Over the past decade, research has increasingly focused on studying patient safety in the general population. Little attention, however, has been given to disease specific measures of patient safety that are relevant to populations with chronic illness like CKD. In this analysis, we focused on hyperkalemia as one measure of disease specific patient safety relevant to health care provides managing patients with CKD.
Our results demonstrate that patients with CKD were significantly more likely than patients without CKD to have a hyperkalemic event at all stages of renal disease. The results, however, indicate that patients with CKD treated with a RAAS blocker are slightly less likely to have both moderate and severe hyperkalemia than CKD patients who are not on this treatment. The 1-day odds of death were greater after a hyperkalemic event compared to a normokalemic event. However, hyperkalemic events in patients without CKD were associated with higher odds of 1-day mortality than hyperkalemic events in patients with CKD. There tended to be an inverse relationship between the severity (stage) of CKD and odds of 1-day mortality following a hyperkalemic event, and more severe hyperkalemia was associated with higher odds of death.
Prior studies7, 9, 21–23
have documented modest hyperkalemia associated with the use of ACE-I and/or ARB in patients with CKD in the setting of a clinical trial. In six separate clinical trials of over 1500 individuals with renal insufficiency, elevations in serum potassium levels between 0.3 and 0.6 mg/dl occurred in 3–5% of subjects randomized to an ACE inhibitor24
. Other trials have shown similar increases among patients assigned to treatment with ARBs24
. The observation in the present study that hyperkalemia is less common among patients with CKD treated with a RAAS blocker has several potential explanation. It is possible that the predisposition of CKD patients to developing hyperkalemia may cause treating physicians to screen out prior to treatment of patients who are prone to this metabolic disturbance. In those patients in whom they elect to treat with a RAAS blocker, physicians may increase their surveillance for hyperkalemia or spend more time determining means by which a patient can avoid this consequence of therapy. However, our ability to elucidate the mechanism underlying this finding is limited and beyond the scope of this study.
The observed lower 1-day mortality rate among patients with CKD versus those patients without CKD and hyperkalemia has some plausible explanations. First, as kidney function declines, there is likely to be an adaptive response which leads to a new increased steady state serum potassium level. In patients with more severe kidney disease, there is also an increased level of gut potassium excretion..
Potassium adaption is the response of the kidneys to a high dietary potassium intake25;26
. In patients with chronic renal insufficiency, prior studies have described a compensatory response to chronic hyperkalemia in which the body eventually develops a new steady state potassium level which is often significantly higher than normal27–31
. As GFR declines, serum potassium levels increase as potassium filtration and secretion fall. When aldosterone or other kaliuretic factors fail to maintain potassium homeostasis, extracellular [K+
] may rise until it reaches a level sufficient to produce a sustained increase in renal potassium excretion32
. Increased extrarenal potassium excretion through the gut is another adaptive mechanism which gradually develops in patients with chronic renal failure as kidney function declines33–35
The lower mortality seen with hyperkalemia in CKD is consistent with evidence suggesting that these patients may be less susceptible to cardiac toxicity from this metabolic disturbance than patients without kidney disease. This may be attributable to the fact that patients with CKD are more likely to develop chronic hyperkalemia, which is reported to be better tolerated than an acute rise29;36;37
. It has been noted that patients with CKD who develop chronic hyperkalemia can have serum potassium levels in excess of 6.0 mg/dl without apparent electrocardiographic or cardiovascular manifestations38–40
. Acute hyperkalemia can cause a rapid reduction in resting membrane potential leading to increased cardiac depolarization, muscle excitability and possible ECG changes41;42
. These cardiac changes may be altered in the renal population where the presence of other electrolyte disturbances could influence the cardiac membrane potential36
The findings reported in this study have important clinical implications. They suggest that patients with CKD and those who are treated with RAAS blocker have an increased risk of hyperkalemia, but that risk may be somewhat lowered with proper patient selection for RAAS treatment. The increased risk of death associated with hyperkalemia underscores the importance of clinical monitoring and follow-up of patients with CKD or who are treated with RAAS blockers to avoid the adverse outcomes that are associated with this metabolic disturbance. Others have reported that a substantial portion of patients who have hyperkalemia detected in a clinical setting do not have timely follow-up of this abnormal lab value43;44
Even though this study revealed an attenuation in the morality risk associated with hyperkalemia and CKD consistent with the adaptive mechanisms described, the higher frequency of this metabolic disturbance in this disease population suggests that patients with CKD should be closely monitored to minimize adverse outcomes.
Retrospective analyses such as this one have several inherent limitations which should be considered when interpreting the findings. First, the incidence of hyperkalemia is only detected at the time of a clinically ordered blood test and does not account for the occurrence of this metabolic disturbance at unobserved times. Therefore, our estimation of the incidence of hyperkalemia is subject to the frequency of laboratory monitoring, which is non-random among the veterans in this cohort. Nevertheless, the demonstrated odds of death associated with hyperkalemia in both inpatient and outpatient labs, highlights the significance of the detected events in this study. Using 1-day mortality as the outcome, we were able to minimize the influence of confounding by severity of illness in the study. The results of this study only included RAAS blockers, which are known to increase serum potassium levels. However, it is quite possible that other agents may have influenced the incidence of hyperkalemia. The emphasis in this study, however, was on that class of agents which are a key element to disease management in CKD. Finally, patients with Stage 5 CKD may have included individuals with ESRD who are on dialysis and as a result may handle potassium differently than those subjects who were dialysis independent. Given the small number of patients with Stage 5 CKD in the cohort, the proportion on dialysis was likely to be small.
The findings of this study support the consideration of hyperkalemia as a patient safety measure in CKD. We have shown that this metabolic disturbance is more common in CKD than in patients without this condition. Moreover, hyperkalemia is linked to increased odds of mortality although the risk is lower in CKD versus non-CKD populations. These findings suggest that the role of disease management in the manifestation of this candidate safety measure is complex. However, given the association of hyperkalemia with CKD and the elevated odds of death associated with hyperkalemia, this metabolic disturbance should be considered a disease-specific safety event. More work is needed to see to what extent alterations in disease management will reduce the incidence of this patient safety indicator.