Patients with acute kidney injury (AKI) have a higher risk of short-term and long-term mortality and of chronic kidney injury and are also a significant healthcare burden.1–4 Sepsis is the trigger for AKI development in approximately 50% of critically ill patients.5 Sepsis-induced AKI increases mortality from sepsis by 50–60% and also extends intensive care unit (ICU) stay.6 The pathophysiology of septic AKI, although not as yet firmly established, is considered to be different from AKI of other aetiologies. In response to a drop in blood pressure, circulating angiotensin I, under the action of the angiotensin-converting enzyme (ACE), is hydrolysed to angiotensin II, which causes systemic micro-artery contraction, increased peripheral resistance and raised blood pressure. Thus, the renin-angiotensin-aldosterone system could play a key role in sepsis-related AKI.7

Renin-angiotensin system blockers, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are frequently used in clinical practice.8 Since angiotensin II constricts efferent arterioles in glomeruli, ACEIs cause efferent arteriolar dilatation. This action mechanism might be hazardous in clinical situations where kidney blood flow is prone to decrease, resulting in further drops in intra-glomerular pressure and the glomerular filtration rate. While ACEIs are known to slow down the progression of chronic kidney disease, their role in AKI remains controversial. Studies of ACEIs and ARBs as used by surgery patients have reported disparate findings.9,10 Some have demonstrated an increased risk for postoperative AKI, others a decreased risk and others no impact on the risk. In sepsis in particular, the use of ACEIs and ARBs has been identified as contributing to the development of AKI.11 Thus, National Clinical Guideline Centre recommendations for AKI include temporarily suspending ACEIs and ARBs in adults with sepsis until clinical condition has improved and stabilised.12 However, the role played by ACEIs and ARBs in long term kidney function recovery has not been extensively evaluated.

The aim of this study was to assess the association of ACEI and ARB use prior to a septic shock episode with development, prognosis and long-term recovery from AKI.

Exposure to ACEIs/ARBs prior to septic shock episodes is associated with AKI development and severity but has no influence on ICU and hospital survival and on kidney function recovery after sepsis resolution.

This is, to our knowledge, the first study that evaluates the association of ACEIs/ARBs not only with AKI development but also with longer-term kidney function recovery in patients with septic shock. The use of ACEIs/ARBs affects kidney injury in septic patients because they are known to decrease intraglomerular pressure. This action mechanism is potentially hazardous in cases of severe sepsis and septic shock where renal blood flow tends to decrease, resulting in further reductions in intraglomerular pressure and GFR.20,21

Our finding that use of ACEIs/ARBs prior to ICU admission was associated with a doubled risk of AKI development in patients with sepsis corroborates the findings of previous studies.11,22 Both Plataki et al.11 and Suh et al.22 found ACEI/ARB use to be an independent risk factor for AKI development in patients with sepsis, for OR=1.88 and OR=2.06, respectively. However, we observed no significant differences in 1-month and 3-month creatinine levels in relation to ACEI/ARB exposure. Furthermore, previous use of ACEIs/ARBs did not affect kidney function recovery and did not extend the recovery period.

We observed no association of ACEIs/ARBs with clinical outcomes (ICU or hospital survival), contrary to Mortensen et al., who found angiotensin II receptor blocker exposure previous to sepsis episodes to be associated with a halving of the 30-day mortality rate.23 Our study, however, is not directly comparable because of differences in population characteristics and survival outcomes.

The role of the renin-angiotensin-aldosterone system in sepsis is unclear. Some studies have reported an association between high angiotensin II levels and organ failure and mortality24 and a more recent study has found low serum levels of angiotensin II and angiotensin-converting enzyme to be associated with worse outcomes.25

The causal link between sepsis and AKI is extensively established.26–29 Sepsis is the trigger for the development of approximately 50% of cases of AKI among critically ill patients and sepsis-related AKI is associated with sepsis mortality rates of up to 50–60%, depending on severity.30 This study reports a rate for KDIGO-defined AKI of 80.8% (312 of 386 patients with septic shock), a rate consistent with the previous data. An observational cohort study of 390 patients with septic shock in a single-centre ICU reported that some 2 out of 3 patients developed AKI.11 In a recent retrospective multicentre study of 4532 patients with septic shock from Canada, USA and Saudi Arabia, a similar percentage of patients (77.6%) developed AKI.31

In our study, septic AKI was more prevalent in older and male patients. The impact of demographic factors on septic AKI development is uncertain. Two studies showed that age was a risk factor6,22 for AKI onset, whereas Plataki et al.11 found no significant differences in age between patient groups with and without AKI. Whether there is a predisposition for men to develop AKI is also unclear. In our study, being male was a risk factor for AKI development, a finding corroborated by that of a German study that reported male predominance in the development of AKI in patients with severe sepsis and septic shock.29 In contrast, no significant differences were observed between the sexes in two other studies.6,22

The negative impact of septic AKI on survival is unquestionable.27,29 The presence of AKI in our population of septic shock patients was associated with tripled ICU and hospital mortality rates. Note that the global mortality rates observed in our study (16.8% ICU and 23.8% hospital) are noticeably lower than those reported by other studies of patients with septic shock and AKI6,29 – possibly explained by the implementation of a surviving sepsis campaign during the study period.32

The pathophysiology of septic AKI is not completely understood. Recent evidence suggests that septic AKI may represent a unique form of AKI with a distinct pathophysiology. Although AKI is often considered a haemodynamic disease resulting from renal ischaemia, inflammation and apoptosis have been implicated in its pathogenesis in septic patients.33 Our results support the role of hypoperfusion in the pathogenesis of septic AKI. Our patients with septic AKI had significantly higher lactate levels and lower mean arterial pressure rates on ICU admission. Nonetheless, a resuscitation protocol focused on maintaining adequate tissue perfusion with haemodynamic support failed to reduce AKI development. We thus observed no significant differences between the patients with and without sepsis AKI with respect to the number of EGDT goals achieved and compliance with the whole package. Our finding corroborates the results of a recently published paper.34 Moreover, three randomized controlled trials conducted in the USA, Australia/New Zealand and England showed that EGDT compared with standard care did not significantly decrease mortality in patients with septic shock.35–37

The main limitation of the study is that, as a single-centre observational study, its findings cannot be generalized. Also, we had no data on dosages and length of exposure to ACEIs/ARBs and so cannot dismiss the potential effects of these factors on our results. In addition, we evaluated together the potential effect of both, ACEIs and ARBs, and for that reason it cannot be determined to which of the two study drugs in particular corresponds the effect found. Neither did we evaluate the potential effects of other nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs or iodinated contrast or clinical factors like diabetes mellitus, which could also contribute to AKI development. Finally, another limitation is the possibility of temporal trends in AKI biasing our results. During the study period a surviving sepsis campaign with accompanying guidelines was implemented in our hospital, but variability in compliance could have influenced AKI development and, in particular, mortality. We believe this source of bias to have been small because we found no differences regarding the number of EGDT goals achieved and compliance with the whole package. EGDT reflects the quality of resuscitation and is the factor that potentially could have most biased our results.

In this cohort study, use versus non-use of ACEIs/ARBs before septic shock episodes was associated with AKI development and severity, but did not affect ICU and hospital survival rates or kidney function recovery after sepsis resolution. Large, multi-centre randomized trials are needed to provide information on optimal ACEI/ARB use in relation to sepsis and AKI.

The authors declare no conflict of interest.