In this prospective, single-center cohort, we found that > 80% of AKI patients had fluctuations in sNa during the first ten days of hospitalization. Uncorrected hypernatremia was associated with an increase (> 3-fold) in death probability, even after adjusting for potential confounders. We also found that uncorrected hyponatremia was associated with a higher need for KRT initiation, and these associations were stronger in patients with more comorbidities and worse AKI stage.
Dysnatremia and kidney injury may be separate manifestations of a common underlying disease or reflect the severity of the patient's illness and comorbidities. Many pathological conditions may lead to both dysnatremia and AKI, such as changes in the volume status. Hypo- and hypernatremia is reported to occur during AKI in all acutely ill patients (22), or patients with cardiorenal syndrome (23), cancer (24), liver transplantation (25), and in HIV-infected patients (26).
In our cohort, AKI with uncorrected hypernatremia was associated with a higher incidence of death, very similar to Darmon and colleagues' study. The authors showed that hypernatremia was associated with a greater risk of death in AKI patients by more than 4-fold (27) with short-term mortality of approximately 50–60% (7). Association of hypernatremia with force clinical outcome has been reported extensively. The etiology of hypernatremia includes free water loss (e.g., diabetes insipidus), hypotonic fluid loss (osmotic diarrhea), or hypertonic fluid gain (7). Volume depletion, which often leads to hypernatremia, is also a frequently recognized cause of AKI (28). Hypernatremia by increasing tonicity could potentially damage the cellular cytoskeleton and DNA (29). The variability in sNa levels is likely more harmful than the absolute sodium value (9). The sNa variability results in osmotic stress and induces water shifts across the cell membranes, leading to threatened cell survival (29, 30. 31). Besides, it can evoke multiple apoptotic pathways, inhibit anti-apoptotic gene expression, and induce cytokine and reactive oxygen species generation [32, 33, 34 ]. It also causes dysregulation of the interaction between protein phosphatase 6 and apoptosis signal-regulating kinase 3 and the cell volume recovery system (9).
The impact of sodium correction speed in hypernatremic patients on clinical outcomes is debated with scarce evidence. Historically, it has been considered that the rapid correction of hypernatremia is associated with adverse events. Olsen et al. reported that rapid correction of hypernatremia with a rate of > 0.5 mmol/L/hr could be associated with an increased risk of mortality by about 10% (35). It is noticeable that some authors suggest that the rapid correction of hypernatremia in ICU patients may not be associated with higher mortality or neurological alterations (36), even though Chauhan et al. do not describe the incidence of AKI. This evidence, along with our findings, suggests the benefits of earlier hypernatremia correction even in the presence of AKI.
We also found uncorrected hyponatremia was common among AKI patients who needed KRT. Hyponatremia leads to hypotonicity, which can cause cellular swelling and membrane rupture (29). Hyponatremia in AKI could represent a specific phenotype seen in sepsis (37), inflammation (38), or volume overload (39). Our demonstrations in the association of KRT requiring AKI in hyponatremic patients are consistent with previous studies (40).
The sNa trajectories in patients with AKI can serve as a modifiable prognostic marker used in outcome prediction and clinical complication prevention. This notion is particularly strengthened when correcting dysnatremia during hospitalization was associated with fewer complications.
Our subgroup analysis indicated that specific patient populations were more vulnerable to worse outcomes. Patients with more comorbidities had a higher risk of death, which could be due to more limited physiological reserves to allow them to counteract the negative dysnatremia consequences.
Our study has some limitations. The included cohort of patients is relatively small. Besides, we were not able to adjust sNa for the serum glucose levels. The 10-day follow-up during hospitalization was short, but it has been shown that the vast majority of patients who required KRT for AKI were initiated on KRT within the follow-up period (14). Due to the investigation's observational nature, the causal relationship between dysnatremias and clinical outcomes could not be established. Thus, our investigation solely serves as a hypothesis-generating study. Although we adjusted for known common variables associated with the studied outcomes, unmeasured confounding could not be completely ruled out. Some more rare sNa trajectories were not considered for study, although we tried to capture those that seemed most relevant to the study's objectives. Finally, we did not report the specific management strategies that were used for sodium level correction.
Our article has some strengths. To our knowledge, our cohort is the first that identifies correlations between sNa trajectories in AKI patients with death and the need for KRT initiation. The prospective observational design of our study enhances its validity. We were able to adjust for potential confounders that reinforce the association of these variables.
In conclusion, we found that in most patients with AKI during the first ten days of hospitalization, sNa fluctuations were frequently observed. Uncorrected hypernatremia was associated with death, and uncorrected hyponatremia was correlated with the need for KRT initiation. Larger cohort studies and randomized trials are needed to confirm our findings.