In this prospective cohort, we found that 60.8% of patients with AKI develop dyskalemia. These patients are more likely to die within the first 10 days of hospitalization, specifically those who had a trajectory from normoK to hyperK and those with uncorrected hyperK, where the risk is even higher, as expected, they were also at higher risk of initiating KRT.
We note that normoK to hyperK and uncorrected hyperK were associated with an increased probability of death by 37% and 63%, respectively. Compared with the normoK group, this association was not attenuated, despite considering multiple subgroups according to comorbidities and exposures.
The association of hyperK and mortality has been previously reported and is consistent with other studies. In a retrospective analysis of 932 cliticall ill hospitalized adults, high rates of arrhythmia and cardiac arrest occurred in patients with hyperK ≥ 6.5 mEq/L (23). In this study, AKI increased the risk of death more than two-fold. In our cohort, patients with AKI who had normoK and excess sK+ during their hospitalization had a higher risk of died. An et al. also found that increases in sK+ levels preceded death in critically ill patients (23). Additionally, McMahon et al. described in critically ill patients who had even minor elevations in sK+ (to levels 4.5–5.0 meq/L) conferred an increased risk of death (24). Khanagavi et al. reported on hospitalized patients with sK+ >5.1 meq/L and AKI that the duration of hyperK increased four-fold th mortality risk. The total duration of hyperK was also associated with death (10).
The association between hyperK and mortality in patients with AKI could be driven mostly by cardiac rhythm abnormalities [25]. HyperK decreases the transmembrane potassium gradient, leading to increased potassium conductance, which shortens the duration of the action potential (26). As potassium rises from 5.5 to 6.5 mmol/L, peaked T-waves and a prolonged PR segment may be seen, along with progressive widening of the QRS complex, fascicular and bundle branch blocks, a “sine-wave” appearance, and asystole (27). However, the actual causes of death in patients with hyperK are poorly described, and the causal relationship between hyperK and outcome remains controversial (28).
We observed that more than half of our patients had dyskalemia (60.8%), a result that could be explained because, in addition to the AKI event with its respective decrease in glomerular filtration rate that explains the impairment of renal elimination of sK+, our cohort had patients with documented risk factors for the development of hyperk (29), such as the greater prevalence of men (58%), one-third had diabetes (33.7%), presence of patients with CKD (15.7%), almost half had sepsis (45%), including patients with cardiorenal syndrome (12.8%), and most were classified as having severe AKI (stage 3) (63.9%).
As a secondary outcome, we considered initiation of KRT by sK+ trajectories
In our cohort, one-third of patients were started on KRT during the follow-up, and those patients in the uncorrected hyperK group had an increased risk of 40%. This is an intuitive result that is not surprising, since kiperK is a frequent indication for the initiation of KRT in patients with AKI (30, 31), especially if there is no decrease in hyperK, despite treatment (32). However, the sK+ concentration that should serve as a trigger for KRT remains debated. Gaudry et al. demonstrated, in a randomized clinical trial, that a strategy of delayed KRT ultimately avoided KRT in many patients who received medical treatment for hyperK (33). Another trial evaluated hypertonic sodium bicarbonate in critically ill patients with severe acidaemia (pH < 7.2) and reported that the intervention group had a lower sK+, less need for KRT, and a longer delay to initiation of KRT in those patients ultimately requiring KRT (34). Last, if strategies to correct hyperK fail, KRT is the most effective way to eliminate excess sK+ (35). In the setting of high blood and dialysate flow and low dialysate potassium concentration, sK+ drops within minutes of initiation, and sK+ will decrease more slowly after 2 h of hemodialysis and rebound after stopping the therapy (28). When facing an episode of AKI, specifically when hyperK exists, all strategies should be tried to decrease sK+ and avoid starting KRT and death. Failure of hyperK to correct by > 1.0 mEq/L within 48 h after initial measurement predicts death (24). The benefit of correction of hyperK was also observed in our cohort, when we noted that those patients in the corrected hyperK trajectory had no association with start of KRT or death during follow-up.
Interestingly, there was a higher percentage of patients with diabetes mellitus in the corrected hypoK group. It is well known that severe hyperglycemia in diabetes can cause osmotic diuresis leading to dehydration and electrolyte loss, particularly sodium, sK+, chloride and magnesium. Dehydration in turn induces secondary hyperaldosteronism that exacerbates sK+ loss. The excessive use of insulin is associated with hypokalemia. On another hand, drugs like thiazide or loop diuretics, used for treating comorbid conditions like hypertension in diabetes may also cause hypokalemia (36). It is to be assumed that the correction of the hyperglycemia, as well as the suspension of these drugs during the hospitalization would correct the hypoK.
Our group showed that fluid adjustment was associated with a 42% risk reduction in initiation of KRT (37); it could be that, through this fluid adjustment, sK+ can decrease and thus improve the clinical course of these patients. In this line, utilization of balanced solutions with physiological concentrations of chloride (Ringer’s lactate and Plasmalyte) prevents the development of metabolic acidosis and is associated with lower sK+ levels compared to NaCl 0.9% (38). Other strategies that have shown benefit by decreasing potassium in patients with AKI are calcium salts, which increase the cardiac threshold potential and stabilizes the myocellular membrane (39); hypertonic sodium solution, which increases the action potential rising velocity in isolated cardiomyocytes (40); hypertonic sodium bicarbonate (150 mL of 8.4% sodium bicarbonate over 20 min) in patients with metabolic acidosis (34); polarizing solutions, including use of insulin (41) and β-adrenergic agonists (42) to shift potassium from the extracellular to the intracellular compartment; loop diuretics, which have shown to be effective in patients with hyperK and concomitant volume overload (43); and finally, potassium-binding agents (44). It is very important to keep monitoring sK+ levels when implementing strategies to decrease them. It is likely that there will be rebounds with elevations after treatment, especially if the treatments used do not eliminate sK+. We measured sK+ with a median of three times during a mean of 8.5 days of hospitalization. The monitoring of sK+ levels is particularly important considering the results of our study. Since we must ensure that hyperK is corrected, we observed that the highest risk of dying was in patients with uncorrected hyperK. In line with this, it would be as important that, in patients with AKI, we carry out strategies to prevent increases in sK+, as it has been reported that up to 60% of cases of hyperK develop during hospitalization (23).
Our study has some limitations. The included cohort of patients is relatively small. We do not consider the amount of potassium administered during hospitalization, such as antibiotics, intravenous fluids, and enteral or parenteral diet. This contribution could have modified its trajectory, neither the strategies that could have decreased sK+. We believe that it would be practically impossible to calculate the exact amount of potassium that is administered to a patient in these scenarios.
The 10-day follow-up during hospitalization was short, but it has been shown that most patients who required KRT had initiation of KRT within a short follow-up period (45). Due to the observational nature of the investigation, the causal relationship between dyskalemia 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 rare sK+ trajectories were not considered for our 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 sK+ level correction.
One of the strengths of our cohort lies in its prospective nature, since most of the data on hyperK and mortality are retrospective cohorts (29). To the best of our knowledge, this is the first time that a study was able to dissect the trajectory of sK+ levels in patients with AKI, and with this, we obtained a better perspective of which patients are most susceptible to death.