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.1 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.2 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 angiotensin‐converting 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.3, 4 In this latter condition, a persistent increase in serum creatinine was found in up to 10% of patients treated with an ACE inhibitor.4

In this issue of the Journal of Clinical Hypertension, Chaumont and colleagues5 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 m². 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 m². 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 low BP 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.6 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 m² to 40 mL/min/1.73 m². 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 colleagues7 have demonstrated in patients with congestive heart failure that switching from captopril, a short‐acting 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 or to prescribe a short‐acting inhibitor. This is the main reason why low‐dose ACE inhibitors were developed for heart failure and why it is strongly recommended to reduce the doses of ACE inhibitors when renal function declines, eg, in patients with chronic kidney disease and elderly patients. Surprisingly, in the study by Chaumont and coworkers, 45% of patients taking ACE inhibitors were overdosed at the time of admission, suggesting that the message definitely needs to be reactivated.5

Chaumont and colleagues recommend using ARBs rather than ACE inhibitors in patients with a low GFR and an increased risk of AKI. Is the risk of AKI really significantly lower with ARBs than with ACE inhibitors? The largest comparison between an ACE inhibitor and an ARB was made in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET),8 which compared ramipril with telmisartan and the combination of both in patients with high cardiovascular risk. In this study, the risk of developing an acute renal event such as the need for acute dialysis was comparable with the ACE inhibitor and the ARB and was significantly increased only when both drugs were combined.9 Thus, although ARBs and ACE inhibitors differ in their elimination pathways and also in their impact on other hormonal systems, their functional effects on the kidneys are not substantially different, at least as far as the risk of AKI is concerned. In a recent meta‐analysis of randomized controlled trials including 113,386 patients older than 65 years receiving an ARB‐based treatment or a control treatment, the use of ARBs was associated with a 48% increase in risk of AKI and a 56% higher risk of developing hypotension.10 Thus, one would rather suggest applying similar recommendations of prudence with the use of ACE inhibitors and ARBs in patients with low baseline BP, volume depletion, and/or dehydration. Temporary withdrawal of RAS blockers may be warranted in these situations to prevent the development of AKI. Diuretics, which are strong activators of the RAS, should also be withheld in order to restore an effective blood volume. Whether RAS blockers should actually be maintained in elderly patients with advanced renal diseases remains controversial.11

Interestingly, the clinical characteristics of the patients enrolled in Chaumont's study were quite similar to those of a subgroup of the recently published Systolic Blood Pressure Intervention Trial (SPRINT), ie, age older than 75 years, chronic kidney disease, high cardiovascular risk, and multiple drug treatments including a RAS blocker and diuretics.12 In SPRINT, reaching the systolic BP target of <120 mm Hg was associated with a significant increase in renal outcomes including AKI. Thus, the hazard ratio for AKI or acute renal failure was 66% higher in the intensive treatment group and the hazard ratio for a serious adverse event or an emergency visit due to AKI was 71% higher in the low BP group. The increased risk of AKI was associated with greater use of RAS blockers and diuretics. These observations suggest that even though all‐cause mortality was significantly reduced in the intensive treatment arm, there may be a consequent price to pay with a significantly higher risk of AKI and hospitalizations when targeting a BP <120 mm Hg. Since SPRINT was terminated earlier than expected, the real impact of the increased incidence of AKI is certainly underestimated. Thus, in the future, a careful observation of the change in AKI incidence would be necessary if a lower target BP were to be proposed for all hypertensive patients with an increased cardiovascular risk including elderly and chronic kidney disease patients.

In conclusion, AKI is not an uncommon complication in patients treated with an ACE inhibitor or an ARB. ARBs may indeed be easier to handle in patients with reduced renal function because the doses do not need to be adapted as GFR declines. Nonetheless, physicians should always be careful with this class of agents in situations of low BP, hypovolemia, or dehydration and especially in elderly patients. They should inform their patients that RAS blockers and diuretics should be withdrawn temporarily if they cannot maintain adequate hydration in order to avoid acute kidney injury.

Disclosure

The author has no conflict of interest to disclose.