We describe an association between abnormally decreased and elevated levels of serum sodium and higher all-cause mortality in a large, nationally representative group of US veterans with non-dialysis dependent CKD. These associations were linearly proportional with the severity of the underlying hyponatremia and hypernatremia, and were independent from comorbid conditions such as CHF or liver disease. Both lower and higher serum sodium were associated more strongly with mortality when modeling them in a time-dependent manner, with weak or no effects associated with baseline levels of the same factors, suggesting that both hypo- and hypernatremia represent acute (short term), rather than chronic (long term) risk factors for mortality. Severity of kidney disease did not appear to affect the mortality associated with hyponatremia, but patients with more advanced CKD displayed a relatively lower mortality associated with hypernatremia compared to patients with less severe stages of CKD.
Studies examining the predictive value of serum sodium level have concentrated largely on hyponatremia, have examined mostly patients who were hospitalized, and were usually derived from data obtained from single medical centers. Such studies have described associations of hyponatremia with a variety of adverse outcomes including all-cause mortality,3-20
length of inpatient stay,20, 21
gait imbalance and falls,22
and higher hospitalization costs.27-29
Some of the studies examined unselected groups of patients,18, 20
but others focused on groups with some underlying comorbid condition such as CHF,7, 11, 14
or liver disease.4, 13
Irrespective of the setting or the patients included, all studies have found that hyponatremia is associated with an increased risk of the studied end points. Similar associations were reported for hypernatremia too,20
although this abnormality has been in general under-emphasized.
Ours is the first study that examined patients with non-dialysis dependent CKD, and the first to provide data that is nationally representative for the US. The uniqueness of the CKD population is that kidney disease affects the organ responsible for maintaining water homeostasis, and as such it is possible that both the prevalence of dysnatremias and their clinical consequences could be magnified. While we did report a relatively high prevalence and incidence of hyponatremia (13% of the patients in our study had hyponatremia at baseline, and twice as many had at least one episode of hyponatremia during follow-up), the lack of information about the general population prevents us from determining whether CKD results in an increased incidence or prevalence of dysnatremias. Regarding outcomes, we did not find differences in the association of hyponatremia with mortality in patients with different severities of CKD, but hypernatremia appeared to predict less severe outcomes in patients with more advanced stages of CKD. This latter observation could be the result of end-organ adaptation to a state of increased extracellular osmolality in patients with advanced CKD who experience a gradual accumulation of various uremic solutes with advancing severity of kidney disease. One implication of our results is that it establishes hypo- and hypernatremia as robust outcome predictors in patients with all stages of CKD. On the other hand, it is unclear yet if these abnormalities should be considered treatment targets in these patients. Both hypo- and hypernatremia can have direct adverse effects on various organs’ function, most notably on the central nervous system.43-46
This underlying pathophysiology could serve as one potential explanation of why abnormal serum sodium level is associated with increased mortality; our results indicating a more marked association with short term, rather than long term mortality also supports this hypothesis. Since abnormal water homeostasis usually develops as a result of another underlying pathology it is also possible that hyponatremia and hypernatremia are merely surrogate markers of more severe disease states. Similar to other studies, we did not detect any effect modification by known disease states that affect serum sodium level, which makes it more likely that abnormal serum sodium level has an independent effect on survival. Furthermore, a study of maintenance hemodialysis patients enrolled in the Hemodialysis (HEMO) study also reported a significant association of hyponatremia with mortality, even though in anuric dialysis patients the development of low serum sodium is unrelated to the stimulation of arginine-vasopressin by underlying comorbidities.19
Arguing against a causal effect of hyponatremia was a recent study in hospitalized patients in whom the authors could link fatalities associated with severe hyponatremia (<120 mEq/l) to more severe underlying disease processes rather than the hyponatremia itself.47
Nevertheless, observational studies cannot completely overcome the problem of residual confounding, which can be better addressed by randomized controlled trials. One such large trial in patients that examined the effects of the vasopressin V2 receptor antagonist tolvaptan on mortality in patients with CHF did not detect a significant benefit on mortality,48
but more interventional studies are needed to determine if other patient populations, other treatment regimens, or patients with different severities of hyponatremia might show different outcomes.
Our study is notable for its very large sample size and event numbers, and for it being representative of the entire geographic United States. Our study also has a number of limitations that need to be considered when interpreting its results. Our study population consisted mostly of male patients; hence the results may not apply to females. We used data obtained during the course of clinical practice, hence selection bias is possible. However, the key laboratory variables used for cohort definition (serum creatinine and sodium) are part of routine panels that are measured in most patients receiving healthcare, hence it is unlikely that a significant proportion of actively enrolled veterans would have been excluded. We defined CKD using the CKD-EPI equation as it is more accurate than other estimating equations (such as the Modification of Diet in renal Disease (MDRD) equation) in patients with normal and mildly decreased GFR. The CKD-EPI equation was, however, meant to be used with serum creatinine measured by the IDMS-traceable method, which was not ubiquitous at the time when our cohort was defined (2005-2006), and hence it is unclear how accurate the staging of CKD in our cohort was. The associations between serum sodium and mortality did not change, however, if we used the MDRD equation to estimate GFR in our cohort participants (data not shown). We did not collect information about hospitalizations, hence we cannot determine if the mortality associated with hypo- or hypernatremia occurred in context of hospitalizations. We adjusted our analyses for a significant number of potential confounders, but we cannot rule out the presence of residual confounding. We used diagnostic codes to define comorbid conditions that could act as confounders in the association of serum sodium with mortality, which may have resulted in underestimation of their prevalence. By including laboratory variables reflecting abnormal liver function and/or structure we were able to alleviate this concern as far as the confounding imparted by liver disease, but we did not have similar data to assess the presence and/or severity of the other relevant comorbid conditions. We had relatively few patients with extremely high or extremely low serum sodium levels, hence our ability to characterize outcomes associated with very severe degrees of hypo- and hypernatremia may be limited.