\begin{table}[htbp]
\centering
\caption{Predictors of $S_K$ at baseline and during follow-up}
\label{table_2}
\begin{tabular}{lcccc}
\hline
 & \multicolumn{2}{c}{Predictors of $S_K$ at Baseline ($n = 729$)$^{a}$} & \multicolumn{2}{c}{Predictors of $S_K$ over Time ($n = 5111$)$^{b}$} \\
Predictors & Estimate & $P$ & Estimate & $P$ \\
\hline
Male gender & 0.18 & $<0.0001$ & 0.18 & $<0.0001$ \\
Serum CO$_2$ (mEq/L) & $-0.05$ & $<0.0001$ & $-0.03$ & $<0.0001$ \\
eGFR (per 10 ml/min per 1.73 m$^2$) & $-0.02$ & 0.39 & $-0.06$ & $<0.0001$ \\
Diabetes & 0.10 & 0.029 & 0.06 & 0.030 \\
ACEI use & 0.21 & $<0.0001$ & 0.17 & $<0.0001$ \\
Diuretic use & $-0.07$ & 0.76 & $-0.12$ & $<0.0001$ \\
Calcium channel blocker use & $-0.06$ & 0.12 & $-0.09$ & $<0.0001$ \\
Statin use & 0.11 & 0.001 & 0.12 & $<0.0001$ \\
\hline
\end{tabular}

All variables from Table~\ref{tab:table_1} were tested in the selection models, with significant variables retained ($\alpha = 0.05$).

$^{a}$All variables simultaneously entered in a multiple linear regression model.

$^{b}$All variables simultaneously entered in a repeated measures regression model. The values of all covariates (except gender) were allowed to change with follow-up time.
\end{table}

For the composite outcome of death or ESRD (Figure~\ref{fig:figure_3c}), a U-shaped relationship between $S_K$ and the composite outcome was evident. There was a significantly higher hazard of death or ESRD at lower serum $S_K$, the significance of which was attenuated by adjustment for serum albumin in the model. As a categorical variable, lower $S_K$ levels remained a significant predictor of the composite outcome before and after adjustment for serum albumin (Table~\ref{tab:table_3}). Higher $S_K$ was not significantly associated with the composite outcome.

A total of 190 cardiovascular events (70 coronary, 50 cerebrovascular, and 70 peripheral vascular) that required hospitalization were documented during the course of the study. A significant quadratic relationship was seen between $S_K$, and the relative hazard of first cardiovascular event or death (Figure~\ref{fig:figure_3d}) was noted. Unlike overall mortality, this was statistically significant for $S_K > 5.5$ mmol/L but not for lower potassium ($< 4.0$ mmol/L). After addition of serum albumin to the model, higher $S_K$ but not lower $S_K$ was associated with the composite outcome (Table~\ref{tab:table_3}).

\section{Discussion}

To the best of our knowledge, this is the first study to investigate systematically the prevalence and mortality associated with $S_K$ levels that are obtained during routine clinical practice in a large and diverse nondialysis prospective CKD cohort. Our main finding is that $S_K$ level $< 4.0$ mmol/L was associated with a higher risk for death and ESRD compared with $S_K$ between 4.1 and 5.5 mmol/L. These observations are of clinical importance, because most physicians consider $S_K$ values of 3.5 to 3.9 mmol/L to be ``within normal limits.'' Our multivariable analyses show that the lowest risk for mortality was in the $S_K$ range of 4.1 to 5.5 mmol/L and that mortality or ESRD risk was not significantly higher even at $S_K$ levels of 5.5 to 5.9 mmol/L, a range of $S_K$ values that almost always evokes clinical concern with or without intervention (e.g., dietary advice, prescription of loop diuretic, discontinuation of potassium-sparing diuretics). This modest level of hyperkalemia seemed to be well tolerated in this patient population from the perspective of predicting mortality risk.

The link between relatively normal or low-normal levels of $S_K$ (3.5 to 4.0 mmol/L) and mortality has not been previously documented in the CKD population. This finding is not altogether surprising, however. Low $S_K$ levels affect myocardial resting membrane potential, which increases the probability of ventricular arrhythmias and sudden cardiac death \cite{11}. Hypokalemia can also predispose patients to develop diastolic dysfunction, digoxin toxicity, and insulin resistance, all of which increase the risk for cardiovascular events and death \cite{12,13,14,15,16}. Dietary potassium depletion has been linked to the genesis of hypertension, and supplementation can improve BP control \cite{17,18,19}. Data from the cardiovascular literature suggest that serum potassium levels $< 4.0$ mmol/L portend a worse prognosis among those who have a history of heart failure or acute myocardial infarction \cite{20,21}. Current American Heart Association/American College of Cardiology guidelines recommend that serum potassium levels be maintained between 4.0 and 5.0 mmol/L in those with chronic heart failure \cite{22}. Our study provides observational evidence that necessitates similar guidelines for patients with CKD.

Not surprisingly, diuretic use was associated with lower $S_K$ levels in this study. Non--potassium-sparing diuretic use has been linked with increased mortality and hospitalization that can likely be attributed to low $S_K$ levels \cite{23}. Several case-control studies reported an increased risk for cardiac arrest among patients who received high dosages of thiazide diuretics. This risk was lowered when thiazide therapy was combined with potassium-sparing diuretics \cite{24,25,26}. Because diuretics are very commonly used for volume and BP control in the CKD population and hypokalemia is a frequent complication of this class of medications, these results suggest that clinicians need to monitor $S_K$ levels closely and consider using potassium-sparing diuretics and/or potassium supplements in patients who have CKD and are prone to hypokalemia; however, clinical trials will need to be performed before formulating defini-