1. What are the risk factors for cardiovascular disease (CVD) in patients receiving a kidney transplant?

See Table 61.1 .

2. Are statins beneficial in patients receiving kidney transplant?

Statins are the treatment of choice, and studies show there is a benefit to using them in the kidney transplant population. The incidence of dyslipidemia is high in kidney transplant patients secondary to immunosuppressive medications, proteinuria, transplant dysfunction, and the higher incidence of metabolic syndrome and new-onset diabetes after transplant. Various trials have shown improved cardiovascular outcomes with the use of lipid therapy in patient with chronic kidney disease. The Assessment of Lescol in Renal Transplantation (ALERT) study aimed to see if statin therapy reduced the primary outcome of a major cardiovascular event, including cardiac death or a cardiac intervention. The trial did not reach this primary end point due to insufficient power but did show a reduction in nonfatal myocardial infarctions. In the extended follow-up of ALERT participants, the incidence of major adverse cardiac events was reduced in patients treated with statin; however, there was no difference in patient mortality or allograft function. A Cochrane Database review stated that statins may reduce cardiovascular events in kidney transplant patients. However, statin treatment had no clear benefit in affecting overall mortality, stroke rate, kidney function, and toxicity outcomes in kidney transplant patients.

Statin use is associated with decreased proteinuria, decreased C-reactive protein, and decreased interstitial fibrosis incidence in transplant protocol biopsies, all which may confer additional benefit.

3. Which patients should be started on a statin post transplant?

If a patient is younger than 30 years without established atherosclerotic cardiovascular disease (ACVD) or diabetes, then based on the benefit-to-risk ratio, the patient can start a statin. Ideally all kidney transplant patients older than 30 years should be considered for a statin.

4. How do we monitor lipid levels?

Patients should have an initial lipid profile checked. The American College of Cardiology recommends follow-up in 4 to 12 weeks for compliance and then at least yearly lipid profile checks. Kidney Disease Improving Global Outcomes (KDIGO) guidelines differ in that they do not require to repeat lipid profiles, because the indication for treatment is the higher cardiovascular risk, not the low-density lipoprotein (LDL) level.

5. What are the goals of lipid lowering therapy?

In the general population, target goals for the lipid profile have been replaced by the aim of therapy being to reduce ACVD risk. As mentioned earlier, KDIGO guidelines follow with this. However, although the KDIGO guidelines do not require repeat lipid profiles, it might be prudent to recheck a lipid profile after statin therapy to confirm compliance, response to therapy, and reevaluation ACVD risk.

6. Are there any risks of statin use in transplant recipients?

Yes. Most statins are metabolized by the same cytochrome P450 system (CP3A4) as calcineurin inhibitors (CNIs). As a consequence, CNIs (particularly cyclosporine) may accumulate in plasma and may be associated with a greater frequency of rhabdomyolysis. Data on tacrolimus are sparse, although pharmacokinetic studies on concomitant atorvastatin and tacrolimus therapy did not demonstrate significant interactions. Fluvastatin and pravastatin may be safer because they are metabolized through non-CP3A4 mechanisms. Fluvastatin, pravastatin, rosuvastatin, simvastatin, and atorvastatin have all been used in kidney transplant patients. These patients should be closely monitored for side effects from statin therapy. It is important to note that cyclosporine inhibits the metabolism of statins, and so the statin dose is usually kept low and not aggressively titrated up.

7. What are the causes of hypertension (HTN) in patients who have undergone kidney transplant?

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  Primary HTN

  
  
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  Secondary HTN related to native kidneys

  
  
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  Recipient factors, including male gender, genetic profile, metabolic syndrome, and diabetes

  
  
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  Donor factors, inducing HTN history, age, allograft quality, and donor-recipient size discrepancy

  
  
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  Immunosuppression in particular CNIs

  
  
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  Kidney allograft dysfunction

  
  
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  Allograft vascular compromise

  
  
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  Obstructive sleep apnea

  
  
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  Kidney artery stenosis

8. What is the optimal blood pressure medication for kidney transplant recipients?

Because there is no evidence that a particular class of antihypertensive agents is more effective than other classes, the choice of medications should be individualized and based on various comorbidities. Calcium channel blockers (CCBs) are an attractive first-line agent, mainly because they counteract the vasoconstrictive effects of CNIs. CCB use may cause untoward effects, particularly nondependent edema and worsening proteinuria. In addition, CNI doses may need reduction with the use of nondihydropyridine CCBs.

The use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) in kidney transplant recipients is safe. However, the effectiveness has been questioned. Hiremath et al. performed a meta-analysis of eight trials involving a total of 1502 patients, with only two trials going beyond 5 years. The study did not show an improvement in kidney outcomes. Other studies have shown the use of ACE inhibitors/ARBs has been associated with prolonged allograft and patient survival. In summary, ACE inhibitors/ARBs should be used thoughtfully, weighing the pros and cons in the transplant patient.

Because the combination of afferent arteriolar vasoconstriction from CNI and efferent arteriolar vasodilation as a result of renin-angiotensin system (RAS) blockade can predispose to acute kidney injury, we routinely advise our patients to discontinue their ACE inhibitors/ARBs if they are acutely ill and at risk for volume depletion. In addition, we advise postponing the addition of RAS blockers until 3 months post transplantation to avoid superfluous kidney biopsies.

Beta blockers should be considered in all kidney transplant patients with CVD. Diuretics can be used to control volume-mediated HTN and to enhance the antihypertensive effects of ACE inhibitors/ARBs. These drugs help with volume control and augment urine output. Thiazide-type diuretics are particularly effective at countering CNI-induced hyperkalemia. Alpha-1 blockers and centrally acting agents may be necessary to achieve blood pressure goals.