DISCUSSION
This large cohort study demonstrated risk factors associated with developing AKI in patients with salicylate intoxication and its impact on outcomes and resource utilization. Overall, 9.3% of salicylate intoxication patients developed AKI. Factors associated with increased risk of AKI included presence of chronic kidney disease, sepsis, older age, volume depletion, more recent period of hospitalization, male sex, anemia, ventricular arrhythmia/cardiac arrest, congestive heart failure, and hypertension. Requirement of renal replacement therapy, invasive mechanical ventilation support, non-invasive ventilation support, and blood component transfusion was higher in salicylate intoxication patients with AKI. Furthermore, AKI was associated with an increased risk of organ failure and in-hospital mortality, as well as longer length of stay and higher hospitalization cost.
In our study, AKI occurred in 9.3% of patients hospitalized with salicylate toxicity, while in general the incidence of AKI range from 10 to 20% in hospitalized patients10-16 and 30 to 50% in critically ill patients.17,18Development of AKI in salicylate intoxication is attributed to several factors, as described above. Our study identified independent factors associated with an increased risk of AKI. Pre-existing chronic kidney disease represented the highest risk factor predisposing to AKI in our study, with the adjusted odds ratio of 7.0. Not suprizingly, baseline chronic kidney disease has always been considered the risk factor for developing AKI.19Moreover, the lower eGFR was associated with the higher risk of AKI.20 The reduction of renal reserve due to precipitating factors, such as hypotension, hypovolemia, use of nephrotoxic agents, is the probable explainion of chronic kidney disease patients being at risk for AKI.21 Sepsis also has strong association with AKI, development of AKI in critically ill patients has been attributed to sepsis in 47.5% of cases.22 Although sepsis-induced AKI is common, the pathogenesis has not been clearly explained. Several mechanisms may contribute to an increased risk of AKI in sepsis, including hemodynamic instability induced renal hypoperfusion, the injury of renal tubular endothelial cells by inflammatory mediators, microcirculation alteration, and mitochondrial dysfunction.23 Other previously reported risk factors for AKI are older age, diabetes mellitus, hypertension, congestive heart failure, use of vasopress/inotropic agents, hemodynamic instability, and anemia, requiring blood transfusion.24-26
Our study also addressed the impact of AKI among patient with salicylate intoxication on clinical outcomes. Overall, presence of AKI in salicylate intoxication patients was associated with increased in-hospital mortality. The in-hospital mortality was 4.3%, with the odds ratio of 4.93 (p<0.001). AKI has also been reported to increase the mortality in several conditions, such as critical illness, acute coronary syndrome, solid organ/hematologic transplantation, cirrhosis, stroke, and cardiac surgery.27-35 In addition, greater degree of resource utilization, including renal replacement therapy, invasive/non-invasive mechanical ventilation support, and blood transfusion has been correlated with AKI. As previously described, at therapeuric doses, 10-30% of salicylate is eliminated through renal exctretion as free salicilyc acid, while the remainder is metabolized by the liver.1 In a setting of salicylate overdose, the oversaturation of hepatic metabolism, especially if accompanied by renal function impairment, results in accumulation of salicylate. This accumulation can lead to severe complications, including acidosis, acute lung injury, and central nervous system toxicity.5 Regarding pharmacokinetic physiology, salicylates are highly bound to protein at therapeutic doses. In contrast, protein binding becomes saturated at supratherapeutic dose, increasing free salicylate serum concentration. Hemodyalysis is another option for salicylate elimination. Although used only in certain settings and mainly in severe cases, hemodialysis is very efficient in eliminating salicylate and restoring acid-base balance.1,3Some cases of salicylate intoxication require ventilation support. Acute encephalopathy, severe acidosis, and acute lung injury could be the contributing factors to respiratory failure requiring ventilation support in severe cases.1 In addition to respiratory failure, development of AKI in patients with salicylate intoxication was associated with an increased risk of other organ systems failure.
Salicylic acid has a pKa value of 3, which essentially means that alkaline pH stabilizes more than 99% of salicylate in the ionized form. In its ionized form, the drug loses ability to easily penetrate cell membrane. On the other hand, nonionized form of salicylate in a setting of acidosis, is able to penetrate cells more readily, particularly the central nervous system, leading to neurologic toxicity.1,3The consequence of acidosis also manifests its effects in cardiovascular system. Previous studies demonstrate that acidosis could result in myocardial dysfunction and vascular dilatation.36 Finally, salicylates also affect the liver and hematological system, resulting in liver injury, thrombocytopenia, and coagulopathy.37-39 As described above, the accumulation of saliciylate due to delayed clearance precipitated by AKI, enhances the severity of disease and leads to organ failure.
Nevertheless, our study has some limitations. According to the NIS structure, hospitalized database, we could not evaluate the long term outcome of AKI, such as renal recovery or long-term mortality. Secondly, data obtained from the NIS was extracted using diagnosis codes. Therefore, we could not conclude that these complications were consequences from AKI or concomitant complications of salicylate intoxication. The effect of co-ingestion was also not evaluated in our study, which might demonstrate some degree of effects not accounted for in this study. Finally, this study did not address the variability in outcomes between acute and chronic intoxication.