Document downloaded from http://www.elsevier.es, day 23/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. n e f r o l o g i a 2 0 1 6;3 6(4):347–353 Revista de la Sociedad Española de Nefrología www.revistanefrologia.com Brief review Hyperchloremia – Why and how Glenn T. Nagami Nephrology Section, Department of Medicine, VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, United States a r t i c l e i n f o a b s t r a c t Article history: Hyperchloremia is a common electrolyte disorder that is associated with a diverse group of Received 5 April 2016 clinical conditions. The kidney plays an important role in the regulation of chloride concen- Accepted 11 April 2016 tration through a variety of transporters that are present along the nephron. Nevertheless, Available online 3 June 2016 hyperchloremia can occur when water losses exceed sodium and chloride losses, when the capacity to handle excessive chloride is overwhelmed, or when the serum bicarbonate is low Keywords: with a concomitant rise in chloride as occurs with a normal anion gap metabolic acidosis Hyperchloremia or respiratory alkalosis. The varied nature of the underlying causes of the hyperchloremia Electrolyte disorder will, to a large extent, determine how to treat this electrolyte disturbance. Serum bicarbonate Published by Elsevier Espana,˜ S.L.U. on behalf of Sociedad Espanola˜ de Nefrologıa.´ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Hipercloremia: por qué y cómo r e s u m e n Palabras clave: La hipercloremia es una alteración electrolítica frecuente que se asocia a una serie de dis- Hipercloremia tintos trastornos clínicos. El rinón˜ desempena˜ una función importante en la regulación de la Alteración electrolítica concentración de cloruro a través de diversos transportadores que se encuentran a lo largo Bicarbonato sérico de la nefrona. Sin embargo, puede aparecer hipercloremia cuando la pérdida hídrica sea mayor que la de sodio y cloruro; cuando se sobrepase la capacidad de excretar el cloruro en exceso; o cuando la concentración sérica de bicarbonato sea baja y al mismo tiempo haya un aumento de cloruro, como sucede en la acidosis metabólica con brecha aniónica normal o en la alcalosis respiratoria. La heterogénea naturaleza de las causas subyacentes de la hipercloremia determinará, en gran medida, el modo de tratar esta alteración electrolítica. Publicado por Elsevier Espana,˜ S.L.U. a nombre de Sociedad Espanola˜ de Nefrologıa.´ Este es un artıculo´ Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/ licencias/by-nc-nd/4.0/). E-mail address: [email protected] http://dx.doi.org/10.1016/j.nefro.2016.04.001 0211-6995/Published by Elsevier Espana,˜ S.L.U. on behalf of Sociedad Espanola˜ de Nefrologıa.´ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Document downloaded from http://www.elsevier.es, day 23/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. 348 n e f r o l o g i a 2 0 1 6;3 6(4):347–353 Chloride is the most abundant anion in the extracellular A + fluid (ECF) compartment. Hyperchloremia is defined as an 3Na Na+ increase in the chloride concentration in the plasma water. ATP + 2K Organic anions, glucose Hyperchloremia and a relative excess of chloride in the + – bicarbonate, phosphate Na HCO3 body have been linked to the development of reduced renal Cl– Cl– 1,2 ↑ – blood flow, increased interstitial edema including in the CI 3 Anion– kidney and gastrointestinal system, excess morbidity and 4,5 mortality in critically ill patients, and reduced survival and 6 recovery in patients with acute kidney injury. Like sodium and other chemicals in the ECF compartment, chloride con- B – – centration is regulated. The organ that is responsible for the Cl ↑ CI + maintenance of chloride balance in the body is the kidney. 3Na + Na ATP This article reviews the handling of chloride by the kidney 2K+ H+ and clinical situations in which hyperchloremia can occur. Formic or oxalic Base, acid anion – acid Cl (formate, oxalate) Cl– Renal handling of chloride The level of the chloride in the plasma is regulated by the kid- Fig. 1 – (A) In the early proximal tubule, isotonic sodium ney. The kidney freely filters chloride across the basement absorption occurs with organic solutes, bicarbonate, membranes of the glomeruli. The amount of chloride that phosphate along with water resulting in a rising chloride is excreted into the urine is determined by the chloride fil- concentration. (B) The high chloride concentration in the tered by the glomeruli and by a series of transport processes lumen also favors transcellular and paracellular transport. that occur along the nephron. Under normal circumstances, Intercellular junctions in the later proximal tubule become over 60% of the filtered chloride is absorbed along the proxi- more permeable to chloride facilitating paracellular mal tubule. In the early proximal tubule, sodium is absorbed transport. Even when bicarbonate concentration falls in the + + with a proportional amount of water so that the concentra- lumen, Na –H exchange continues to play a role in NaCl tion of sodium does not change. By contrast, bicarbonate and reabsorption. Transcellular sodium chloride absorption can + + other non-chloride anions are rapidly absorbed with sodium occur via the coupling of Na –H exchange with 7 and removed from the filtrate (Fig. 1A). As sodium and non- chloride-organic anion (formate, oxalate) exchange. The chloride anions are absorbed in the early proximal tubule organic acid (formic or oxalic acid) is recycled into cells. 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 The intracellular positive potential that would be generated by chloride concentration is high with respect to its plasma con- the movement of chloride out of the cell is counterbalanced + + centration allowing chloride to be passively absorbed down by the basolateral electrogenic Na –K ATPase that transports its concentration gradient (Fig. 1B). The transepithelial per- sodium out of the cell in exchange for potassium into the cell meability for chloride is higher than the permeability for in a 3–2 ratio. ROMK potassium channels on the apical TALH bicarbonate so that despite the peritubular-to-lumen gradient cell membrane contributes to the lumen positive (intracel- for bicarbonate, the transport of chloride leaving the lumen lular negative) potential through the conductive movement exceeds the bicarbonate entering the tubular fluid. of potassium ions from cell to lumen. The overall effect is In the early portion of the proximal tubule, chloride absorp- that chloride, sodium and potassium enter the cell via NKCC2, tion also occurs via apical chloride-anion (formate, oxalate, and, for the most part, chloride exits the cell via the basolat- base) exchangers and it exits the cell via basolateral mem- eral ClC-NKB chloride channel, sodium exits the cell via the 8 + + brane transporters (Fig. 1B). In hyperchloremic metabolic Na –K ATPase and potassium recycles back into the lumen acidosis due to HCl- or ammonium chloride-loading, the chlo- via the ROMK channel or exits basolaterally via the KCl co- ride reabsorption in the proximal tubule is reduced, in part, transporter. The tight coupling between sodium and chloride because of the reduction in organic anion transporters that transport in the TALH is underscored by one of the varieties 9 facilitate sodium chloride transport as well as the reduction of Bartter syndrome in which defects in basolateral chloride in lumen-to-peritubular gradient for chloride. channels disrupt sodium chloride reabsorption and mimics The thick ascending limb of the loop of Henle (TALH) is the renal defect observed with abnormal NKCC2 proteins. 10 an important site for chloride reabsorption. At this site, Although other transporters on the peritubular side of the TAL sodium, potassium and chloride are concurrently transported cell such as the KCl co-transporter will transport chloride in via a sodium-potassium-2 chloride co-transporter (NKCC2) a sodium-independent manner, most of the chloride that is (Fig. 2). Chloride enters the TALH cell and leaves its basolat- absorbed by the TALH is coupled with sodium reabsorption. eral aspect down an electrogenic chloride channel or via the Therefore, factors that increase sodium reabsorption in this electroneutral potassium chloride co-transporter. The move- segment will also increase chloride reabsorption. ment of chloride through the basolateral chloride channel In the distal convoluted tubule, sodium and chloride are (CLC-NKB) contributes to the generation of a transepithelial transported from the lumen into the cell by a sodium-chloride 11 positive (lumen) to negative (basolateral) potential gradient. co-transporter (NCC) (Fig. 3). The driving force for movement Document downloaded from http://www.elsevier.es, day 23/05/2017. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. n e f r o l o g i a 2 0 1 6;3 6(4):347–353 349 Lumen Blood A Lumen Blood + – Na 3Na+ CI – 2CI ATP + Principal cell Na + K+ 2K+ Aldosterone + + Negative lumen 3Na+ SPAK K+ ATP 2k+ ENaC + CI– K WNK K+ K+ – CI– ROMK ROMK CLC-Kb Fig. 2 – The thick ascending limb of the loop of Henle B + + − absorbs chloride via the apical Na –K –2Cl cotransporter Lumen Blood (NKCC2) and chloride exit from the cell via a basolateral Type B intercalated cell + − + + chloride channel and by K –Cl cotransport.