrated that renin-angiotensin-aldosterone blockade reduced CV events and ameliorated CNI-induced interstitial fibrosis and tubular atrophy.8 However, the favorable impact on patient and graft survival has not been consistently demonstrated.9

  • Potential advantages and disadvantages of different classes of antihypertensive agents in kidney transplant recipients are shown in Table 14-2.


  • Dyslipidemia is common after transplantation. Similar to the nontransplant settings, dyslipidemia is an important risk factor for coronary artery disease.

    TABLE 14-2 Potential Advantages and Disadvantages of Different Classes of Antihypertensive Agents

    Classes of drugs

    Advantages/beneficial effects

    Disadvantages/adverse effects

    Angiotensin-converting enzyme (ACE) inhibitors

    Angiotensin receptor inhibitors

    Beneficial in patients with proteinuria, DM, LVH

    Potential renoprotective and cardioprotective effects

    Beneficial in posttransplant erythrocytosis

    Potential worsening anemia

    GFR decline, hyperkalemia

    Aldosterone receptor blockers (eg, spironolactone, eplerenone)

    May improve outcome in patients with HFrEF. Data are lacking (see text).

    May improve blood pressure control in patients with difficult-to-treat hypertension

    Severe hyperkalemia when used in combination with ACE inhibitor or ARB, particularly in patients with poor kidney function

    α-Blockers (eg, prazosin)

    Beneficial in patients with benign prostatic hypertrophy or neurogenic bladder

    Orthostatic hypotension

    β-Blockers (eg, carvedilol, metoprolol, bisoprolol)

    Beneficial in patients with CAD or ischemic heart disease

    Blunting of hypoglycemic unawareness, erectile dysfunction, hyperlipidemia, bronchospasm, hyperkalemia (nonselective > selective β1-blockers)

    Calcium channel blockers (dihydropyridine: amlodipine, nifedipine)

    Amlodipine may be used in patients with HFrEF.

    Nifedipine, amlodipine (peripheral edema)

    Nifedipine (reflex tachycardia)

    Calcium channel blockers (nondihydropyridine: diltiazem, verapamil)

    Ameliorate CNI-induced vasoconstriction

    Increase CNI level, allowing CNI dose reduction: Diltiazem may permit CNI dose reduction by up to 40% and verapamil by 30%-50%.

    Increased risk of bradycardia when used with β-blockers (verapamil > diltiazem)

    Central α-agonist (eg, clonidine, methyldopa)

    Beneficial in patients with diabetic autonomic dysfunction


    Diuretics (loop and thiazide diuretics)

    Beneficial in patients who are volume expanded

    Thiazide may improve hyperkalemia commonly seen in CNI-treated patients. Its use may also increase BMD and decrease fracture risk (beneficial in osteoporosis).

    Hyperuricemia, gout

    Thiazides generally ineffective when GFR <30 ml/min/1.73m2

    Direct vasodilators (eg, hydralazine, minoxidil)

    Minoxidil: may be beneficial in difficult to treat hypertension

    Hydralazine/isosorbide dinitrate combination: may be beneficial in HFrEF among African Americans

    Minoxidil (peripheral edema, reflex tachycardia, hirsutism), hydralazine (lupus syndrome and anti-neutrophilic cytoplasmic antibody [ANCA] vasculitis)

    Abbreviations: ARB, angiotensin receptor blocker; BMD, bone marrow density; CAD, coronary artery disease; CNI, calcineurin inhibitor; DM, diabetes mellitus; GFR, glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; LVH, left ventricular hypertrophy.

  • Risk factors6

    • Immunosuppressive agents: Corticosteroids, the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus, and the calcineurin inhibitors cyclosporine and tacrolimus.

      • Of all immunosuppressive agents, tacrolimus has the least adverse effect on the lipid profiles whereas mTOR inhibitors are associated with the worst lipid profiles (particularly hypertriglyceridemia).

        • image CV risk has not consistently been shown to be higher in kidney transplant recipients treated with mTOR inhibitors compared with CNI-treated patients.

        • image The antiproliferative and cardioprotective effects of mTOR inhibitors and the reduction in CNI-related risk factors may offset the adverse effects of hyperlipidemia.

        • image Limited data in heart transplant recipients suggests that CNI to sirolimus conversion therapy may attenuate cardiac allograft vasculopathy (CAV) progression and CAV-related events compared with CNI continuation.10

    • Nonimmunosuppressive medications: β-blockers, diuretics

    • Others: diet, rapid weight gain, hyperinsulinemia, hypothyroidism, preexisting hypercholesterolemia, allograft dysfunction, proteinuria, genetic predisposition

  • Management of hyperlipidemia

    • Lipid goals for patients at risk for atherosclerotic CVD in the general population (2017 American Association of Clinical Endocrinologists and American College of Endocrinology)

      • Total cholesterol levels <200 mg/dL

      • Low-density lipoprotein cholesterol (LDL-C) levels

        • image LDL-C <130 mg/dL (low risk)

        • image LDL-C <100 mg/dL (moderate and high risk)

        • image LDL-C <70 mg/dL (very high risk)

        • image LDL-C <55 mg/dL (extreme risk)

      • Triglyceride (TG) levels <150 mg/dL

    • Kidney transplantation is regarded as a risk factor for coronary heart disease similar to other conventional cardiac risk factors. Hence, despite the lack of evidence-based recommendations, most transplant centers assess and treat dyslipidemias aggressively with lifestyle modification and statin therapy (or other lipid-lowering agents if intolerant or refractory to statin therapy).

    • Lifestyle changes play a critical role in CVD risk reduction and should not be overlooked. Heart-healthy diet, regular exercise, weight reduction or maintaining a healthy weight, and tobacco avoidance should be emphasized. Referral to a registered dietitian should be considered at the discretion of the clinician. Suggested Therapeutic Lifestyle Changes (TLC) diet for adults is discussed in chapter 17.

    • Adherence to lifestyle modification should be regularly assessed prior to or in conjunction with statin therapy (or other lipid-lowering agents).

    • Pharmacologic therapy

      • Statins

        • image In addition to their lipid-lowering effect, statins may protect against CVD via their antiproliferative and anti-inflammatory properties and ability to reduce circulating endothelin-1, C-reactive protein levels, systolic and diastolic BP, and pulse pressure.

        • image The clinical benefits of statins in the general population have been demonstrated in several large randomized controlled trials. There has been only one single prospective randomized trial in transplant recipients comparing statins (fluvastatin) with placebo—the Assessment of LEscol in Renal Transplantation (ALERT) trial11:

          • A prospective, multicenter, double-blind, placebo-controlled trial involving 2,102 renal transplant recipients with total cholesterol 4.0 to 9.0 mL/L.

          • Patients were randomized to receive either statin (fluvastatin) or placebo.

          • Primary end points: first occurrence of a major adverse cardiac event, defined as cardiac death; nonfatal myocardial infarction (MI) verified by hospital records; or coronary revascularization procedure, including coronary artery bypass graft or percutaneous coronary intervention

          • Results

            • ▲ Mean follow-up of 5.1 years

            • ▲ Fluvastatin lowered LDL-C concentrations by 32%.

            • ▲ Risk reduction with fluvastatin for the primary end point (risk ratio 0.83 [95% CI, 0.64-1.06], P = .139) was not significant, although there were fewer cardiac deaths or nonfatal MI (70 vs 104, risk ratio 0.65 [0.48-0.88] P =.005) in the fluvastatin group than in the placebo group.

            • ▲ Coronary intervention procedures and other secondary end points did not differ significantly between groups.

            • ▲ Further analysis demonstrated a beneficial effect of early initiation of fluvastatin on outcome. The earlier the initiation of therapy, the greater the reduction in cardiac events. Patients who received statin therapy within the first 4 years after transplantation had a risk reduction of 64% compared with 19% for those who received therapy after 10 years.

        • image Caution: The concomitant use of statins and CNIs, particularly cyclosporine, often results in a several-fold increase in statin blood level and an increased risk for myopathy and rhabdomyolysis. Rhabdomyolysis associated with tacrolimus and statin use is generally seen in patients on concomitant diltiazem therapy (see chapter 2 for drug-drug interactions).

      • Nonstatin therapy: ezetimibe

        • image Ezetimibe and statin combination therapy has been suggested to improve cholesterol control because of their complementary mechanisms of action. Ezetimibe blocks intestinal absorption of dietary cholesterol, whereas statin inhibits hepatic cholesterol synthesis.

        • image Study of Heart and Renal Protection (SHARP) trial12

          • Chronic kidney disease (CKD) patients were randomized to receive either simvastatin 20 mg plus ezetimibe 10 mg or placebo.

          • Statin and ezetimibe combination therapy conferred a 17% CV risk reduction compared with placebo at a median follow-up of 4.9 years.

        • image Limited studies suggest that statin and ezetimibe combination therapy is safe and effective in the treatment of dyslipidemia in kidney transplant patients who are refractory to statin therapy.13

        • image Currently available data do not support the routine addition of nonstatin drug to statin therapy for CVD risk reduction in the general population or in the transplant setting. However, based on the safety and efficacy data of ezetimibe use among CKD patients, ezetimibe may be used as second-line treatment option for high-risk kidney transplant recipients who are intolerant of statin or who are refractory to statin therapy.

      • Proprotein convertase subtilisin/kexin type 9 inhibitors

May 8, 2019 | Posted by in NEPHROLOGY | Comments Off on Posttransplantation Cardiovascular Disease

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