Clinical Disorders of Hyperkalemia

Basic Concept for the Movement of K ⁺ Ions Across Cell Membranes

K ⁺ is the principal cation in cells. The movement of K ⁺ ions across cell membranes has two requirements; first, there must be a driving force; second there must be an open K ⁺ channel in a cell membrane.

Driving Force

K ⁺ are kept inside the cell by an electrical force; the cell interior has a negative voltage. It follows that a more negative cell voltage is required to shift K ⁺ into cells. The negative voltage in cells is generated by the activity of the electrogenic cation pump, the Na ⁺ , K ⁺ ATPase (Na-K-ATPase). This pump exports three sodium (Na ⁺ ) ions while importing only two K ⁺ ions; hence there is a net export of {1/3} of a positive charge per Na ⁺ that exits from cells via the Na-K-ATPase ( Figure 51.1 ). Because, intracellular anions are largely macromolecular phosphates such as RNA, DNA, and phospholipids, which remain inside the cell, a negative intracellular voltage is generated when Na ⁺ exits the cell via the electrogenic Na-K-ATPase.

There are three ways to acutely increase ion pumping by the Na-K-ATPase: First, a rise in the concentration of its rate-limiting substrate—intracellular Na ⁺ ; second, an increase in the affinity for Na ⁺ or in the V _max of the existing Na-K-ATPase units in cell membranes; third, an increase in the number of active Na-K-ATPase pump units in the cell membrane by recruitment of new units. A chronic increase in Na-K-ATPase pump activity requires the synthesis of new pump units as occurs with exercise training.

The driving force for the secretion of K ⁺ by principal cells in the late distal convoluted tubule, the connecting segments and the cortical collecting duct (the abbreviation CCD is used in this Chapter to indicate all these nephron segments) is a lumen-negative voltage. This lumen-negative voltage is generated by the electrogenic reabsorption of Na ⁺ (reabsorption of more Na ⁺ ions than of their accompanying anion, chloride (Cl ⁻ ) ions).

Ion Channels for K ⁺

There are several different types of channels that permit the diffusion of K ⁺ through cell membranes. Some of these channels are regulated by voltage, others by ligands such as calcium ions (Ca ²⁺ ), and yet others by metabolites such as adenosine di-phosphate (ADP)—the latter are called K _ATP channels. Because K ⁺ ions do not reach diffusion equilibrium, control is exerted not only by modulating the number but also the conductance and gating of these channels.

The major K ⁺ channel that adjusts the intracellular voltage is the K ⁺ _ATP channel. It is a misnomer to call these channels K ⁺ _ATP as the concentration of ATP in cells does not change sufficiently to provide a signal for regulating these channels. The signal that regulates these channels may be the result of a change in the concentration of a related nucleotide, ADP. When the concentration of ADP rises, K ⁺ _ATP channels will open; conversely, when the concentration of ADP falls, K ⁺ _ATP channels will close. This regulation of K ⁺ _ATP channels adjusts the negative voltage in cells, which in turn regulates other ion channels. The best example is the voltage-gated Ca ²⁺ channel, which is opened by a less negative voltage in cells. Ionized Ca ²⁺ is a major signal for regulation of a number of intracellular processes.

Example : Regulation of the K ⁺ _ATP channel by ADP plays a critical role in the release of insulin. When the concentration of glucose in plasma (P _Glucose ) is high, a metabolic signal is generated in ß-cells of the pancreas to cause the release of insulin ( Figure 51.2 ). When the rate of oxidation of glucose rises in ß-cells, the concentration of ADP in these cells falls. This lower concentration of ADP causes the K ⁺ _ATP channels to close and thus the ICF compartment becomes less negative because fewer K ⁺ ions (positive charges) exit ß-cells. This less negative voltage in ß-cells increases the conductance of voltage-gated Ca ²⁺ channels and hence the intracellular concentration of ionized Ca ²⁺ rises—this provides the signal to release insulin from ß-cells ( Figure 51.2 ).

A similar logic can be used to deduce how the blood flow to exercising muscle may be controlled using intracellular Ca ²⁺ as the signal ( Figure 51.3 ). During a sprint, L-lactic acid is released from skeletal muscle cells. When lactic acid enters vascular smooth muscle cells, H ⁺ and/or lactate anions lead to the opening of the K ⁺ _ATP channels. As a result, K ⁺ exit and the voltage in these cells become more negative. This causes closure of voltage-gated Ca ²⁺ channels and less entry of Ca ²⁺ into cells and hence vasodilatation.

Several types of K ⁺ channels including renal outer medullary K ⁺ channels, ROMK (K _ir 1.1) (which have similar biophysical prosperities and regulatory mechanism as that of the small conductance K ⁺ channels identified in mouse and rat CCD), a Ca ²⁺ activated big-conductance K ⁺ channel (BK) and the double-pore K ⁺ channel, are expressed in the apical membrane of principal cells in CCD. ROMK are the K ⁺ channels most important for the secretion of K ⁺ in CCD. Big K ⁺ conductance “BK” or maxi-K ⁺ channels are activated by a rise in intracellular Ca ²⁺ and are thought to play an important role in flow dependent K ⁺ secretion. Although these channels likely mediate K ⁺ secretion in patients with Bartter’s syndrome that is due to a loss of function mutation in ROMK, their role in physiological regulation of renal excretion of K ⁺ is not clear. BK channel activity has been detected in both principal cells and intercalated cells in CCD. It is difficult to explain the contribution of BK located in intercalated cells to K ⁺ secretion as these cells have low Na-K-ATPase pump content. BK channel activity is increased in the CCD from rats on a high K ⁺ diet. Furthermore, in BK-α subunit knocked mice, increase in flow failed to stimulate K ⁺ secretion in distal nephron. Notwithstanding, deletion of BK-α subunit does not affect net K ⁺ excretion in mice fed a high K ⁺ diet. It is important to recall that the role of these channels was examined in laboratory rodents which consume 10-fold more K ⁺ per kg body weight and close to three-fold more Na ⁺ per kg body weight compared to human subjects consuming a typical Western diet. Therefore, it is possible that the BK channel may provide a way for a “speedy” K ⁺ excretion if there is a large intake of K ⁺ and if flow through CCD were augmented. Although, the same limitations imposed by the magnitude of the lumen negative voltage on the rate of secretion of K ⁺ by these channels will apply, it is possible that “conductance” through ROMK may be rate limiting when there is a need for a high rate of excretion of K ⁺ over a short period of time.

Acute Control of the Plasma K ⁺

Distribution of K ⁺ between the ECF and ICF Compartments

The Na-K-ATPase

The activity of the Na-K-ATPase is higher when the concentration of its substrate, Na ⁺ in cells rises. The impact of this increase in the net exit of Na ⁺ on the trans-membrane voltage, however, depends on whether the Na ⁺ entry step into cells is electroneutral or electrogenic.

Electroneutral Entry of Na ⁺ into Cells : This occurs when Na ⁺ ions enter cells in exchange for hydrogen ions (H ⁺ ) via the Na ⁺ /H ⁺ exchanger-1 (NHE-1) ( Figure 51.4 , left side). The NHE-1 is normally inactive in cell membranes, as can be deduced from the fact that the concentrations of its substrates (Na ⁺ in the extracellular fluid (ECF) and H ⁺ in the intracellular fluid (ICF) compartment) are considerably higher than that of its products (Na ⁺ in the ICF compartment and H ⁺ in the ECF compartment) in steady state. The two major activators of NHE-1 are a higher concentration of H ⁺ in the ICF compartment near NHE -1 and insulin. Monocarboxylic acids (e.g., L-lactic acid) enter cells on the monocarboxylic acid cotransporter (M-CT) ( Figure 51.4 ). If the M-CT is located in close proximity to NHE in a cell membrane, the release of H ⁺ from these acids may cause a high concentration of H ⁺ in the local area of NHE-1, which activates NHE-1 and hence increases the electroneutral entry of Na ⁺ into cells ( Figure 51.4 , left side).

Electrogenic entry of Na ⁺ into Cells : The Na ⁺ channel in cell membranes is normally gated by voltage. When open, one cationic charge enters the cell per Na ⁺ transported. Since only 1/3 of a charge exits per Na ⁺ ion that is exported out of the cell via the Na-K-ATPase ( Figure 51.1 ) ; the net effect would be to diminish the degree of intracellular negative voltage and this leads to net exit of K ⁺ out of cells. This explains a rise in the P _K during intense exercise. It could explain the development of hyperkalemia in patients with hyperkalemic periodic paralysis.

K ⁺ Secretion

The secretory process for K ⁺ by principal cells in the CCD, has two elements. First, a trans-epithelial lumen negative voltage must be generated by electrogenic reabsorption of Na ⁺ via epithelial Na ⁺ channels (ENaC) ( Figure 51.5 ). Second, open ROMK channels must be present in the luminal membrane of principal cells.

Aldosterone actions lead to an increase in the number of open ENaC units in the luminal membrane of principal cells in CCD ( Figure 51.5 ). The steps involved include binding of aldosterone to its receptor in the cytoplasm of principal cells, entry of this hormone-receptor complex into the nucleus, and then the synthesis of new proteins including the serum and glucocorticoid regulated kinase-1 (SGK-1). SGK-1 increases the expression of ENaC in the apical membrane of principal cells. The mechanism seems to be related to the effect of SGK-1 to phosphorylate and inactivate the ubiquitin ligase Nedd-4-2. Nedd-4-2 ubiquinates ENaC subunits, leading to their removal from the cell membrane and degradation in proteasomes. Therefore, inhibition of the Nedd-4-2 induced endocytosis of ENaC leads to increased expression of ENaC in the luminal membrane, which increases the transport of Na ⁺ . Another mechanism by which aldosterone activates ENaC involves proteolytic cleavage of the channel by serine proteases. Aldosterone induces production of “channel activating proteases” (CAP 1–3). These proteases activate ENaC by increasing their open-probability, rather than by increasing their expression in the luminal membrane.

The driving force for Na ⁺ reabsorption in the CCD is a higher concentration of Na ⁺ in the lumen of CCD than that in principal cells (~10–15 mmol/L) and a negative voltage inside cells, owing to the actions of the Na-K-ATPase at the basolateral membrane of these cells. The concentration of Na ⁺ in luminal fluid is limited by the presence of urea osmoles and that the osmolality of luminal fluid in CCD will be equal to plasma osmolality in the presence of vasopressin. The rate of electrogenic Na ⁺ reabsorption is limited by constraints on the magnitude of luminal negative voltage that can be generated in CCD because of limitations on transport of Cl ⁻ . At a trans-epithelial lumen negative voltage of −61 mV and a plasma Cl ⁻ of 100 mmol/L, the minimum luminal Cl ⁻ concentration would be 10 mmol/L. Therefore, under most circumstances, the concentration of Na ⁺ in luminal fluid is sufficient for the activity of ENaC. Variations in the luminal concentration of Na ⁺ in the CCD do not regulate the net secretion of K ⁺ .

The reabsorption of Na ⁺ in the CCD can be electroneutral, if the rate of reabsorption of its major accompanying anion Cl ⁻ matches its rate of reabsorption, or electrogenic, if more Na ⁺ than Cl ⁻ are reabsorbed in CCD ( Figure 51.5 ). The pathway(s) for the reabsorption of Cl ⁻ in the CCD is (are) not well defined, but it is thought that paracellular pathways play an important role. Recently an electroneutral, thiazide-sensitive and amiloride-resistant Na ⁺ -Cl ⁻ transport was identified in the intercalated cells of the cortical collecting duct in mice. This seems to be mediated by the parallel activity of the Na ⁺ -dependent ${\mathrm{Cl}}^{-}{/\text{HCO}}_3^{-}$ exchanger (NDCBE), which promotes the electroneutral exchange of one intracellular Cl ⁻ with one Na ⁺ , two ${\mathrm{HCO}}_3^{-}$ and the Na ⁺ independent ${\mathrm{Cl}}^{-}{/\text{HCO}}_3^{-}$ exchanger (pendrin). This transport mechanism is apparently responsible for as much as 50% of Na ⁺ -Cl ⁻ transport in CCD of the mouse while mineralocorticoids act. To play a role in modulating the rate of K ⁺ secretion, this mechanism of electroneutral NaCl reabsorption needs to be expressed in the late DCT and the connecting tubule.

An increase in the concentration of ${\mathrm{HCO}}_3^{-}$ and/or an alkaline luminal fluid pH seem to increase the amount of K ⁺ secreted in the CCD. It was suggested that this may be due to a decrease in the apparent permeability of Cl ⁻ and/or an increase in ROMK open probability in this nephron segment. It is also possible that the increase in luminal ${\mathrm{HCO}}_3^{-}$ concentration in CCD, inhibits the ${\mathrm{Cl}}^{-}{/\text{HCO}}_3^{-}$ exchanger (pendrin), and hence the NDCBE and the electroneutral NaCl reabsorption, perhaps leading to a higher rate of electrogenic reabsorption of Na ⁺ .

If the rate of reabsorption of Na ⁺ in CCD is not appreciably higher than the rate of reabsorption of Cl ⁻ , a large lumen-negative voltage cannot develop. The hyperkalemia in patients with the syndrome of “Familial Hyperkalemia with Hypertension” (also known as type II pseudohypoaldosteronism or Gordon’s syndrome) may be an example for this pathophysiology. Two factors are important to achieve this near-equal rate of ion transport in the CCD. First, low delivery of Na ⁺ and Cl ⁻ to the CCD occurs because the reabsorption of Na ⁺ and Cl ⁻ is augmented in the distal convoluted tubule because of increased activity of Na ⁺ -Cl ⁻ cotransporter (NCC). Second, effective arterial blood volume expansion suppresses the release of aldosterone; this leads to fewer numbers of open ENaC in the luminal membrane of principal cells in CCD. Hence the rate of reabsorption of Cl ⁻ in the CCD may match that of Na ⁺ .

ROMK channels are abundant and have a high open-probability on a K ⁺ -rich diet. Therefore ROMK channels do not seem to be rate-limiting for net secretion of K ⁺ unless the P _K falls to the mid-3 mmol/L range in rats. Dietary K ⁺ intake is an important regulator of ROMK channels. Low K ⁺ intake decreases, whereas a high K ⁺ intake increases the number of ROMK channels in the luminal membrane of principal cells. The membrane trafficking of ROMK is modulated by phosphorylation of tyrosine in the channel protein, such that phosphorylation of tyrosine stimulates endocytosis and de-phosphorylation of tyrosine induces exocytosis. K ⁺ depletion increases the expression and activity of the protein tyrosine kinase and tyrosine phosphorylation of ROMK channels results in their endocytosis. Angiotensin II (ANG _II ) inhibits ROMK activity in K ⁺ -restricted rats, but not in rats on a usual K ⁺ diet. The effect of ANG _II may be mediated via activating NADPH oxidase II and the production of superoxide anions, which increases the expression of protein tyrosine kinase. The WNK ( With No Lysine ) kinases seem to play a role in modulating K ⁺ secretion. There are two isoforms of WNK1; a ubiquitous full-length WNK1 (WNK1-L) and a kidney-specific, short WNK1 lacking the kinase domain (WNK1-S). WNK1-L induces endocytosis of ROMK whereas WNK1-S inhibits this effect of WNK1-L. The ratio of WNK1-S to WNK1-L transcripts is reduced by K ⁺ restriction (more endocytosis of ROMK) and is increased by K ⁺ loading (less endocytosis of ROMK).

Flow Rate in the CCD

When vasopressin acts and aquaporin-2 water channels (AQP2) have been inserted in the luminal membrane of principal cells, the late distal nephron is permeable to water, the osmolality of fluid in the terminal CCD is equal to the plasma osmolality and hence is relatively fixed. Therefore, the flow rate in terminal CCD is determined by the number of osmoles in the luminal fluid.

The osmoles that are present in the lumen of the terminal portion of CCD are largely urea, NaCl, and K ⁺ with an accompanying anion. While there is little reabsorption or secretion of electrolytes in the nephron segments distal to terminal CCD, and hence the number of electrolyte osmoles in terminal CCD is close to their rate of excretion in the urine, this is not the case for urea. A quantitative analysis of the process of intra-renal urea recycling reveals that the amount of urea delivered to the early DCT is about two-fold larger than the quantity of urea that is excreted in the urine. In the following paragraphs, we shall illustrate that urea recycling aids the excretion of K ⁺ ; this process is especially important in subjects with disorders or those who are taking drugs that lead to a less lumen-negative voltage in the CCD.

Urea Recycling, Process and Quantitative Analysis

For simplicity, we shall begin with the absorption of urea in the inner medullary collecting duct (MCD) ( Figure 51.6 ). This absorption requires the presence of urea transporters in the luminal membrane of cells of the inner MCD (vasopressin phosphorylates and causes the insertion of urea transporters UT-A1 in the luminal membrane of cells in this nephron segment ), and a higher concentration of urea in the luminal fluid in the inner MCD than that in the interstitial fluid in the inner medulla. This later requirement is achieved because all the segments of the distal nephron that are upstream to the inner MCD, are likely to be impermeable to urea, but most of the water delivered to the early DCT is reabsorbed in the CCD and MCD owing to the insertion of AQP2 into the luminal membranes of principal cells. The concentration of urea rises to higher than 600 mmol/L in the luminal fluid that is delivered to the inner MCD ( Figure 51.6 ).

The bulk of the urea that is reabsorbed in the inner MCD leaves the inner medulla via the ascending vasa recta, because it has UT-A2 and, as a result, is permeable to urea. Once in the deep outer medulla, most urea will enter the luminal fluid of the descending thin limbs (DtL) of the loop of Henle of superficial nephrons that have their bends deep in the outer medulla, as they possess the UT-A2 and the concentration of urea is higher in the interstitial compartment than in the luminal fluid of the DtL, which allows for a high rate of delivery of urea to the early DCT.

To obtain a quantitative estimate of the amount of urea that is recycled, one needs an estimate of the amount of urea that is delivered to the early DCT and the amount of urea that is excreted in the urine over a given period of time. Since the amount of urea delivered to the early DCT cannot be measured in human subjects, it is essential to use data from experiments using the micropuncture technique in the early DCT in fed rats. In these studies, the amount of urea in the early DCT was 1.1 times the amount of urea that was filtered. Extrapolated to a human adult with a GFR of 180 L/day, and a plasma urea concentration of 5 mmol/L, a reasonable estimate of the daily delivery of urea to the early DCT is approximately 1000 mmol/day. Since subjects eating a typical Western diet excrete close to 400 mmol of urea per day, the amount of urea that recycles would be approximately 600 mmol per day.

Importance of Urea Recycling for the Excretion of K ⁺

This process of urea recycling adds an extra 2 L to the flow rate in terminal CCD (600 mosmol divided by a luminal fluid osmolality that is equal to that in plasma or ~300 mOsm/L). A reasonable estimate of the number of liters of fluid that exit the terminal CCD per day is close to 5 L (1500 mosmol/day in the terminal CCD (1000 mosmol of urea/day and 500 mosmol/day of electrolytes) divided by 300 mosmol/L). This means, in quantitative terms that 40% of the flow rate in terminal CCD is the result of this process of recycling of urea.

Implications for the Patient with Hyperkalemia

Patients who develop chronic hyperkalemia have a renal defect that is characterized by an inability to generate a sufficiently large trans-epitheleal (TE) lumen-negative voltage in the CCD to secrete all their daily intake of K ⁺ while maintaining a normal P _K . These patients, however, will achieve a steady state in which they will excrete all the K ⁺ they ingest and absorb that is not lost via non-renal routes. To understand how this steady state is achieved, we shall consider how a K ⁺ load of 70 mmol/day is handled in normal subjects and a patient with an electrical defect that leads to a diminished ability to raise the concentration of K ⁺ in the lumen of terminal CCD ([K ⁺ ] _CCD ) ( Figure 51.7 ).

Normal subjects have a much larger capacity to secrete K ⁺ in their CCD compared to the usual daily intake of K ⁺ ; they excrete most of their daily intake over a relatively short period of time close to noon. This likely reflects an increase in the lumen negative voltage in CCD owing to a larger delivery of NaHCO ₃ to the CCD at the time of the alkaline tide in urine pH. If a normal subject has a P _K of 4 mmol/L and a TE voltage in the CCD of -61 mvolts, the [K ⁺ ] in luminal fluid in CCD would be 10 times the P _K or 40 mmol/L. If this voltage could be maintained while 1-L of fluid exits the CCD, 40 mmol of the 70 mmol of K ⁺ would be excreted in this time period (approximately five hours). For the next 19-hours, if 4-L of fluid would exit the terminal CCD with a concentration of K ⁺ of only close to 8 mmol/L, the remaining 30 mmol of K ⁺ can be excreted to achieve K ⁺ balance.

Let us now consider a patient who has a large defect that leads to a lumen negative TE voltage in the CCD of only −29.1 mvolts ( Table 51.1 and Figure 51.7 ). At this TE voltage, the K _CCD /P _K can rise to a value of only three. At a P _K of 4.7 mmol/L, the [K ⁺ ] _CCD will be close to 14 mmol/L; hence at the usual flow rate in terminal CCD of 5-L/day, this patient could excrete 70 mmol of K ⁺ daily and maintain a normal P _K . The point to emphasize is that this precise balance is dependant on intra-renal urea recycling and thereby maintaining the daily flow rate in the terminal CCD of 5-L. Therefore, if this patient were to be put on a protein restricted diet (decrease the number of osmoles of urea in the terminal CCD), a smaller number of liters of fluid will exit the CCD per day and hyperkalemia may develop. To put this in a quantitative perspective, if the number of liters exiting the CCD per day were 4-L instead of 5-L, and if the K _CCD /P _K were three, while this patient continued to consume 70 mmol of K ⁺ /day, in steady state, the P _K will need to rise to 5.8 mmol/L to maintain K ⁺ balance and only if this maximum rate of K ⁺ secretion is maintained throughout the 24 hours period. To further emphasize this point, consider a patient who may have markedly impaired urea recycling due to a disease that involves the inner medulla (perhaps an example may be a patient with sickle cell disease). This patient may have a flow rate in the terminal CCD that is only 3-L/day rather than 5-L/day. If such a patient has a disease that leads to a reduced ability to generate a high lumen negative TE voltage in the CCD, a more severe degree of hyperkalemia will develop unless K ⁺ intake is markedly reduced. In quantitative terms, if the TE voltage in the CCD is −29.1 mvolts, the [K] _CCD will be three-fold higher than P _K . Therefore, if the volume of filtrate that exits the terminal CCD is only 3-L/day, the P _K would have to be close to 8 mmol/L to excrete 70 mmol of K ⁺ /day.

Integration of the Response to Dietary K ⁺ Intake: A Paleolithic Perspective

Virtually all our major control mechanisms developed in Paleolithic times; the important ones provided an advantage for survival. There have been no pressures in modern times that have enough control strength to over-ride these control mechanisms. The diet of our most ancient ancestors consisted mainly of fruit and berries; a diet that provides sugar, K ⁺ and organic anions, but little NaCl. In addition, this intake of K ⁺ was episodic, but large at times. Therefore, there was a need to have a mechanism in place to rapidly shift K ⁺ into the liver before it reaches the heart to avoid the risk of cardiac arrhythmia. Furthermore, the renal response needed to be orchestrated to switch from a NaCl conservation mode to a K ⁺ excretion mode. It is important in this regard to note that aldosterone can be a NaCl retaining or a kaliuretic hormone, in what has been dubbed as the “aldosterone paradox”. In more detail, when aldosterone acts, it causes the insertion of a larger number of open ENaC units in the luminal membrane of principal cells in CCD, which permits both NaCl retention or K ⁺ secretion. Thus, there must be another signal to select one of these possible effects. Of note, the secretagogue for aldosterone is ANG _II when its release is in response to a low effective arterial blood volume. On the other hand, a higher P _K directly stimulates the release of aldosterone, however, ANG _II in this setting, will be suppressed.

Shift of K ⁺ into Hepatocytes

While it is well known that there is a rise in the P _L-lactate in portal venous blood after absorption of dietary glucose, the physiological importance of this high P _L-lactate was not evident when viewed solely in metabolic terms. We suggested that a possible function of this high portal P _L-lactate is to prevent hyperkalaemia in hepatic venous blood following the absorption of K ⁺ from the diet. The process begins by increasing the rate of aerobic glycolysis in enterocytes; as a result of performing more work by intestinal cells and thereby the generation of more ADP, the other substrate (beside glucose) for glycolysis. This extra metabolic work occurs because the sodium linked glucose transporter (SLGT) in this location is SLGT-1. Hence, when 1 mmol of glucose is absorbed, 2 mmol of Na ⁺ must be absorbed; therefore more ATP will be converted to ADP to absorb a given quantity of glucose. Should glycolysis occur at a faster rate than that of pyruvate oxidation, L-lactate will released into the portal vein. In the liver, the uptake of L-lactic acid on the M-CT could lead to a rise the concentration of H ⁺ in the sub-membrane region of hepatocytes and hence activation of NHE-1. This electroneutral entry of Na ⁺ into hepatocytes and its subsequent exit via Na ⁺ /K ⁺ -ATPase in an electrogenic fashion, will lead to a higher negative intracellular voltage and hence the retention of K ⁺ in hepatocytes. This mechanism requires the presence of insulin, which is released in response to the dietary sugar load with the ingestion of fruit and berries. Perhaps, because of its effect, to cause the translocation of more Na ⁺ /K ⁺ -ATPase units to the cell surface of hepatocytes, insulin is required for this effect of L-lactic acid to cause a shift of K ⁺ into hepatocytes.