Contrast induced acute kidney injury and the role of beta-blockers in its prevention

Contrast-induced acute kidney injury (CI-AKI) is a well-known plight after diagnostic or interventional procedures requiring iodinated contrast media. It is actually the third cause of renal breakdown in hospitalized patients, and an everyday concern for procedures with high contrast use like coronary angioplasty (1).

In the last setting the risk of CI-AKI is independently associated with baseline comorbidities: chronic kidney disease (CKD), impaired left ventricular systolic function, anaemia, diabetes, acute coronary syndrome (ACS) presentation and hemodynamic instability (2-4). According to the patient risk profile, the risk of AKI may range from less than 3% in low-risk patients with normal renal function (i.e., eGFR >45 mL/min/1.73 m²) who undergo an elective procedure (5) to >10–30% in patients presenting with acute myocardial infarction (AMI) (6-9). When AMI is complicated by cardiogenic shock, AKI prevalence increases to more than 50% of the patients (10).

Recognizing the patients with the higher risk of developing this complication is therefore mandatory, in order to set up in good time the best preventive manoeuvres. This fact is so important because CI-AKI is not only deleterious for the kidney per se, but because it has been independently associated with short- and long-term risk for death and major adverse cardiovascular events (MACE) and with 30-day major bleeding (11,12): it increases the risk of mortality up to 20% and sometimes leads to permanent impairment of renal function (11,13,14). Over the simple but essential evaluation of serum creatinine levels (and estimated glomerular filtration rate), some scores have been developed to help physicians in patients’ stratification: the most famous is the Mehran score which was derived from a cohort of 8,357 patients (4). Another interesting score is the one by Bartholomew et al. (15), who studied 20,479 patients who formerly received contrast medium during percutaneous coronary intervention (PCI). Recently, Maioli et al. (16) developed an easy scoring to predict CI-AKI before coronary angiography and elective percutaneous coronary intervention (PCI). A summary of these scores with the included variables and the risk stratification is presented in Figure 1.

Figure 1 Some of the most used risk scores [Mehran score (4), Bartholomew score (15) and Maioli score (16)] for CI-AKI with the derived classification and associated risk. CIN, contrast-induced nephropathy; CI-AKI, contrast-induced acute kidney injury.

A good preventive strategy obviously starts from the knowledge of the pathophysiological mechanism, but to date the etiopathogenesis of contrast induced nephropathy remains largely unclear. The contrast medium is thought to induce CI-AKI through different levels of damage: Firstly, it may promote renal vasoconstriction, resulting in an augmentation of intrarenal resistance with a fall in renal blood flow and therefore in glomerular filtration rate (17,18). Secondly, it has a both a direct cytotoxic effects on endothelial and tubular cells (which in turn leads to epithelial vacuolization and necrosis of proximal tubules) and an indirect toxic effects trough the reduction in nitric oxide (NO) production that promote the formation of reactive oxygen species and increase the angiotensin-II effects causing direct constriction of descending vasa recta and subsequently medullary hypoxia (19). Finally, the iodinated contrast medium might increase the active sodium reabsorption in the Henle’s loop (thus increasing the O₂ demand and as a result worsening medullary hypoxia) (20). All these mechanisms participate in reducing cell survival, finally escalating in acute kidney injury that in turn may favour inflammation leading to apoptosis and fibrosis at the cellular level (12,21) [and the sympathetic stimulation has been demonstrated to increase the ischemia/reperfusion renal damage (22)], and also fluid retention leading to cardiac instability. To aggravate the situation, patients who develop CI-AKI usually have a worse cardiovascular risk profile and a higher prevalence of comorbidities.

As above mentioned, CI-AKI has also been reported to be associated with bleedings. From the first report by Levy et al. (23) who described a 38% prevalence of bleeding events among patients with CI-AKI to the exhaustive pooled analysis from the HORIZONS-AMI and ACUITY trials by Giacoppo et al. who reported CI-AKI as the strongest predictor of bleeding (12), a variety of causal mechanisms have been postulated to explain the increased bleeding propensity in the setting of CKD: anomalous platelet function and aggregation (24) with altered platelet-endothelial interactions (25,26), an enhanced NO production (27) with unbalanced prostaglandin metabolism (25) and impaired serotonin uptake and release (28) and the presence of an abnormal von Willebrand factor (29).

Once recognized patients who deserve adequate prevention for contrast-induced nephropathy (CIN), this is mainly based on extracellular volume expansion after the results of many randomized trial (30). Pretreatment with high-dose statins may be of interest (31). Conflicting results however have been obtained with nebivolol and other beta-blockers, furosemide, theophylline, calcium-channel blockers, N-acetylcysteine, sodium bicarbonate and hemodialysis (32-34).

The potentially preventive role of beta-blockers in patients undergoing coronary angiography is particularly attractive since the common use of such drugs in ischemic patients, with a well-known prognostic impact in who experienced myocardial infarction. Indeed, AMI patients are at high-risk for developing AKI: the risk factors for this complication are related to comorbidities [high prevalence of diabetes and CKD (35)], to the revascularization procedures with use of iodinated contrast medium and to cardiac complications (hemodynamic instability, heart failure) and their weight in each clinical setting have already been extensively studied (4,11,35,36).

The renewed interest in AKI after AMI is due to the increasing evidence of the association between AKI with in-hospital and long-term mortality (6,8-10,12), even after 10 years of follow-up (6). These studies identified a new concern regarding the prevention of AKI after AMI: as suggested by guidelines (37,38), ST-elevation myocardial infarction (STEMI) patients benefit from the early use of β-blockers (39) and from a kidney perspective there are data that β-blockers also improve endothelial dysfunction in renal ischemia because of the abovementioned endothelial NO synthase (eNOS) activation (18,33,40). In addition, sympathetic activity plays a pivotal role in renal damage that β-blockers might interdict (22). Actually, the retrospective study by Queiroz et al. showed that β-blocker use (mainly propranolol) was protective against AKI occurrence during hospitalization in 406 patients with STEMI (41). In the paper by Leung et al. on 5,991 patients with ACS, the use of beta-blockers remained associated with lower mortality in both individuals with and without AKI (42).

Among beta-blockers, nebivolol is particularly captivating due to its antioxidant and vasodilator properties by facilitating NO release through several mechanisms (18,40,43). Nebivolol is able to both increasing eNOS expression and activity (44), while decreasing asymmetric dimethyl-arginine which is a natural eNOS inhibitor (45) and also the degradation of eNOS itself (46).

Since both vasoconstriction and oxidative stress in the renal medullary capillaries may be responsible for development of CIN, several studies explored whether nebivolol can prevent CIN or not (33,47): Avci et al. compared post angiographic results of 55 patients who used nebivolol and 35 patients who used metoprolol and they showed that the occurrence of CIN was significantly lower in the nebivolol group (33). But, as noted by Bowden’s editorial comment, the non-randomized strategy and the small sample size of this study reduce the conclusion strength (33).

Toprak et al. previously described the protective role of nebivolol in CI-AKI. No difference between patients receiving nebivolol or no was detected during six-days serum creatinine monitoring, but intravenous nebivolol reduced the severity of histological damages and the levels of oxidative stress markers (48).

Finally, Altunoren et al. used serum neutrophil-gelatinase associated lipocalin (NGAL), a more sensitive marker of renal damage than CrCl, to evaluate the role of nebivolol as a preventive treatment. After investigating 159 patients they concluded that it does not seem to prevent CI-AKI after coronary angiography (49).

The PROCOMIN study tried to address the issue of AKI prevention by means of beta-blockers administration in 1,309 patients presenting to the cath lab with a diagnosis of AMI (1). In this prospective observational study, the authors excluded patients with severe kidney disease (eGFR at admission <15 mL/min), and guaranteed adequate hydration according to guidelines suggestion. Patients were assigned into two groups according to β-blockers use or non-use within 24 h of the perioperative period (with 1,074 patients in the β-blockers group and 235 in the non-β-blockers group). They tested serum creatinine from the admission to 3 days after the procedure, and the follow-up after hospital discharge was 48 months. They concluded that taking β-blockers might be associated with a reduced risk of CI-AKI and long-term mortality among AMI patients sent to coronary angiography and/or PCI.

Despite the goodness of the aim of this study, some considerations arise regarding the data displayed. First, no mention of the proportion of STEMI and NSTEMI patients is available in the text or in the tables: since NSTEMI may have been studied even later than 24 h from admission, a sub-analysis of STEMI patients and NSTEMI patients may be recommended to better clarify the role of early administration of such drugs since on the long term the protective role of these drugs has been already clarified (50,51). Indeed, it should be presumed that the majority of AMI patients would have received b-blockers at the moment of hospital discharge. Nevertheless, no mention of discharge therapy is found in the paper. Secondly, we know the absolute importance that reperfusion time has on the prognosis of patients with AMI. As a matter of fact, that protection is also related with AKI development: when early reperfusion is performed there is less myocardial damage resulting in lower probability of heart failure and hemodynamic instability. More data about this time interval and its inclusion in the multivariate analysis may be of interest to better explore the role of beta-blockers, which effects on heart rate is known and since a long-lasting higher heart rate has been previously showed to correlate with AKI.

In conclusion, despite several limits the PROCOMIN trial however has the credit to light on again the need to not underestimate the role of acute kidney injury in the emergency department and in the cath lab. Beta-blockers are commonly prescribed in myocardial patients and an interpretation of this study data implies, at least, that an AMI patient who cannot receive β-blockers early after admission must be observed by physicians as a patient with a higher risk of developing AKI. This paper also remembers us the difficulty in obtaining strong evidences of a direct effect of β-blockers on renal function, even after adjusting for many variables: indeed, only a randomized study could satisfactorily answer this question, but it is not achievable because of the already known and important beneficial effect of β-blockers on mortality in the AMI setting.

Acknowledgments

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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