The level of the chloride in the plasma is regulated by the kidney. The kidney freely filters chloride across the basement membranes of the glomeruli. The amount of chloride that is excreted into the urine is determined by the chloride filtered by the glomeruli and by a series of transport processes that occur along the nephron. Under normal circumstances, over 60% of the filtered chloride is absorbed along the proximal tubule. In the early proximal tubule, sodium is absorbed with a proportional amount of water so that the concentration of sodium does not change. By contrast, bicarbonate and other non-chloride anions are rapidly absorbed with sodium and removed from the filtrate7 (Fig. 1A). As sodium and non-chloride anions are absorbed in the early proximal tubule segments (S1 and S2), the chloride concentration in the lumen of the proximal tubule increases. By the time the tubular fluid reaches the last segment of the proximal tubule (S3), the chloride concentration is high with respect to its plasma concentration allowing chloride to be passively absorbed down its concentration gradient (Fig. 1B). The transepithelial permeability for chloride is higher than the permeability for bicarbonate so that despite the peritubular-to-lumen gradient for bicarbonate, the transport of chloride leaving the lumen exceeds the bicarbonate entering the tubular fluid.

Fig. 1.

(A) In the early proximal tubule, isotonic sodium absorption occurs with organic solutes, bicarbonate, phosphate along with water resulting in a rising chloride concentration. (B) The high chloride concentration in the lumen also favors transcellular and paracellular transport. Intercellular junctions in the later proximal tubule become more permeable to chloride facilitating paracellular transport. Even when bicarbonate concentration falls in the lumen, Na+–H+ exchange continues to play a role in NaCl reabsorption. Transcellular sodium chloride absorption can occur via the coupling of Na+–H+ exchange with chloride-organic anion (formate, oxalate) exchange. The organic acid (formic or oxalic acid) is recycled into cells.

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In the early portion of the proximal tubule, chloride absorption also occurs via apical chloride-anion (formate, oxalate, base) exchangers and it exits the cell via basolateral membrane transporters8 (Fig. 1B). In hyperchloremic metabolic acidosis due to HCl- or ammonium chloride-loading, the chloride reabsorption in the proximal tubule is reduced, in part, because of the reduction in organic anion transporters that facilitate sodium chloride transport9 as well as the reduction in lumen-to-peritubular gradient for chloride.

The thick ascending limb of the loop of Henle (TALH) is an important site for chloride reabsorption.10 At this site, sodium, potassium and chloride are concurrently transported via a sodium-potassium-2 chloride co-transporter (NKCC2) (Fig. 2). Chloride enters the TALH cell and leaves its basolateral aspect down an electrogenic chloride channel or via the electroneutral potassium chloride co-transporter. The movement of chloride through the basolateral chloride channel (CLC-NKB) contributes to the generation of a transepithelial positive (lumen) to negative (basolateral) potential gradient. The intracellular positive potential that would be generated by the movement of chloride out of the cell is counterbalanced by the basolateral electrogenic Na+–K+ ATPase that transports sodium out of the cell in exchange for potassium into the cell in a 3–2 ratio. ROMK potassium channels on the apical TALH cell membrane contributes to the lumen positive (intracellular negative) potential through the conductive movement of potassium ions from cell to lumen. The overall effect is that chloride, sodium and potassium enter the cell via NKCC2, and, for the most part, chloride exits the cell via the basolateral ClC-NKB chloride channel, sodium exits the cell via the Na+–K+ ATPase and potassium recycles back into the lumen via the ROMK channel or exits basolaterally via the KCl co-transporter. The tight coupling between sodium and chloride transport in the TALH is underscored by one of the varieties of Bartter syndrome in which defects in basolateral chloride channels disrupt sodium chloride reabsorption and mimics the renal defect observed with abnormal NKCC2 proteins. Although other transporters on the peritubular side of the TAL cell such as the KCl co-transporter will transport chloride in a sodium-independent manner, most of the chloride that is absorbed by the TALH is coupled with sodium reabsorption. Therefore, factors that increase sodium reabsorption in this segment will also increase chloride reabsorption.

Fig. 2.

The thick ascending limb of the loop of Henle absorbs chloride via the apical Na+–K+–2Cl− cotransporter (NKCC2) and chloride exit from the cell via a basolateral chloride channel and by K+–Cl− cotransport. K+ recycling into the lumen and basolateral conductive Cl− exit via CLC-Kb contribute to the positive-to-negative lumen to basolateral transepithelial gradient. Intracellular chloride may regulate NKCC2 transport through a chloride-sensing WNK kinase (WNK) that can activate the STE20/SPS1-related proline/alanine rich kinase (SPAK) and NKCC2 when intracellular Cl− is low. On the other hand, when chloride accumulates in the cell due to defects in basolateral chloride channel exit pathway, NKCC2 transport is blocked. When NKCC2 is stimulated, for example by antidiuretic hormone, chloride entry is increased, but basolateral Cl-conductance is also enhanced.

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In the distal convoluted tubule, sodium and chloride are transported from the lumen into the cell by a sodium-chloride co-transporter (NCC)11 (Fig. 3). The driving force for movement of chloride from lumen into cells comes from the lumen-to-cell sodium gradient that is generated by the basolateral Na+–K+ ATPase which pumps sodium out of the cell thereby maintaining low intracellular sodium concentrations. Further regulation of NCC and NKCC may occur through WNK kinases, which may serve as chloride sensors12 and can regulate these transporters by modifying trafficking or their phosphorylation state.13 In later portions of the distal convoluted tubule, a negative lumen potential generated by movement of sodium through the apical epithelial sodium channel (ENaC) can also serve as a driving force for passive chloride reabsorption. Thus, the segments of distal convoluted tubule display direct coupling of sodium and chloride transport via the NCC and indirect coupling of transport via passive movement down an electrochemical gradient.

Fig. 3.

In the distal convoluted tubule, sodium and chloride in the lumen are taken up into the cell via a Na+–Cl− cotransporter (NCC). Transport via NCC is driven by a low intracellular sodium mostly generated by the basolateral Na+–K+ ATPase. The WNK1 kinase may serve as a chloride sensor to block inhibition of NCC by the WNK4 kinase.

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The collecting duct plays an important role in determining the chloride content of the final urine. Chloride reabsorption in this portion of the nephron helps to conserve chloride in response to low chloride intake and can contribute to the hypertensive effects of a high sodium chloride diet. Most of sodium that is reabsorbed in the collecting duct occurs in principal cells via aldosterone-regulated apical epithelial sodium channels. Chloride reabsorption in the collecting duct can occur via paracellular chloride absorption that is driven by the lumen negative transepithelial potential generated by lumen-to-cell sodium flow through ENaC (Fig. 4A). In addition, in B-type and non-A non-B type intercalated cells, chloride can be transported via pendrin, a chloride-bicarbonate exchanger, with chloride moving from lumen-to-cell while bicarbonate secreted into the lumen (Fig. 4B). The relationship between various sodium and chloride transport processes in this portion of the nephron was illustrated in a recent paper by Vallet and colleagues.14 The authors performed a number of physiological maneuvers to determine their effects on ENaC and pendrin protein levels in the kidney. Long-term NaCl loading significantly decreased pendrin protein levels while there was a decrease in the “active” ENaC-γ submit and an enhanced β-subunit. A dissociation between sodium and chloride transport was observed, however, with the inhibition of the sodium-chloride co-transporter with hydrochlorothiazide, pendrin levels fell but ENaC levels increased. NaCl restriction increased pendrin expression.15 An enhanced luminal bicarbonate concentration that would be created by pendrin-mediated bicarbonate secretion affects sodium reabsorption by increasing the activity of downstream ENaC.16 Sodium chloride transport by intercalated cells can also be enhanced by the presence of a thiazide-sensitive apical sodium-dependent chloride-bicarbonate exchanger (NDCBE, Slc4A8) which transports 1 sodium and 2 bicarbonate ions from the lumen into the cell in exchange for 1 chloride ion which leaves the cell. If NDCBE transport is coupled with pendrin-mediated chloride-bicarbonate exchange, the two transporters working together could result in net sodium chloride reabsorption from the lumen, as the bicarbonate recycles into and out of the cell while sodium and chloride enter the cell17 (Fig. 4B). Factors which alter the ratio of the amounts or activities of these two anion exchangers may determine the net impact on bicarbonate secretion and chloride reabsorption. Another transporter which may be involved in excretion of excessive chloride in the body is the Slc26A9 transporter which may act as a chloride channel in the medullary portions of the collecting duct.18 It may modify the impact of chloride loads by increasing chloride secretion under conditions of chloride excess. Knockout of this gene results in a predisposition to hypertension. Mice deficient in this protein develop hypertension when exposed to a high sodium chloride load.18 Although the Slc26a9 transporter appears to play an important role in handling large sodium chloride loads, the regulation of the native transporter activity in response to varied sodium chloride loads remains unknown.

Fig. 4.

(A) Chloride can be secreted or reabsorbed in the collecting duct. A portion of chloride absorption is driven by a lumen negative potential and paracellular movement. (B) Transcellular reabsorption of chloride can also occur via coupling of the apical Pendrin chloride-bicarbonate exchanger to the SLCA48 sodium -dependent chloride-2 bicarbonate exchanger (NDCBE). 2 cycles of Pendrin would result in 2 chlorides entering the cell in exchange for 2 bicarbonate while NDCBE would transport 1 sodium and 2 bicarbonates in exchange for 1 chloride out. The net result would be the transport of 1 sodium and 1 chloride into the cell. Differences in the apical Pendrin and NDCBE activities could determine whether Cl− secretion or absorption predominates.

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The serum chloride level is generally measured as a concentration of chloride in a volume of serum. The biologically active chloride concentration is the concentration of free chloride in the plasma water. Chloride is most frequently measured by using a silver-chloride electrode either in a direct or diluted serum sample.19 Automated methods found in many laboratories involve the dilution of the serum sample with reagent so that the volume of the sample is assumed to have a normal water content and estimations are made based upon assuming a normal dilution factor. When the solid components of the serum are very high, as can occur with hypertriglyceridemia and multiple myeloma, pseudohypochloremia can occur. Pseudohyperchloremia can also be seen in bromide or iodide intoxication. The interaction of bromide or iodide with the silver-chloride electrode generates a greater voltage change than does chloride giving the impression of excessive chloride in the blood.20,21

• 1.

  The kidney plays a key role in maintaining chloride balance in the body. Although renal chloride transport is coupled with sodium transport, chloride transport may sometimes diverge from sodium transport.

• 2.

  Hyperchloremia can result from a variety of conditions including water depletion, excessive chloride exposure and metabolic acidosis.

• 3.

  The pathogenic cause of hyperchloremia will provide guidance on how the disturbance should be treated: water depletion is treated with judicious water repletion; excess chloride administration by withholding further chloride administration; and hyperchloremic metabolic acidosis by giving bicarbonate.

The author declares no conflict of interest.