Renin angiotensin system blockade and acute kidney injury: Risks and benefits

ACHAIKI IATRIKI | 2020; 39(3): 133–136


Marios Papasotiriou1, Vasileios Zavvos2, Evangelos Papachristou1

1Department of Nephrology and Kidney Transplantation, University Hospital of Patras, Patras, Greece
2Center for Diagnosis, Treatment & Research on Kidney Diseases, Hygeia Hospital, Athens, Greece

Received: 30 March 2020; Accepted: 6 July 2020

Corresponding author: Marios Papasotiriou, Department of Nephrology and Renal Transplantation, University Hospital of Patras, Patras, Greece, Tel.: +30 2613 603986, Fax: +30 2610 994424, E-mail:

Key words: ACE inhibitors, angiotensin receptor blockers, acute kidney injury, RAS blockers


Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is recommended as a first-line therapy for the reduction of proteinuria, slowing progression of chronic kidney disease (CKD), and reducing cardiovascular risk, with clear benefits proven through a series of large, well-designed clinical trials [1]. In CKD, RAS blockade is recommended even in the absence of hypertension, because its reno- and cardioprotective effects are, at least in part, independent of blood pressure (BP) reduction. In general, the effects of ACEi or ARBs on hypertension and proteinuria are dose-dependent, while their use should be continued beyond CKD stage 4 [estimated glomerular filtration rate (eGFR): 15-29 ml/min/1.73 m2] [2, 3]. Nevertheless, during intercurrent illness, patients with CKD are vulnerable to drug side effects, particularly hyperkalemia and acute kidney injury (AKI) [4]. For this reason, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that in patients with eGFR below 60 ml/min/1.73 m2 (CKD stages G3a to G5) who have serious intercurrent illness, potentially nephrotoxic and renally excreted drugs should be temporarily discontinued (including ACEi/ARBs, aldosterone inhibitors, direct renin inhibitors, diuretics, nonsteroidal antinflammatory drugs, metformin, lithium, and digoxin) [5].

ACEi and ARBs cause vasodilation of the efferent glomerular arteriole, further reducing intraglomerular pressure already compromised by their BP-lowering effect. Therefore, in patients with renal parenchymal disease, ACEi and ARBs can cause mild or even severe reduction in GFR. When serum creatinine increases more than 30% above the baseline value, 5-7 days after the initiation of ACEi or ARBs, certain co-morbidities should be suspected (bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, diffuse intrarenal small-vessel disease or generalized volume depletion) and the drugs should be discontinued. In an observational Canadian database study that included more than 63,000 patients who were prescribed a RAS blocker, use of RAS blockers increased the risk of AKI independent of common confounding variables. After adjustment for confounders though, the risk fell away and became non-significant for moderate and severe AKI. However, in patients who had RAS blockers prescribed without an evidence-based indication, the risk of AKI remained greater [6]. Another important aspect is ACEi and ARBs induced hyperkalemia, due to reduced potassium excretion [7]. Hyperkalemia within the first year of ACEi/ARB therapy is relatively uncommon among people with eGFR >60 mL/min/1.73 m2, but rates are much higher with lower eGFR [8]. According to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, when serum potassium levels are between 5.1 and 5.5 meq/l, measures must be taken to lower K+ concentration when initiating RAS blockers [9]. This threshold is even lower according to the National Institute for Health and Care Excellence (NICE) and American Heart Association (ACCF/AHA) guidelines which recommend against initiating RAS blockers unless serum K+ concentration is less than 5 meq/l [8-10]. Moreover, hyperkalemia (serum K+ >5.5 meq/l) following the initiation of ACEi or ARBs will lead to discontinuation or down-titration of the drug. Combined administration of ACEi and ARBs is not indicated for the treatment of hypertension as it is associated with an increased risk of hyperkalemia, hypotension, and impaired renal function compared to either class of RAS blocking agent alone especially in diabetic patients, while it offers no benefit regarding mortality or end stage renal disease  [11-13]. In addition, dual RAS blockade is associated with an increased risk of AKI especially in patients with diabetes compared to monotherapy.  However, it is important to note that in the prospective, randomized VA NEPHRON-D study, AKI in the setting of RAS blockade monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of kidney progression compared to dual therapy. This finding probably emphasizes the hemodynamic nature of AKI in the latter group as opposed to more severe underlying disease burden in the former group of patients [14].

Although initiation of RAS blockade can lead to an acute decrease in GFR, recent studies suggest that this does not reflect true tubular injury [15]. From a pathophysiological standpoint, RAS blockade promotes greater vasodilation of efferent arterioles over afferent arterioles which in turn leads to reduced intraglomerular pressure, subsequent decreased glomerular filtration, and impaired capacity for autoregulation of GFR [16]. Impaired autoregulation makes the kidney prone to GFR decline following minor physiologic and hemodynamic insults such as BP reduction or volume depletion. However, the accompanying improvement in tubular blood flow and oxygenation reduces progression of tubulointerstitial fibrosis and thus progression of CKD. Clinical evidence to support this notion were shown in a subgroup analysis of the SPRINT trial where participants who were randomized to the intensive BP lowering arm had reductions in GFR due to lower achieved BP, but at the same time did not have elevated levels of tubular-injury biomarkers compared to those in the standard arm [15]. Therefore, it is essential that all physicians, from primary care providers to tertiary centers, must be able to distinguish true AKI with intrinsic tubular injury from just a clinically insignificant hemodynamic eGFR decline attributed to RAS blockade with no true kidney damage so as to avoid interrupting treatment in the latter case [17].

Recurrent AKI is a common event after hospitalization complicated by AKI. In a retrospective cohort study with more than 38,000 hospitalized patients with AKI, analyses showed that older age, lower eGFR, proteinuria and anemia are associated with recurrent AKI. Comorbidities including heart failure, acute coronary syndrome, diabetes, and chronic liver disease, are also predictors of a recurrent AKI episode. Those who had more acute illness during the initial hospitalization were more likely to have recurrent AKI, but greater AKI severity was not independently associated with increased risk for recurrent AKI. Most importantly, this study showed in multivariate analysis that recurrent AKI was associated with an increased rate of death (HR, 1.66; 95% CI, 1.57-1.77) [18]. In a closer look though, conditions that are predictors of recurrent AKI like diabetes and coronary disease, are also first-class indications for RAS blocker therapy.

How to best medically manage patients who survive hospitalized AKI is unclear, as the use of RAS blockers in this setting may increase the risk of recurrent AKI. To address this question, Hsu et al. included more than 10,000 patients who experienced AKI and survived in a cohort study in Northern California. In this study though, patients with heart failure or prior use of ACEi or ARBs during the preceding 5 years were excluded. Forty-seven percent of the study population had a documented eGFR < 60 ml/min/1.73 m2 or documented proteinuria before hospitalization. With a median follow-up of 3 years, 1,853 (18%) patients were administered ACEis/ARBs and 2,124 (21%) patients experienced recurrent AKI. Crude rate of recurrent AKI was 6.1 (95% CI, 5.9 to 6.4) per 100 person-years off ACEis/ARBs and 5.7 (95% CI, 4.9 to 6.5) per 100 person-years on ACEis/ARBs. Overall, the adjusted (for baseline and potential time-dependent confounders) analysis of these patients concluded that exposure to ACEi/ARB use was not associated with higher incidence of recurrent AKI (adjusted odds ratio, 0.71; 95% CI, 0.45 to 1.12) [19]. Another study from Brar et al. addressed the question of RAS blockade re-initiation after AKI and its potential risks. In this retrospective cohort study that included 46,253 adults, the authors evaluated whether the use of ACEis or ARBs after hospital discharge is associated with better outcomes in patients with AKI. Within 6 months since hospital discharge, 22,193 (48.0%) of the participants were prescribed an ACEi or ARB and their use was associated with lower mortality after 2 years (adjusted hazard ratio, 0.85; 95% CI, 0.81-0.89) while no association was found between ACEi or ARB use and progression to end stage renal disease (ESRD). This finding was true both for patients with a new onset and resumption of treatment. Nevertheless, this came at the cost of a higher risk of hospitalization for a renal cause (adjusted hazard ratio, 1.28; 95% CI, 1.12-1.46) [20].

Overall, on the basis of large observational studies, there is evidence that RAS blockade even after an event of AKI is indeed associated with favorable outcomes in terms of slowing future loss of kidney function and reducing risk of cardiovascular disease events and all-cause death despite a higher risk of (re-)hospitalization. Are patients from all age groups and degrees of frailty candidates for initiation or re-initiation of RAS blockage after an AKI event and, more importantly, when exactly such a therapy should be reconsidered? It seems from the study of Hsu et al. that patients even in the >60 years age group benefit from RAS blockade which should be initiated no prior tο 3 months after an AKI episode [19]. Thus, available evidence suggests that the risk-benefit profile supports the use of ACEi or ARBs in these patient groups and health care providers should be less hesitant to prescribe. Nevertheless, this should be applied only to patients with evidence-based indications for RAS blockade therapy, starting at low doses and carefully up-titrating with close monitoring of kidney function.

Conflict of interest disclosure

None to declare

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