Renin-angiotensin system inhibitors in kidney transplantation: a benefit-risk assessment.

thiazide-sensitive Na-Cl cotransporters that is enhanced by the WNK and SPAK kinases. In normal subjects, calcineurin can inhibit the activity of WNK and SPAK through its phosphatase activity, but the regulatory activity of calcineurin can be inhibited both by tacrolimus and cyclosporine [2, 3], so explaining the volume expansion in CNI-treated transplant recipients. Therefore, post-transplant hypertension can be considered as a sodium dependent hypertension, associated with an increase of peripheral vascular resistances. What treatment should be used in kidney transplant recipients with hypertension? One may argue that, considering the pathogenesis of hypertension in kidney transplantation, a direct vasodilatory drug and a thiazide diuretic should represent the preferred agents to lowering blood pressure. As a matter of fact, calcium channel blockers (CCBs) are considered the agents of choice in this setting, not only because of their strong anti-hypertensive effects but also because they can reduce the rate of delayed graft function, and can improve GFR and renal allograft survival in comparison to placebo or no treatment [4]. However, the nondihydropyridine CCBs diltiazem and verapamil and the dihydropyridine nicardipine should be used with caution, since they can significantly increase the blood levels of CNI, an effect that has been exploited to reduce the dose and, consequently, the cost of CNIs, especially in low-income countries. On the other hand, CCBs can cause peripheral edema, and in combination with cyclosporine may worsen gingival hyperplasia, and cause constipation or gastro-esophageal reflux as a result of smooth-muscle relaxation. Since hypertension in renal transplant recipients is often difficult to control, a multi-drug regimen is often employed to reach the clinical target of <130/80 mmHg. Taking into account the volume expansion that is caused by CNIs through their direct and indirect effect on renal Arterial hypertension is frequent in kidney transplant recipients and may lead to severe complications, including cardiac failure, pulmonary edema, myocardial infarction, stroke, cardiac arrhythmia, and progressive deterioration of allograft function. The pathogenesis of post-transplant hypertension is multifactorial. Apart from patients who are already hypertensive before transplantation, blood pressure can be increased by the use of calcineurin inhibitors (CNIs), corticosteroids, renal graft insufficiency, renal artery stenosis, and older age of the donor [1]. Currently, there is general agreement that the main factor responsible for post-transplant hypertension is the prolonged use of CNIs. These drugs can induce hypertension by several mechanisms. First of all, CNIs can induce an important renal and systemic vasoconstriction by increasing the sympathetic nervous activity and the ratio between vasoconstrictive molecules (e.g., angiotensin II and endothelin) and vasodilating molecules (e.g., nitric oxide and prostacyclin). The resulting vasoconstrictive effect on afferent preglomerular arterioles decreases the glomerular filtration rate (GFR) and natriuresis leading to salt and water retention. Secondly, CNIs act directly on tubular cells by increasing sodium-chloride (Na-Cl) reabsorption, which ultimately leads to further volume expansion and arterial hypertension. This is accomplished through the overexpression of