Blockade of the Renin‐Angiotensin System and the Risk of Acute Kidney Injury

The renin-angiotensin system (RAS) is a cardinal regulator of systemic blood pressure (BP) and renal function. This central role is mediated by the main effector hormone generated by the RAS cascade, ie, angiotensin II (Ang II), which has multiple physiological effects on the vascular wall, the heart, the kidney, the brain, the immune system, and other neurohormonal systems such as the sympathetic nervous system, nitric oxide, and endothelin. In the kidney, Ang II regulates the glomerular filtration rate (GFR), modulating the tonus of renal afferent and efferent arterioles as well as that of glomerular mesangial cells. In addition, the influence of Ang II on the tubular transport of sodium and potassium contributes to the maintenance of fluid and electrolytes balance. Today, blockade of the RAS with angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is a well-accepted and effective approach for the management of patients with essential hypertension or a high cardiovascular risk but also for congestive heart failure, diabetes nephropathy, or chronic kidney diseases. In these indications, RAS blockade has been shown to either reduce mortality or to retard disease progression. However, owing to the important vascular and renal properties of Ang II, it is not surprising that in some circumstances, RAS blockade is associated with the occurrence of untoward side effects such as marked hypotension or the development of acute kidney injury (AKI). Thus, in the early development of the concept of RAS blockade, acute deteriorations of renal function and/or falls in BP were observed both experimentally and clinically, whenever BP and GFR were Ang II-dependent. This was the case, for example, in patients with severe renal artery stenosis or diffuse renal vascular sclerosis but also in elderly patients with congestive heart failure. In this latter condition, a persistent increase in serum creatinine was found in up to 10% of patients treated with an ACE inhibitor. In this issue of the Journal of Clinical Hypertension, Chaumont and colleagues present the results of their retrospective analysis of the association between the use of ACE inhibitors and ARBs and the occurrence of AKI in an emergency setting. To this purpose, they collected data of all patients admitted to the emergency department with an estimated GFR <45 mL/min/ 1.73 m. Of 1897 patients, they included 324 patients with a full data set including a value of serum creatinine before admission to the hospital. The mean age of these patients was 77 years and their mean GFR was 35 mL/min/1.73 m. Forty percent of these patients developed AKI. In the univariate analysis, the use of more than three antihypertensive drugs, a low BP, and dehydration as well as sex and younger age were risk factors for acute renal impairment. However, after stepwise regression analysis, only the use of ACE inhibitors and dehydration were independently associated with the occurrence of AKI. Surprisingly, the use of ARBs was not found to be a risk factor. Because kidneys essentially eliminate ACE inhibitors, the authors focused their analysis on the possible overdosing of ACE inhibitors as a cofactor for the aggravation of renal function. They indeed found that 45% of ACE inhibitor–treated patients were overdosed at the time of admission, suggesting that dosages of these drugs were not adapted according to the level of renal function as recommended. The authors’ data suggest that this might have aggravated the patients’ clinical picture and prolonged their hospital stay. In addition, overdosing was very rare with ARBs, which are cleared by the liver. The finding that the use of RAS blockers is associated with the development of AKI in the emergency department is not a real surprise. Nonetheless, three aspects of this publication deserve comments: the first is the impact of ACE inhibitor dosing in patients with chronic kidney diseases, the second is the astonishing absence of risk of AKI associated with the use of ARBs, and the third is the strong interaction between RAS blockers, diuretics, and dehydration and the role of lowBP as risk factors for AKI. As mentioned earlier, the kidneys eliminate the majority of ACE inhibitors and few of them such as fosinopril and trandolapril have a dual renal and hepatic route of elimination. Therefore, it is recommended to reduce the dose or to increase the dosing interval of ACE inhibitors when the GFR is <30 mL/min/1.73 m to 40 mL/min/1.73 m. The use of higher doses of ACE inhibitors not only increases the intensity of RAS blockade but also the duration of the blockade. A prolonged duration of RAS blockade may have an important impact on renal function. Indeed, Packer and colleagues have demonstrated in patients with congestive heart failure that switching from captopril, a shortacting ACE inhibitor, to enalapril, a longer-acting inhibitor, results in an increased incidence of acute renal failure. Therefore, in high-risk situations, physicians have the option to reduce the ACE inhibitor dose Address for correspondence: Michel Burnier, MD, Service of Nephrology and Hypertension, CHUV, Rue du Bugnon 17, 1011 Lausanne, Switzerland E-mail: michel.burnier@chuv.ch