LETTER

REPLY TO FARFEL ET AL.:

Is enhanced chloride reabsorption in proximal LETTER tubule a possible mechanism of metabolic acidosis in PHAII?

Jen-Chi Chena,b, Shih-Hua Lina, Chou-Long Huangc, and Chih-Jen Chenga,1

Hyperchloremic metabolic acidosis along with of PHAII (7). This process, also known as the “chloride hypertension and hyperkalemia are features of shunt,” will be expected to increase chloride reab- pseudohypoaldosteronism type II (PHAII). Increased sorption and decrease potassium and proton secre- activity of sodium chloride cotransporter (NCC) is tion in the collecting ducts due to the loss of believed to be an important mechanism of these negative charges in the lumen. Effects of WNK4 on phenotypic features (1). Gain-of-function mutations claudins known to regulate the paracellular perme- of WNK4 in PHAII activate NCC in the distal convo- ability or on pendrin provide the potential molecular luted tubule, which leads to enhanced sodium and basis for the chloride shunt hypothesis (8, 9). Much yet chloride reabsorption causing hypertension and di- remains to be investigated regarding whether these minished sodium delivery to the downstream cortical processes indeed exist in PHAII patients. For one, the collecting duct, resulting in hyperkalemia. Our recent findings that NCC-specific thiazide diuretics com- report (2) that chloride-insensitive WNK4 knockin pletely normalizes PHAII phenotypes do not lend sup- mouse exhibits increased WNK4 kinase activity and port for the chloride shunt hypothesis. Taken from the fully recapitulates PHAII phenotype supports the no- proposed chloride shunt mechanism in the collecting tion. Still, as mentioned by Farfel et al. (3), there re- ducts, Farfel et al. (3) propose that increased proximal main debates on the pathogenesis of hyperchloremia tubule luminal chloride concentration (from glomeru- and metabolic acidosis in PHAII. lar filtration of hyperchloremic plasma) will increase par- It is well accepted that hyperkalemia inhibits acellular chloride uptake in the proximal tubule. This ammoniogenesis in the proximal tubule, and hyper- process, in the authors’ view, may reduce the transepithelial kalemia per se can cause hyperchloremic metabolic potential for sodium bicarbonate cotransporter, lead- acidosis (4, 5). This notion is supported by the obser- ing to hyperbicarbonaturia. This hypothesis, how- vation that correcting hyperkalemia by low-potassium ever, has several concerns. First, proximal bicarbonate diet normalizes urinary ammonia excretion, metabolic reabsorption is heavily influenced by the volume sta- acidosis, and hyperchloremia in mouse model and tus. Volume expansion in PHAII will be expected to patients of PHAII (5, 6). In contrast, a recent study reduce proximal bicarbonate reabsorption. Second, showed that normalization of hyperkalemia in another there is no evidence to our knowledge supporting in- PHAII-mimicking mouse model failed to correct met- creased chloride fluxes in the proximal tubule in abolic acidosis, and deletion of chloride-bicarbonate PHAII. While luminal chloride is increased in PHAII, exchanger pendrin is necessary for correction of the peritubular blood chloride concentration is also hyperkalemia and metabolic acidosis. These results increased. Third, increased luminal chloride concen- highlight the potential effects of mutant WNK4 on tration in the early proximal tubule should enhance pendrin expressed in intercalated cells in the patho- the positive transepithelial potential difference gener- genesis of metabolic acidosis. ated by the electrogenic sodium-coupled organic sol- Increased chloride permeability with increased ute transport (10), which theoretically increases the luminal to blood chloride fluxes has long been driving force for bicarbonate reabsorption via sodium postulated as the central mechanism of pathogenesis bicarbonate cotransporter, not hyperbicarbonaturia.

aDivision of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; bGraduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan; and cDivision of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242 Author contributions: J.-C.C., S.-H.L., C.-L.H., and C.-J.C. wrote the paper. The authors declare no conflict of interest. Published under the PNAS license. 1To whom correspondence may be addressed. Email: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1910215116 PNAS Latest Articles | 1of2 Downloaded by guest on September 27, 2021 1 H. Mayan et al., Pseudohypoaldosteronism type II: Marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density. J. Clin. Endocrinol. Metab. 87, 3248–3254 (2002). 2 J.-C. Chen et al., WNK4 kinase is a physiological intracellular chloride sensor. Proc. Natl. Acad. Sci. U.S.A. 116, 4502–4507 (2019). 3 Z. Farfel, H. Mayan, S. J. D. Karlish, Familial hyperkalemia and hypertension and a hypothesis to explain proximal renal tubular acidosis. Proc. Natl. Acad. Sci. U.S.A., 10.1073/pnas.1909494116 (2019). 4 F. E. Karet, Mechanisms in hyperkalemic renal tubular acidosis. J. Am. Soc. Nephrol. 20,251–254 (2009). 5 A. N. Harris et al., Mechanism of hyperkalemia-induced metabolic acidosis. J. Am. Soc. Nephrol. 29, 1411–1425 (2018). 6 H. Nahum et al., Pseudohypoaldosteronism type II: Proximal renal tubular acidosis and dDAVP-sensitive renal hyperkalemia. Am. J. Nephrol. 6, 253–262 (1986). 7 K. Yamauchi et al., Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc. Natl. Acad. Sci. U.S.A. 101, 4690–4694 (2004). 8 K. I. L ´opez-Cayuqueo et al., A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis. Kidney Int. 94,514–523 (2018). 9 Y. Gong et al., KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8. Proc. Natl. Acad. Sci. U.S.A. 112, 4340–4345 (2015). 10 C. A. Berry, F. C. Rector, Jr, Electroneutral NaCl absorption in the proximal tubule: Mechanisms of apical Na-coupled transport. Kidney Int. 36,403–411 (1989).

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