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.