Acidosis and Urinary Calcium Excretion: Insights from Genetic Disorders

BRIEF REVIEW www.jasn.org

† † ‡ R. Todd Alexander,* Emmanuelle Cordat, Régine Chambrey, Henrik Dimke,§ and ‡| Dominique Eladari

Departments of *Pediatrics and †Physiology, University of Alberta, Edmonton, Canada; ‡Institut National de la Santé et de la Recherche Médicale U970, Paris Centre de Recherche Cardiovasculaire, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; §Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Demark; and |Department of Physiologie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France

ABSTRACT Metabolic acidosis is associated with increased urinary calcium excretion and re- EFFECT OF ACID-BASE lated sequelae, including nephrocalcinosis and nephrolithiasis. The increased uri- PERTURBATIONS ON BONE nary calcium excretion induced by metabolic acidosis predominantly results from increased mobilization of calcium out of bone and inhibition of calcium transport Acute or chronic administration of ex- processes within the renal tubule. The mechanisms whereby acid alters the integrity ogenous acid increases urinary calcium and stability of bone have been examined extensively in the published literature. excretion. Initial studies exploring the Here, after briefly reviewing this literature, we consider the effects of acid on calcium effects of acid loading on overall calcium transport in the renal tubule and then discuss why not all gene defects that cause handling concluded that intestinal cal- renal tubular acidosis are associated with hypercalciuria and nephrocalcinosis. cium absorption is not affected3,4,10; however, recent work found increased J Am Soc Nephrol 27: 3511–3520, 2016. doi: 10.1681/ASN.2016030305 solvent drag mediated calcium flux and altered expression of tight junction proteins in the duodenum of rats with chronic metabolic acidosis.11,12 Given It has been appreciated for nearly a capacity for calcium due to the direct in- that the vast majority of calcium in the century that metabolic acidosis is asso- hibition of calcium transport within the body is stored in bone as part of the hy- ciated with increased urinary calcium nephron; this is evidenced by classic hu- droxyapatite crystal, it is expected that – excretion.1 3 Overall, this occurs via at man studies where metabolic acidosis dissolution of bone during acid loading least two mechanisms: release of calcium was induced and urinary calcium wast- leads to urinary calcium wasting. Exten- from bone4 and changes in calcium ing observed, despite a fall in the filtered sive evidence from multiple experimen- transport within the renal tubule.5 Given load of calcium.5 However, genetic distal models is consistent with this.7 There that bone is an important reservoir of eases causing renal tubular acidosis vary is an acute physicochemical buffering of buffer (with both calcium carbonate with regard to increased calcium excre- hydrogen ions (H+) followed by a more and phosphate), there is a myriad of tion and sequelae resulting from exces- chronic effect on cells mediating bone data and a strong rationale to implicate sive urinary calcium losses, such as turnover. its role in buffering acid.6,7 Dissolution nephrocalcinosis and nephrolithiasis.8,9 of bone releases calcium, either as car- In this review, we will first brieflysum- bonate or phosphate. The net movement marize over 90 years of experiments of calcium from bone into blood leads to examining the relationship between aci- Published online ahead of print. Publication date excess calcium being excreted in urine, dosis and urinary calcium excretion. available at www.jasn.org. in an effort to stabilize systemic calcium We will then highlight selected genetic Correspondence: Dr.R.ToddAlexander,De- concentrations. Metabolic acidosis in- disorders of altered acid-base balance, partment of Pediatrics, 4-585 Edmonton Clinic, Health Academy, 11405– 87 Ave, University of Al- creases ionized calcium in blood, by de- using them to understand why a direct berta, Edmonton, AB T6G 2R7, Canada. Email: creasing the amount bound to albumin. coupling between acidosis and renal cal- [email protected]

Furthermore, metabolic acidosis causes cium losses and their associated sequelae Copyright © 2016 by the American Society of alterations in the renal reabsorptive are not consistently observed. Nephrology

J Am Soc Nephrol 27: 3511–3520, 2016 ISSN : 1046-6673/2712-3511 3511 BRIEF REVIEW www.jasn.org

Acute Acidosis sodium handling.5,25,26 In order to con- The link between transcellular sodium Studies examining the mechanisms by sider how these alterations occur, we flux and paracellular calcium absorption which bone buffers H+ have been elo- must first review tubular calcium reab- under conditions of metabolic acidosis quently reviewed previously.6,7 In brief, sorption along the nephron. are yet to be clearly elucidated. NHE3 is the surface of bone is littered with nega- Ionized calcium that is filtered by the essential for proximal tubular bicarbonate tively charged sites that bind both glomerulus is reabsorbed via both pas- reabsorption.27 Consequently, metabolic sodium and potassium. During acute sive paracellular and active transcellular acidosis increases NHE3 activity,39,40 an metabolic acidosis (,3hours)thereis pathways. The proximal tubule and thick effect that should attenuate increased uri- an exchange of both these monovalent ascending limb (TAL) of the Henle loop nary calcium excretion accompanying cations with H+ thereby increasing demonstrate predominantly, if not ex- metabolic acidosis. However, metabolic plasma pH.13–15 There is also some rapid clusively, passive paracellular transport. acidosis dissociates sodium reabsorption direct dissolution of calcium carbonate In the proximal tubule, water absorption from calcium reabsorption distal to the and hydroxyapatite from bone releasing is driven by transcellular sodium move- late proximal tubular micropuncture calcium, which is likely part of the rap- ment, which is largely mediated by the site, causing increased urinary calcium ex- idly exchangeable pool of calcium.13,14,16 apical sodium hydrogen exchanger 3 cretion relative to sodium.25,41 The overall Both of these physicochemical processes (NHE3).27 Luminal water removal in- contribution of the TAL to changes in occur independently of bone cell activity. creases the concentration of different calcium transport under conditions of solutes, such as calcium, that are not re- metabolic acidosis remains to be fully elu- Chronic Acidosis absorbed via secondary active transport cidated. Given our current understanding In contrast to the acute situation, expo- processes. Calcium then moves down its of TAL transport, one could envision that sure of bone to chronic metabolic aci- concentrationgradientorwithwater increased ionized calcium in blood (both dosis i.e., for 24 hours or more, affects through the tight junction.28 In the mobilized from bone and due to de- bone cell function. Osteoclast activity is TAL, removal of water in the relatively creased binding to albumin) would in- stimulated and osteoblast activity is in- calcium impermeable thin descending crease claudin-14 expression by activating hibited by lower pH.17–19 Importantly, limb,29 and a lumen positive voltage, the CaSR, thereby altering the permeabil- the converse is true; metabolic alkalosis provides the driving force for paracellu- ity of the paracellular pore. This would increases osteoblastic activity and in- lar calcium flux. Activity of the apically increase urinary calcium excretion hibits osteoclastic activity, favoring expressed sodium potassium chloride and could contribute to the dissociation bone formation.20 One mechanism cotransporter2(NKCC2)inconcert between increased NHE3 activity and whereby acidosis mediates its effect on with potassium efflux back into the lu- increased urinary calcium excretion ob- bone involves the release of PGE2,which men via the renal outer medullary po- served with metabolic acidosis. However, stimulates the expression of receptor ac- tassium channel is necessary to create direct evidence in support of this hypoth- tivator of nuclear factor k-B (RANK) li- the lumen positive potential. Consistent esis has not been presented, and one gand altering osteoclast differentiation, with a role in calcium reabsorption, ge- must also consider the reduced sensitiv- maturation and H+ATPase activity netic deletion or pharmacological inhi- ity of the CaSR at acidic pH.42 thereby increasing resorption.21–23 bition of either NKCC2 or NHE3 causes Although the majority of calcium is hypercalciuria.30–34 reabsorbed by the proximal tubule and Paracellular calcium transport requires TAL, the remaining ,10% is reabsorbed EFFECTS OF ACID-BASE both a driving force, and tight junction by the distal convoluted tubule and con- PERTURBATIONS ON THE RENAL permeability. Calcium permeation of the necting tubule. This occurs in an active TUBULE proximal tubule and TAL is conferred by transcellular fashion and discernable specific tight junction proteins called changes in transport within this region Metabolic acidosis causes renal calcium claudins.35 Their identity is better delin- have been clearly documented during wasting not only via the liberation of eated in the TAL where claudins-16 and acidosis.43 Apical calcium influx occurs calcium from bone, but also by directly -19 form a cation permeable pore,36 and through the transient receptor potential altering calcium handling within the re- claudin-14, whose expression is directly cation channel subfamily V member 5 nal tubule. This is evident as an increase induced via the calcium-sensing receptor (TRPV5) channel.44 The calcium bind- in urinary calcium excretion occurs (CaSR) signaling in the presence of in- ing protein calbindin-D28K buffers ion- despite a decrease in filtered calcium creased ionized calcium levels, prevents ized calcium, which is extruded across load.5,24 Furthermore, metabolic acido- calcium reabsorption.37 In the proximal the basolateral membrane via calcium sis alters renal tubular calcium handling tubule, claudin-2 may form a cation per- dependent ATPases (plasma membrane irrespective of changes in parathyroid meable pore.38 However, further work is Ca2+ ATPase) or a sodium calcium ex- hormone (as patients with hypoparathy- required to clearly delineate the proteins changer.45,46 Micropuncture studies roidism demonstrate this phenome- permitting calcium permeation across demonstrate that calcium reabsorption non), and independent of tubular this segment. from the distal nephron is inhibited by

3512 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 3511–3520, 2016 www.jasn.org BRIEF REVIEW metabolic acidosis, independent of excretion or increases urinary calcium creased PTH enhances bone resorption changes in parathyroid hormone excretion less so than a similar decrease in favoring calcium mobilization into (PTH), inferring a direct effect on renal pH caused by a metabolic acidosis.52–54 blood. However, considerable evidence 41,47,48 transport processes. Consistent As noted earlier, prostaglandin (PG) E2 exists that the effect of acid on bone, and with this, renal Trpv5 expression is de- promotes osteoclast maturation and H+ consequently calciuria, occurs indepen- creased by systemic acid loads and met- ATPase activity via the RANK pathway dently of PTH.58–60 Similarly, reduced abolic alkalosis increases expression.49 thereby increasing bone resorption.21–23 1,25-dihydroxyvitamin D levels decrease Moreover, metabolic acidosis does not PGE release is preferentially stimulated intestinal calcium uptake, which should further augment existing calcium wast- by experimental metabolic acidosis reduce urinary calcium excretion. How- ing in the Trpv5 knockout mice.49 rather than respiratory acidosis.22 More- ever, many, but not all, studies found that Together, this data suggests that systemic over, elegant in vitro studies manipulat- metabolic acidosis increases urinary acid-base status, at least in part, alters ing bicarbonate levels independent of calcium excretion without altering in- urinary calcium excretion via an effect pH demonstrate that calcium mobiliza- testinal calcium absorption,4,60,61 and on the expression and activity of Trpv5 tion from bone in response to a meta- argued against a direct role for 1,25- in the distal tubule. Importantly, Trpv5- bolic acidosis occurs to a greater extent dihydroxyvitamin D in this process. deficient mice display reduced bone when bicarbonate concentration is Indeed 1,25-dihydroxyvitamin D gener- thickness due to increased osteoclast- simultaneously reduced.55,56 This may ationinresponsetothecalciuriaof mediated bone resorption, likely as a explain why respiratory acidosis is less any metabolic acidosis is indirectly consequence of renal calcium wast- potent than metabolic acidosis in pro- suppressed by bone resorption which ing.50 However, Trpv5 is also expressed moting urinary calcium wasting.52–54 elevates plasma calcium.62 in the ruffled border of the osteoclast, Consistent with this, in vitro models of The ingestion of protein has many where it partakes in vectorial calcium acidosis with elevated bicarbonate levels diverse physiologic effects including the transport from the subosteoclastic re- can actually increase carbonate incorpo- production of hormones and nonvolatile sorption zone.51 Therefore, the effect of ration into bone.57 Consequently, acid. A meta-analysis examining dietary metabolic acidosis on Trpv5-mediated plasma bicarbonate levels themselves, interventions to increase acid producing calcium reabsorption in kidney, inde- independent of pH, affect bone forma- food ingestion found a proportionate pendent of loss of Trpv5 in osteoclasts, tion and dissolution. Thus, when con- increase between urinary acid excretion remains to be determined. sideringtheeffectofacid-basestatus and urinary calcium excretion.63 The on calcium homeostasis, one must also calcium was assumed to come from consider bicarbonate, because it appears bone. However, this has been called CONSIDERATION OF TYPE OF to have a greater effect on bone than into question because another meta- ACIDOSIS changes in pH. We are unaware of stud- analysis by the same group found that ies directly examining renal tubular total calcium balance and markers of Studies described thus far were limited calcium handling in the presence of re- bone breakdown were not altered by in- to very controlled situations where acid- spiratory acidosis. However, the effects creased dietary acid consumption.64 A base status was manipulated by strict of hypercarbia on luminal bicarbonate high protein diet itself can increase in- administration of an acid or alkali. Fur- concentration may increase distal cal- testinal calcium uptake, growth hor- thermore, the effect of respiratory cium absorption, further attenuating mone, and insulin like growth factor 1 perturbations on acid-base status and urinary calcium excretion. levels as well as lower PTH, which are calcium handling reveals an important factors that favor bone formation.65 role for bicarbonate. Moreover, other Different Exogenous Acids Thus, translating models of ammonium than causing metabolic acidosis, addi- Hydrochloric acid and ammonium chloride induced acidosis into recom- tional effects of specificacidsandtheir chloride administration have been em- mendations on protein consumption to counter ions on calcium homeostasis ployed to model disease states such as the promote bone health, one needs to con- and consequently urinary calcium ex- acidosis observed in renal failure or that sider confounding factors. Similarly, di- cretion further complicate the situa- induced by ingestion of a high protein abetic ketoacidosis and lactic acidosis are tion. However, consideration of these diet. These models simplify complex typically associated with volume con- effectsaidsourunderstandingofthe disease processes and conclusions from traction, which reduces urinary calcium dynamic physiologic processes occur- them must therefore be carefully con- excretion by increasing proximal tubular ring simultaneously. sidered. In the case of uremic metabolic calcium reabsorption. However, the os- acidosis, it is typically accompanied by an motic diuresis caused by the former Metabolic Versus Respiratory elevated PTHand suppressed active1,25- would attenuate proximal tubular cal- Acidosis dihydroxyvitamin D levels. These hor- cium reabsorption. This and decreased In different studies respiratory acidosis mones have significant effects on urinary insulin levels partially explain the more either does not increase urinary calcium calcium excretion by themselves. In- severe urinary calcium loss observed in

J Am Soc Nephrol 27: 3511–3520, 2016 Acidosis and Calcium Excretion 3513 BRIEF REVIEW www.jasn.org diabetic ketoacidosis relative to lactic was recently discussed.9 Although many have a significant net positive calcium acidosis.66 factors are considered, including other balance in order to mineralize bone, polymorphisms, the authors provide a and a reduced ability to concentrate their strong argument for decreased intravas- urine79,80; both these factors would fur- INSIGHT FROM HUMAN DISEASES cular volume and low sodium intake in ther attenuate the effect of acidosis on preventing hypercalciuria. Importantly, hypercalciuria. Distal Renal Tubular Acidosis ATP6V1B1 has been implicated in so- Patients with incomplete dRTA due to Distal renal tubular acidosis (dRTA) is dium absorption, and children with milder mutations in ATP6V1B1 often dis- a disease characterized by a failure to these mutations also have salt-losing play hypercalciuria and a tendency to acidify urine, i.e., an inappropriately el- nephropathy.72,73 The relationship form kidney stones.81,82 The etiology of evated urine pH in the presence of a between sodium ingestion and calcium nephrocalcinosis in these patients is due nonanion gap (or hyperchloremic) met- excretion is well known.74 The molecu- to intraluminal precipitation of calcium abolic acidosis. The genetic causes of lar details linking the two are less phosphate in the inner medullary collect- this disease are often, but not always, clear. Given that paracellular calcium ab- ing duct, likely resulting from an elevated accompanied by hypercalciuria and sorption is driven by sodium reabsorp- intraluminal pH.83 However, it raises the nephrolithiasis and/or nephrocalcinosis tion from the proximal tubule and intriguing question as to why some hyper- (Table 1). Given the previous discussion TAL,75–77 it can be argued that a low so- calciuric disease states result in frank cal- on the effect of metabolic acidosis on dium diet leads to increased sodium re- cifications throughout specific parts of the bone, one would predict severe osteopo- absorption and consequently increased kidney, i.e., nephrocalcinosis, whereas rosis in these patients. However, this is driving force for calcium across these others cause discrete calcification as a rarely observed; instead, a mild reduc- nephron segments (Figure 1). Similarly, stone, i.e., nephrolithiasis. tion in bone density has been reported, intravascular volume status strongly af- which can be ameliorated by the admin- fects proximal tubule sodium, water, and ATPV0A4 istration of alkali.67,68 The molecular consequently calcium reabsorption.78 Mutations in the a 4 subunit of the H+- cause of dRTA has been ascribed to mu- Consistent with this, Coe et al.57 found ATPase cause dRTA, which is sometimes tations in the H+-ATPase b 1 subunit that hypercalciuria associated with am- associated with deafness.84,85 Nephro- (ATP6V1B1),69 a 4subunit(ATP6V0A4), monium chloride-induced metabolic ac- calcinosis was observed in all patients and the anion exchanger 1 (AE1/SLC4A1). idosis was prevented by salt restriction for whom data are reported, although We discuss urinary calcium excretion with and only when subjects became salt nephrolithiasis is rare. As with ATP6V1B1 respect to specific gene defects below. replete did hypercalciuria ensue. It is mutations, a minority presented with- therefore likely that the lower sodium out hypercalciuria.85–87 Interestingly, ATP6V1B1 diet ingested by infants who are either the patients without hypercalciuria Patients with mutations in ATP6V1B1 breast-fed or fed formulae masks the hy- were aged ,6 months. It is therefore typically have dRTA accompanied by percalciuria induced by metabolic acido- likely that a low sodium intake, vol- deafness, and nearly all reported cases sis. Furthermore, when these children ume contraction, and/or a net positive display nephrocalcinosis.69–71 Why some start to consume solids more sodium calcium balance contributed to their younger children with mutations in would be ingested and they consequently normocalciuria, despite significant met- ATP6V1B1 do not have hypercalciuria develop hypercalciuria. Finally, infants abolic acidosis.

Table 1. RTA gene defects, calciuria, nephrocalcinosis and nephrolithiasis Gene/protein Hypercalciuria, % Nephrocalcinosis, % Nephrolithiasis, % References dRTA ATP6V1B1/ V1-ATPase B1 subunit 89 (25 of 28) 100 (38 of 38) 72 (13 of 18) 9,69,71,117–121 ATP6V0A4/ V0-ATPase A4 subunit 78 (7 of 9) 100 (9 of 9) Not reported 85,86 SLC4A1/AE1, Anion Exchanger isoform 1 89 (8 of 9) 66 (21 of 32) 50 (12 of 24) 90,92,122–124 Mixed RTA CA2/carbonic anhydrase 2 0 (0 of 12) Not Reported Not Reported 106–108,125,126 pRTA + - 97,127–129 SLC4A4/NBCe1, electrogenic Na /HCO3 cotransporter 0 (0 of 5) 0 (0 of 6) 0 (0 of 6) Fanconi syndrome CTNS/cystinosin 60 (38 of 63) 68 (43 of 63) 17 (11 of 63) 130,131 CLCN5/ CLC-5, Dent disease 89 76 41 132 ORCL1/OCRL-1, oculocerebrorenal syndrome of Lowe 88 (22 of 25) 48 (12 of 25) 24 (6 of 25) 133,134 (but mutations can also cause Dent disease)

3514 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 3511–3520, 2016 www.jasn.org BRIEF REVIEW

Figure 1. Effect of metabolic acidosis on calcium homeostasis. Metabolic acidosis via a physicochemical process is acutely buffered by exchange of + + surface sodium (Na ) and potassium ions (K ) with protons on bone. Chronically, via osteoclast specific mechanisms, CaCO3 and Ca10(PO4)6(OH)2 - are liberated. These processes are also significantly affected by serum HCO3 levels. Calcium liberated from bone is filtered by the glomerulus; however, acidosis also directly alters tubular handling. In the distal convoluted tubule (DCT) and connecting tubule (CNT), acidosis effects the expression of TRPV5, but also the luminal H+ concentration has direct effects on TRPV5 activity (H+ inhibits). Consequently, bicarbonaturia, by increasing luminal pH increases TRPV5 activity. There is debate as to whether there is significant calcium reabsorption from the collecting duct. However, a intercalated cells in this segment, when unable to secrete protons such as with dRTA, will fail to acidify the urine altering the solubility of calcium salts. In the proximal tubule, a high pH inhibits citrate reabsorption (as observed in pRTA). Further proximal sodium reabsorption, which significantly increases proximal calcium absorption, such as under conditions of hypovoemia, can effect urinary calcium excretion, but also the water 2+ + reabsorption and the supersaturation of calcium (Ca ) salts. C2, claudin-2; calb 28K, calbindin-D28K;NaDC1,Na dicarboxylate contransporter 1; NBCe1, sodium bicarbonate exchanger e1; NCX, sodium calcium exchanger; PMCA, plasma membrane calcium ATPase; PO4, phosphate.

The Apical H+-ATPase, Volume reabsorption via this mechanism. Con- SLC4A1 Regulation, and Calcium sequently, patients with mutations in Mutations in AE1 (SLC4A1) cause dRTA, Homeostasis the H+-ATPase would be prone to vol- which can be transmitted in either Patients with dRTA have long been ume contraction and, as has been an autosomal dominant or recessive appreciated to also have a disorder of suggested for mutations in NCC, have fashion. Patients present without deaf- sodium wasting.73 The molecular details increased proximal tubular sodium and ness but commonly have hypercalciuria, of how the vacuolar H+-ATPase in the consequently calcium reabsorption. nephrolithiasis, and nephrocalcino- collecting duct contributes to sodium re- Thus, if volume contracted, these sis.90–93 Interestingly, not all patients absorption were recently described. In patients would further attenuate hyper- with nephrolithiasis have nephrocalci- combination with pendrin and Slc4A8, calciuria induced by metabolic acidosis. nosis and vice versa.90 Hypercalciuria the H+-ATPase mediates thiazide-sensitive However, it should also be noted that and its sequelae appear to be suppressed sodium reabsorption through the b- volume contraction could exacerbate through the administration of alkali, intercalated cell under situations of nephrocalcinosis and nephrolithiasis suggesting that urinary calcium excre- volume depletion.72,88,89 Mutations in by decreasing urinary ﬂow resulting in tion is driven largely by the metabolic either disease causing subunits would increased urine supersaturation of cal- acidosis. As with all causes of dRTA, pa- therefore prevent transcellular sodium cium, phosphate, or oxalate. tients are unable to acidify their urine.

J Am Soc Nephrol 27: 3511–3520, 2016 Acidosis and Calcium Excretion 3515 BRIEF REVIEW www.jasn.org

Unfortunately, an alkaline pH increases enzyme is required for both acid secre- intestinal calcium absorption, bone the supersaturation of calcium phos- tion in the a intercalated cell but also for turnover, and consequently affects uri- phate in the tubular lumen, thereby bicarbonate reabsorption from the prox- nary calcium excretion, as is often seen augmenting the risk of stone formation imal tubule. Consequently, individuals with Fanconi syndrome. (calcium oxalate supersaturation re- lacking CA2 activity demonstrate Defects in CLC5 cause Dent dis- mains relatively independent of urinary both bicarbonaturia and the inability to ease.111 This type of Fanconi syndrome pH). Finally, stone risk is further en- acidify their urine in the presence of is characterized by hypercalciuria and hanced in dRTA patients due to reduced metabolic acidosis.104,106,107 Given the nephrocalcinosis. CLC5 is a proton- urinary excretion of citrate.94 discussion, one would predict that chloride exchanger expressed in endo- these patients have severe osteoporosis. cytic vesicles in the proximal tubule, where Proximal Renal Tubular Acidosis However, this is not the case. They dem- it colocalizes with the H+ATPase.112 Im- Isolated metabolic acidosis due to a de- onstrate osteopetrosis resulting from portantly, defects in CLC5 can cause dis- fect in proximal tubular bicarbonate insufficient bone resorption.106,108 This orders other than Dent disease. It has reabsorption is referred to as type 2 or occurs because CA2 is required to gen- been suggested that hypercalciuria in proximal RTA (pRTA). This disease is erate protons secreted into the subosteo- these patients is a result of increased vi- most commonly associated with global clastic resorption pits by the osteoclasts, tamin D. This is thought to occur due to renal dysfunction, i.e., Fanconi syn- so that the mineralized matrix can be reduced 24-hydroxylation of vitamin D drome (see below). pRTA rarely occurs dissolved.109 Hence, even with metabolic in the proximal tubule. Ultimately this without other types of proximal tubular acidosis there is impairment of calcium would suppress PTH, increasing urinary dysfunction. To date, only mutations in dissolution from bone, reinforcing the calcium excretion. However, not all pa- NBCe1 have been found to cause isola- notion that bone loss during chronic tients with Dent disease display increased ted pRTA in humans.8,95,96 Patients with metabolic acidosis is mediated by altered vitamin D levels and only one of the two this disorder do not have evidence of al- osteoclast activity and is not simply a knockout mice strains has increased tered bone breakdown, hypercalciuria, physicochemical response. Conse- vitamin D levels.113,114 Calcium is reab- or nephrocalcinosis; however, they typi- quently, CA2-deficient mice do not dis- sorbed in a paracellular fashion from the cally display decreased growth, a likely play hypercalciuria (R.T. Alexander, proximal tubule; consequently, endo- consequence of their metabolic acido- unpublished observation), and patients cytic defects caused by mutations in sis.8,95,97–99 The lack of hypercalciuria with CA2 deficiency are not reported to CLC5 could alter the permeability to is surprising because loss of proximal have hypercalciuria.106–108 As with and/or the molecules generating the bicarbonate reabsorption would result pRTA, the tubular lumen of the distal driving force for calcium across the prox- in decreased sodium and consequently convoluted tubule would contain signif- imal tubule, thereby resulting in hyper- calcium reabsorption,100 which might icant bicarbonate to increase TRPV5 calciuria. Further confusing the situation overwhelm distal tubular calcium reab- activity, further preventing the hypercal- is that although uncommon, mutations sorption capacity. However, this obser- ciuria associated with their metabolic in the OCRL gene can also cause hyper- vation could be explained by an elevated acidosis. calciuria and nephrocalcinosis without luminal pH of the distal tubule, which metabolic acidosis.115,116 Understanding would increase the surface expression Fanconi Syndrome the mechanisms causing CLC5 and OCRL and activity of the apical calcium chan- The Fanconi syndrome describes the mutations to cause calciuria and nephro- nel, TRPV5, and consequently calcium presence of multiple defects in proximal calcinosis will undoubtedly provide absorption.101 Finally, in contrast tubular reabsorptive capacity including further information on the complex in- to dRTA and patients with metabolic pRTA, phosphaturia, glucosuria, amino terplay between metabolic acidosis and acidosis, patients with pRTA have sig- aciduria, and low molecular weight pro- urinary calcium excretion. nificantcitrateintheirurine(dueto teinuria. There are many genetic defects inhibition of proximal citrate reabsorp- that can cause this disorder and discus- tion by an alkaline luminal pH). This sing them all is beyond the scope of this SUMMARY would help prevent calcium precipitation review. However, a few points are worth and stone formation in patients with considering. Twenty-five-hydroxyvita- It is an oversimplification to suggest that pRTA.102,103 min D circulates bound to the vitamin urinary calcium excretion occurs merely D binding protein. This complex is in response to acidosis-induced bone Type 3 RTA and Carbonic filtered at the glomerulus and is reabsor- dissolution. Although bone is a buffer, Anhydrase 2 Deficiency bed by theproximal tubule, providing the the concentration of serum bicarbonate, Renal tubular acidosis of a mixed nature, 1-a hydroxylase enzyme with sub- i.e., type of acidosis, has a strong influ- i.e., both proximal and distal, is called strate.110 Failure to endocytose this com- ence on calcium release from bone. type 3. This is caused by a defect in car- plex results in decreased conversion Moreover, pH has a strong effect on tu- bonic anhydrase 2 (CA2).104,105 This to active vitamin D, which reduces bular calcium handling, independent of

3516 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 3511–3520, 2016 www.jasn.org BRIEF REVIEW

PTH and vitamin D. Not only does pH 4. Lemann J Jr, Litzow JR, Lennon EJ: The ef- respiratory, acidosis. Am J Physiol 256: – regulate the expression of calcium trans- fects of chronic acid loads in normal man: F836 F842, 1989 further evidence for the participation of 18. Krieger NS, Sessler NE, Bushinsky DA: Aci- porting proteins in the distal nephron, fl bone mineral in the defense against chronic dosis inhibits osteoblastic and stimulates the pH of the luminal uid is likely to metabolic acidosis. JClinInvest45: 1608– osteoclastic activity in vitro. Am J Physiol directly affect the activity of calcium 1614, 1966 262: F442–F448, 1992 transport mechanisms. Finally, when ex- 5. Lemann J, Litzow JR, Lennon EJ: Studies of 19. Bushinsky DA: Stimulated osteoclastic and amining urinary calcium excretion, the mechanism by which chronic metabolic suppressed osteoblastic activity in meta- acidosis augments urinary calcium excre- bolic but not respiratory acidosis. Am J compensatory aspects of tubular physi- – – i.e., tion in man. J Clin Invest 46: 1318 1328, Physiol 268: C80 C88, 1995 ology must also be considered, 1967 20. Bushinsky DA: Metabolic alkalosis de- volume status and sodium ingestion, be- 6. Bushinsky DA, Frick KK: The effects of acid creases bone calcium efflux by suppressing cause these control calcium reabsorp- on bone. Curr Opin Nephrol Hypertens 9: osteoclasts and stimulating osteoblasts. Am – – tion from more proximal aspects of the 369 379, 2000 JPhysiol271: F216 F222, 1996 7. Krieger NS, Frick KK, Bushinsky DA: Mech- 21. Frick KK, Bushinsky DA: Metabolic acido- nephron and supersaturation of calcium fl anism of acid-induced bone resorption. sis stimulates RANKL RNA expression in salts in luminal uid. Much work re- Curr Opin Nephrol Hypertens 13: 423–436, bone through a cyclo-oxygenase-dependent mains to be done in order to understand 2004 mechanism. J Bone Miner Res 18: 1317–1325, why some transport defects cause hyper- 8. Igarashi T, Inatomi J, Sekine T, Cha SH, 2003 calciuria and nephrolithiasis as opposed Kanai Y, Kunimi M, Tsukamoto K, Satoh H, 22. Bushinsky DA, Parker WR, Alexander KM, Shimadzu M, Tozawa F, Mori T, Shiobara M, Krieger NS: Metabolic, but not respiratory, to nephrocalcinosis. Our emerging un- Seki G, Endou H: Mutations in SLC4A4 acidosis increases bone PGE(2) levels and derstanding of the tight junction and cause permanent isolated proximal renal calcium release. Am J Physiol Renal Physiol paracellular transport may help provide tubular acidosis with ocular abnormalities. 281: F1058–F1066, 2001 these answers. Nat Genet 23: 264–266, 1999 23. Nordström T, Shrode LD, Rotstein OD, 9. Tsai HY, Lin SH, Lin CC, Huang FY, Lee MD, Romanek R, Goto T, Heersche JN, Tsai JD: Why is hypercalciuria absent at di- Manolson MF, Brisseau GF, Grinstein S: agnosis in some children with ATP6V1B1 Chronic extracellular acidosis induces plas- ACKNOWLEDGMENTS mutation? Pediatr Nephrol 26: 1903–1907, malemmal vacuolar type H+ ATPase activity 2011 in osteoclasts. J Biol Chem 272: 6354–6360, 10. Martin HE, Jones R: The effect of ammo- 1997 R.T.A. is an Alberta Innovates Health Solu- nium chloride and sodium bicarbonate on the 24. Stacy BD, Wilson BW: Acidosis and hyper- tions Clinical Scholar and work in his urinary excretion of magnesium, calcium, and calciuria: renal mechanisms affecting cal- laboratory is supported by grants from the phosphate. Am Heart J 62: 206–210, 1961 cium, magnesium and sodium excretion in Women and Children Health Research 11. Charoenphandhu N, Wongdee K, Tudpor the sheep. JPhysiol210: 549–564, 1970 Institute, which is supported by the Stollery K, Pandaranandaka J, Krishnamra N: 25. Sutton RA, Dirks JH: Renal handling of cal- – ’ Chronic metabolic acidosis upregulated cium. Fed Proc 37: 2112 2119, 1978 Children s Hospital Foundation, the Ca- claudin mRNA expression in the duodenal 26. Houillier P, Normand M, Froissart M, nadian Institutes of Health Research, enterocytes of female rats. Life Sci 80: Blanchard A, Jungers P, Paillard M: Calciuric and the Kidney Foundation of Canada. 1729–1737, 2007 response to an acute acid load in healthy H.D. is supported by the Novo Nordisk 12. Charoenphandhu N, Tudpor K, Pulsook N, subjects and hypercalciuric calcium stone – Foundation, the Carlsberg Foundation, Krishnamra N: Chronic metabolic acidosis formers. Kidney Int 50: 987 997, 1996 stimulated transcellular and solvent drag- 27. Schultheis PJ, Clarke LL, Meneton P, Miller the Lundbeck Foundation, and the A.P. induced calcium transport in the duodenum ML, Soleimani M, Gawenis LR, Riddle TM, Møller Foundation. of female rats. Am J Physiol Gastrointest Duffy JJ, Doetschman T, Wang T, Giebisch Liver Physiol 291: G446–G455, 2006 G, Aronson PS, Lorenz JN, Shull GE: Renal 13. Bushinsky DA, Levi-Setti R, Coe FL: Ion mi- and intestinal absorptive defects in mice DISCLOSURES croprobe determination of bone surface lacking the NHE3 Na+/H+ exchanger. Nat elements: effects of reduced medium pH. Genet 19: 282–285, 1998 None. Am J Physiol 250: F1090–F1097, 1986 28. Alexander RT, Dimke H, Cordat E: Proximal 14. Bushinsky DA, Wolbach W, Sessler NE, tubular NHEs: sodium, protons and cal- Mogilevsky R, Levi-Setti R: Physicochemical cium? Am J Physiol Renal Physiol 305: REFERENCES effectsofacidosisonbonecalciumflux and F229–F236, 2013 surface ion composition. JBoneMinerRes 29. Rouse D, Ng RC, Suki WN: Calcium trans- 1. Lamb AR, Evvard JM: The acid-base bal- 8: 93–102, 1993 port in the pars recta and thin descending ance in animal nutrition. J Biol Chem 37: 15. Bushinsky DA, Gavrilov K, Chabala JM, limb of Henle of the rabbit, perfused in vitro. 329–342, 1919 Featherstone JD, Levi-Setti R: Effect of JClinInvest65: 37–42, 1980 2. Williamson BJ, Freeman S: Effects of acute metabolic acidosis on the potassium con- 30. Simon DB, Karet FE, Hamdan JM, DiPietro changes in acid-base balance on renal cal- tent of bone. J Bone Miner Res 12: 1664– A, Sanjad SA, Lifton RP: Bartter’s syndrome, cium excretion in dogs. Am J Physiol 191: 1671, 1997 hypokalaemic alkalosis with hypercalciuria, 384–387, 1957 16. Pirklbauer M, Mayer G: The exchangeable is caused by mutations in the Na-K-2Cl 3. Farquharson RF, Salter WT, Tibbetts DM, calcium pool: physiology and pathophysi- cotransporter NKCC2. Nat Genet 13: Aub JC: STUDIES OF CALCIUM AND ology in chronic kidney disease. Nephrol 183–188, 1996 PHOSPHORUS METABOLISM: XII. The Effect Dial Transplant 26: 2438–2444, 2011 31. Takahashi N, Chernavvsky DR, Gomez RA, of the Ingestion of Acid-producing Substances. 17. Bushinsky DA: Net calcium efflux from live Igarashi P, Gitelman HJ, Smithies O: Un- J Clin Invest 10: 221–249, 1931 bone during chronic metabolic, but not compensated polyuria in a mouse model of

J Am Soc Nephrol 27: 3511–3520, 2016 Acidosis and Calcium Excretion 3517 BRIEF REVIEW www.jasn.org

Bartter’s syndrome. Proc Natl Acad Sci U S wasting, hyperabsorption, and reduced immunoreactive parathyroid hormone in A 97: 5434–5439, 2000 bone thickness in mice lacking TRPV5. JClin man. Kidney Int 8: 263–273, 1975 32. Pan W, Borovac J, Spicer Z, Hoenderop JG, Invest 112: 1906–1914, 2003 59. Batlle D, Itsarayoungyuen K, Hays S, Arruda Bindels RJ, Shull GE, Doschak MR, Cordat E, 45. Hoenderop JG, Nilius B, Bindels RJ: Cal- JA, Kurtzman NA: Parathyroid hormone is Alexander RT: The epithelial sodium/proton cium absorption across epithelia. Physiol not anticalciuric during chronic metabolic exchanger, NHE3, is necessary for renal and Rev 85: 373–422, 2005 acidosis. Kidney Int 22: 264–271, 1982 intestinal calcium (re)absorption. Am J Physiol 46. Alexander RT, Beggs MR, Zamani R, 60. Adams ND, Gray RW, Lemann J Jr: The Renal Physiol 302: F943–F956, 2012 Marcussen N, Frische S, Dimke H: Ultra- calciuria of increased ﬁxed acid production 33. Bomsztyk K, Calalb MB: Bicarbonate ab- structural and immunohistochemical locali- in humans: evidence against a role for 2+ sorption stimulates active calcium absorp- zation of plasma membrane Ca -ATPase 4 parathyroid hormone and 1,25(OH)2-vitamin tion in the rat proximal tubule. J Clin Invest in Ca2+-transporting epithelia. Am J Physiol D. Calcif Tissue Int 28: 233–238, 1979 81: 1455–1461, 1988 Renal Physiol 309: F604–F616, 2015 61. Gafter U, Kraut JA, Lee DB, Silis V, Walling 34. Suki WN, Rouse D, Ng RC, Kokko JP: Cal- 47. Wong NL, Quamme GA, Dirks JH: Actions MW,KurokawaK,HausslerMR,Coburn cium transport in the thick ascending limb of of parathyroid hormone are not impaired JW: Effect of metabolic acidosis in in- Henle. Heterogeneity of function in the during chronic metabolic acidosis. JLab testinal absorption of calcium and phos- medullary and cortical segments. J Clin Invest Clin Med 105: 472–478, 1985 phorus. Am J Physiol 239: G480–G484, 66: 1004–1009, 1980 48. Dubb J, Goldberg M, Agus ZS: Tubular ef- 1980 35. Yu AS: Claudins and the kidney. JAmSoc fects of acute metabolic acidosis in the rat. J 62. Bushinsky DA, Riera GS, Favus MJ, Coe FL:

Nephrol 26: 11–19, 2015 Lab Clin Med 90: 318–323, 1977 Response of serum 1,25(OH)2D3 to variation 36. Hou J, Renigunta A, Konrad M, Gomes AS, 49. Nijenhuis T, Renkema KY, Hoenderop JG, of ionized calcium during chronic acidosis. Schneeberger EE, Paul DL, Waldegger S, Bindels RJ: Acid-base status determines the Am J Physiol 249: F361–F365, 1985 Goodenough DA: Claudin-16 and claudin- renal expression of Ca2+ and Mg2+ trans- 63. Fenton TR, Eliasziw M, Lyon AW, Tough SC, 19 interact and form a cation-selective tight port proteins. J Am Soc Nephrol 17: 617– Hanley DA: Meta-analysis of the quantity of junction complex. J Clin Invest 118: 619– 626, 2006 calcium excretion associated with the net 628, 2008 50. Nijenhuis T, van der Eerden BC, Hoenderop acid excretion of the modern diet under the 37. Dimke H, Desai P, Borovac J, Lau A, Pan W, JG, Weinans H, van Leeuwen JP, Bindels RJ: acid-ash diet hypothesis. Am J Clin Nutr 88: Alexander RT: Activation of the Ca(2+)-sensing Bone resorption inhibitor alendronate nor- 1159–1166, 2008 receptor increases renal claudin-14 expres- malizes the reduced bone thickness of 64. Fenton TR, Lyon AW, Eliasziw M, Tough SC, sion and urinary Ca(2+) excretion. Am J Physiol TRPV5(-/-) mice. J Bone Miner Res 23: 1815– Hanley DA: Meta-analysis of the effect of Renal Physiol 304: F761–F769, 2013 1824, 2008 the acid-ash hypothesis of osteoporosis on 38. Muto S, Hata M, Taniguchi J, Tsuruoka S, 51. van der Eerden BC, Hoenderop JG, de Vries calcium balance. J Bone Miner Res 24: Moriwaki K, Saitou M, Furuse K, Sasaki H, TJ, Schoenmaker T, Buurman CJ, 1835–1840, 2009 Fujimura A, Imai M, Kusano E, Tsukita S, Uitterlinden AG, Pols HA, Bindels RJ, van 65. Cao JJ, Nielsen FH: Acid diet (high-meat Furuse M: Claudin-2-deficient mice are de- Leeuwen JP: The epithelial Ca2+ channel protein) effects on calcium metabolism and fective in the leaky and cation-selective TRPV5 is essential for proper osteoclastic bone health. Curr Opin Clin Nutr Metab paracellular permeability properties of renal bone resorption. Proc Natl Acad Sci U S A Care 13: 698–702, 2010 proximal tubules. Proc Natl Acad Sci U S A 102: 17507–17512, 2005 66. Topaloglu AK, Yildizdas D, Yilmaz HL, 107: 8011–8016, 2010 52. Canzanello VJ, Bodvarsson M, Kraut JA, Mungan NO, Yuksel B, Ozer G: Bone cal- 39. Laghmani K, Preisig PA, Moe OW, Johns CA, Slatopolsky E, Madias NE: Effect cium changes during diabetic ketoacidosis: Yanagisawa M, Alpern RJ: Endothelin-1/ of chronic respiratory acidosis on urinary a comparison with lactic acidosis due to endothelin-B receptor-mediated increases calcium excretion in the dog. Kidney Int 38: volume depletion. Bone 37: 122–127, 2005 in NHE3 activity in chronic metabolic aci- 409–416, 1990 67. Domrongkitchaiporn S, Pongsakul C, dosis. J Clin Invest 107: 1563–1569, 2001 53. Lau K, Rodriguez Nichols F, Tannen RL: Stitchantrakul W, Sirikulchayanonta V, 40. Wu MS, Biemesderfer D, Giebisch G, Renal excretion of divalent ions in response Ongphiphadhanakul B, Radinahamed P, Aronson PS: Role of NHE3 in mediating re- to chronic acidosis: evidence that systemic Karnsombut P, Kunkitti N, Ruang-raksa C, nal brush border Na+-H+ exchange. Adap- pH is not the controlling variable. JLabClin Rajatanavin R: Bone mineral density and tation to metabolic acidosis. JBiolChem Med 109: 27–33, 1987 histology in distal renal tubular acidosis. 271: 32749–32752, 1996 54. Schaefer KE, Hasson M, Niemoeller H: Ef- Kidney Int 59: 1086–1093, 2001 41. Sutton RA, Wong NL, Dirks JH: Effects of fect of prolonged exposure to 15 per cent 68. Domrongkitchaiporn S, Pongskul C, metabolic acidosis and alkalosis on sodium CO2 on calcium and phosphorus metabo- Sirikulchayanonta V, Stitchantrakul W, and calcium transport in the dog kidney. lism. Proc Soc Exp Biol Med 107: 355–359, Leeprasert V, Ongphiphadhanakul B, Kidney Int 15: 520–533, 1979 1961 Radinahamed P, Rajatanavin R: Bone his- 42. Doroszewicz J, Waldegger P, Jeck N, 55. Bushinsky DA: Net proton influx into bone tology and bone mineral density after cor- Seyberth H, Waldegger S: pH dependence during metabolic, but not respiratory, aci- rection of acidosis in distal renal tubular of extracellular calcium sensing receptor dosis. Am J Physiol 254: F306–F310, 1988 acidosis. Kidney Int 62: 2160–2166, 2002 activity determined by a novel technique. 56. Bushinsky DA, Sessler NE, Krieger NS: 69. Karet FE, Finberg KE, Nelson RD, Nayir A, Kidney Int 67: 187–192, 2005 Greater unidirectional calcium efflux from Mocan H, Sanjad SA, Rodriguez-Soriano J, 43. Nijenhuis T, Renkema KY, Hoenderop JG, bone during metabolic, compared with re- Santos F, Cremers CW, Di Pietro A, Bindels RJ: Acid-base status determines spiratory, acidosis. Am J Physiol 262: F425– Hoffbrand BI, Winiarski J, Bakkaloglu A, the renal expression of Ca2+ and Mg2+ F431, 1992 Ozen S, Dusunsel R, Goodyer P, Hulton SA, transport proteins. J Am Soc Nephrol 17: 57. Bushinsky DA, Sessler NE: Critical role of Wu DK, Skvorak AB, Morton CC, Cunningham 617–626, 2006 bicarbonate in calcium release from bone. MJ, Jha V, Lifton RP: Mutations in the 44. Hoenderop JG, van Leeuwen JP, van der Am J Physiol 263: F510–F515, 1992 gene encoding B1 subunit of H+-ATPase Eerden BC, Kersten FF, van der Kemp AW, 58. Coe FL, Firpo JJ Jr, Hollandsworth DL, Segil cause renal tubular acidosis with senso- Mérillat AM, Waarsing JH, Rossier BC, L, Canterbury JM, Reiss E: Effect of acute rineural deafness. Nat Genet 21: 84–90, Vallon V, Hummler E, Bindels RJ: Renal Ca2+ and chronic metabolic acidosis on serum 1999

3518 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 3511–3520, 2016 www.jasn.org BRIEF REVIEW

70. Ruf R, Rensing C, Topaloglu R, Guay- Vogt B, Moe OW, Fuster DG: The Vacuolar cell anion exchanger (Band 3, AE1) gene. J Woodford L, Klein C, Vollmer M, Otto E, H+-ATPase B1 Subunit Polymorphism p. Clin Invest 100: 1693–1707, 1997 Beekmann F, Haller M, Wiedensohler A, E161K Associates with Impaired Urinary 91. Jarolim P, Shayakul C, Prabakaran D, Jiang Leumann E, Antignac C, Rizzoni G, Filler G, Acidification in Recurrent Stone Formers. J L, Stuart-Tilley A, Rubin HL, Simova S, Brandis M, Weber JL, Hildebrandt F: Am Soc Nephrol 27: 1544–1554, 2016 Zavadil J, Herrin JT, Brouillette J, Somers Confirmation of the ATP6B1 gene as re- 83. Evan AP, Lingeman J, Coe F, Shao Y, Miller MJ, Seemanova E, Brugnara C, Guay- sponsible for distal renal tubular acidosis. N, Matlaga B, Phillips C, Sommer A, Woodford LM, Alper SL: Autosomal Pediatr Nephrol 18: 105–109, 2003 Worcester E: Renal histopathology of stone- dominant distal renal tubular acidosis is 71. Hahn H, Kang HG, Ha IS, Cheong HI, Choi Y: forming patients with distal renal tubular associated in three families with hetero- ATP6B1 gene mutations associated with acidosis. Kidney Int 71: 795–801, 2007 zygosity for the R589H mutation in the - - distal renal tubular acidosis and deafness 84. Stover EH, Borthwick KJ, Bavalia C, Eady AE1 (band 3) Cl /HCO3 exchanger. JBiol in a child. Am J Kidney Dis 41: 238–243, N, Fritz DM, Rungroj N, Giersch AB, Chem 273: 6380–6388, 1998 2003 MortonCC,AxonPR,AkilI,Al-Sabban 92. Karet FE, Gainza FJ, Györy AZ, Unwin RJ, 72. Gueutin V, Vallet M, Jayat M, Peti-Peterdi J, EA,BaguleyDM,BiancaS,BakkalogluA, Wrong O, Tanner MJ, Nayir A, Alpay H, Cornière N, Leviel F, Sohet F, Wagner CA, Bircan Z, Chauveau D, Clermont MJ, Santos F, Hulton SA, Bakkaloglu A, Ozen S, Eladari D, Chambrey R: Renal b-intercalated Guala A, Hulton SA, Kroes H, Li Volti G, Cunningham MJ, di Pietro A, Walker WG, cells maintain body fluid and electrolyte MirS,MocanH,NayirA,OzenS, Lifton RP: Mutations in the chloride- balance. JClinInvest123: 4219–4231, 2013 Rodriguez Soriano J, Sanjad SA, Tasic V, bicarbonate exchanger gene AE1 cause 73. Sebastian A, McSherry E, Morris RC Jr: Im- Taylor CM, Topaloglu R, Smith AN, Karet autosomal dominant but not autosomal re- paired renal conservation of sodium and FE: Novel ATP6V1B1 and ATP6V0A4 cessive distal renal tubular acidosis. Proc chloride during sustained correction of mutations in autosomal recessive distal Natl Acad Sci U S A 95: 6337–6342, 1998 systemic acidosis in patients with type 1, renal tubular acidosis with new evidence 93. Rungroj N, Devonald MA, Cuthbert classic renal tubular acidosis. J Clin Invest for hearing loss. J Med Genet 39: 796– AW, Reimann F, Akkarapatumwong V, 58: 454–469, 1976 803, 2002 Yenchitsomanus PT, Bennett WM, Karet FE: 74. Kleeman CR, Bohannan J, Bernstein D, Ling 85. Smith AN, Skaug J, Choate KA, Nayir A, A novel missense mutation in AE1 causing S, Maxwell MH: Effect of Variations in Bakkaloglu A, Ozen S, Hulton SA, Sanjad autosomal dominant distal renal tubular Sodium Intake on Calcium Excretion in SA, Al-Sabban EA, Lifton RP, Scherer SW, acidosis retains normal transport function Normal Humans. Proc Soc Exp Biol Med Karet FE: Mutations in ATP6N1B, encoding but is mistargeted in polarized epithelial 115: 29–32, 1964 a new kidney vacuolar proton pump 116-kD cells. J Biol Chem 279: 13833–13838, 2004 75. Ng RC, Peraino RA, Suki WN: Divalent cat- subunit, cause recessive distal renal tubular 94. Zuckerman JM, Assimos DG: Hypoci- ion transport in isolated tubules. Kidney Int acidosis with preserved hearing. Nat Genet traturia: pathophysiology and medical 22: 492–497, 1982 26: 71–75, 2000 management. Rev Urol 11: 134–144, 2009 76. Friedman PA, Figueiredo JF, Maack T, 86. Karet FE, Finberg KE, Nayir A, Bakkaloglu A, 95. Horita S, Yamada H, Inatomi J, Moriyama N, Windhager EE: Sodium-calcium interac- Ozen S, Hulton SA, Sanjad SA, Al-Sabban Sekine T, Igarashi T, Endo Y, Dasouki M, tions in the renal proximal convoluted EA, Medina JF, Lifton RP: Localization of a Ekim M, Al-Gazali L, Shimadzu M, Seki G, tubule of the rabbit. Am J Physiol 240: gene for autosomal recessive distal renal Fujita T: Functional analysis of NBC1 mu- F558–F568, 1981 tubular acidosis with normal hearing tants associated with proximal renal tubular 77. Bourdeau JE, Buss SL, Vurek GG: Inhibition (rdRTA2) to 7q33-34. Am J Hum Genet 65: acidosis and ocular abnormalities. JAmSoc of calcium absorption in the cortical thick 1656–1665, 1999 Nephrol 16: 2270–2278, 2005 ascending limb of Henle’sloopbyfurose- 87. Gao Y, Xu Y, Li Q, Lang Y, Dong Q, Shao L: 96. Dinour D, Chang MH, Satoh J, Smith BL, mide. J Pharmacol Exp Ther 221: 815–819, Mutation analysis and audiologic assess- Angle N, Knecht A, Serban I, Holtzman EJ, 1982 ment in six Chinese children with primary Romero MF: A novel missense mutation 78. Bartoli E, Romano G, Favret G: Segmental distal renal tubular acidosis. Ren Fail 36: in the sodium bicarbonate cotransporter reabsorption measured by micropuncture 1226–1232, 2014 (NBCe1/SLC4A4) causes proximal tubular and clearance methods during hypertonic 88. Leviel F, Hübner CA, Houillier P, Morla L, El acidosis and glaucoma through ion trans- sodium infusion in the rat. Nephrol Dial Moghrabi S, Brideau G, Hassan H, Parker port defects. J Biol Chem 279: 52238– Transplant 11: 1996–2003, 1996 MD, Kurth I, Kougioumtzes A, Sinning A, 52246, 2004 79. Edelmann CM, Barnett HL, Troupkou V: Pech V, Riemondy KA, Miller RL, Hummler 97. Igarashi T, Inatomi J, Sekine T, Seki G, Renal concentrating mechanisms in new- E, Shull GE, Aronson PS, Doucet A, Wall SM, Shimadzu M, Tozawa F, Takeshima Y, born infants. Effect of dietary protein and Chambrey R, Eladari D: The Na+-dependent Takumi T, Takahashi T, Yoshikawa N, water content, role of urea, and responsive- chloride-bicarbonate exchanger SLC4A8 Nakamura H, Endou H: Novel nonsense + + - ness to antidiuretic hormone. J Clin Invest 39: mediates an electroneutral Na reabsorption mutation in the Na /HCO3 cotransporter 1062–1069, 1960 process in the renal cortical collecting gene (SLC4A4) in a patient with permanent 80. Fomon SJ, Owen GM, Jensen RL, Thomas ducts of mice. J Clin Invest 120: 1627–1635, isolated proximal renal tubular acidosis and LN: Calcium and phosphorus balance 2010 bilateral glaucoma. JAmSocNephrol12: studies with normal full term infants fed 89. Chambrey R, Kurth I, Peti-Peterdi J, 713–718, 2001 pooled human milk or various formulas. Am Houillier P, Purkerson JM, Leviel F, 98. Inatomi J, Horita S, Braverman N, Sekine JClinNutr12: 346–357, 1963 Hentschke M, Zdebik AA, Schwartz GJ, T, Yamada H, Suzuki Y, Kawahara K, 81. Zhang J, Fuster DG, Cameron MA, Hübner CA, Eladari D: Renal intercalated Moriyama N, Kudo A, Kawakami H, Quiñones H, Griffith C, Xie XS, Moe OW: cells are rather energized by a proton than a Shimadzu M, Endou H, Fujita T, Seki G, Incomplete distal renal tubular acidosis sodium pump. Proc Natl Acad Sci U S A 110: Igarashi T: Mutational and functional analysis from a heterozygous mutation of the V-ATPase 7928–7933, 2013 of SLC4A4 in a patient with proximal renal B1 subunit. Am J Physiol Renal Physiol 307: 90. Bruce LJ, Cope DL, Jones GK, Schofield AE, tubular acidosis. Pflugers Arch 448: 438–444, F1063–F1071, 2014 Burley M, Povey S, Unwin RJ, Wrong O, 2004 82. Dhayat NA, Schaller A, Albano G, Tanner MJ: Familial distal renal tubular aci- 99. Lemann J Jr, Adams ND, Wilz DR, Brenes Poindexter J, Griffith C, Pasch A, Gallati S, dosis is associated with mutations in the red LG: Acid and mineral balances and bone in

J Am Soc Nephrol 27: 3511–3520, 2016 Acidosis and Calcium Excretion 3519 BRIEF REVIEW www.jasn.org

familial proximal renal tubular acidosis. genetic studies of CLCN5 mutations in 122. Weber S, Soergel M, Jeck N, Konrad M: Kidney Int 58: 1267–1277, 2000 Japanese families with Dent’s disease. Atypical distal renal tubular acidosis con- 100. Alexander RT, Rievaj J, Dimke H: Para- Kidney Int 58: 520–527, 2000 firmed by mutation analysis. Pediatr cellular calcium transport across renal and 112. Scheel O, Zdebik AA, Lourdel S, Jentsch TJ: Nephrol 15: 201–204, 2000 intestinal epithelia. Biochem Cell Biol 92: Voltage-dependent electrogenic chloride/ 123. Buckalew VM Jr, Purvis ML, Shulman MG, 467–480, 2014 proton exchange by endosomal CLC pro- Herndon CN, Rudman D: Hereditary renal 101. Lambers TT, Oancea E, de Groot T, Topala teins. Nature 436: 424–427, 2005 tubular acidosis. Report of a 64 member CN, Hoenderop JG, Bindels RJ: Extracel- 113. Piwon N, Günther W, Schwake M, Bösl MR, kindred with variable clinical expression lular pH dynamically controls cell surface Jentsch TJ: ClC-5 Cl- -channel disruption including idiopathic hypercalciuria. Medi- delivery of functional TRPV5 channels. Mol impairs endocytosis in a mouse model for cine (Baltimore) 53: 229–254, 1974 Cell Biol 27: 1486–1494, 2007 Dent’s disease. Nature 408: 369–373, 2000 124. Richards P, Wrong OM: Dominant inheritance 102. Norman ME, Feldman NI, Cohn RM, Roth 114. Wang SS, Devuyst O, Courtoy PJ, Wang XT, in a family with familial renal tubular acidosis. KS, McCurdy DK: Urinary citrate excretion Wang H, Wang Y, Thakker RV, Guggino S, Lancet 2: 998–999, 1972 in the diagnosis of distal renal tubular aci- Guggino WB: Mice lacking renal chloride 125. Ballet JJ, Griscelli C, Coutris C, Milhaud G, dosis. JPediatr92: 394–400, 1978 channel, CLC-5, are a model for Dent’s Maroteaux P: Bone-marrow transplantation 103. Brennan S, Hering-Smith K, Hamm LL: disease, a nephrolithiasis disorder associ- in osteopetrosis. Lancet 2: 1137, 1977 Effect of pH on citrate reabsorption in the ated with defective receptor-mediated en- 126. Ohlsson A, Cumming WA, Paul A, Sly WS: proximal convoluted tubule. Am J Physiol docytosis. Hum Mol Genet 9: 2937–2945, Carbonic anhydrase II deficiency syndrome: 255: F301–F306, 1988 2000 recessive osteopetrosis with renal tubular 104. Sly WS, Whyte MP, Sundaram V, Tashian 115. Sliman GA, Winters WD, Shaw DW, Avner acidosis and cerebral calcification. Pediat- RE, Hewett-Emmett D, Guibaud P, Vainsel ED: Hypercalciuria and nephrocalcinosis in rics 77: 371–381, 1986 M, Baluarte HJ, Gruskin A, Al-Mosawi M, the oculocerebrorenal syndrome. JUrol 127. Igarashi T, Ishii T, Watanabe K, Hayakawa H, Sakati N, Ohlsson A: Carbonic anhydrase II 153: 1244–1246, 1995 Horio K, Sone Y, Ohga K: Persistent isolated deficiency in 12 families with the autosomal 116. Hoopes RR Jr, Shrimpton AE, Knohl SJ, proximal renal tubular acidosis–a systemic recessive syndrome of osteopetrosis with Hueber P, Hoppe B, Matyus J, Simckes A, disease with a distinct clinical entity. Pediatr renal tubular acidosis and cerebral calcifi- Tasic V, Toenshoff B, Suchy SF, Nussbaum Nephrol 8: 70–71, 1994 cation. NEnglJMed313: 139–145, 1985 RL, Scheinman SJ: Dent Disease with mu- 128. Winsnes A, Monn E, Stokke O, Feyling T: 105. Sly WS, Hewett-Emmett D, Whyte MP, Yu tations in OCRL1. Am J Hum Genet 76: Congenital persistent proximal type renal YS, Tashian RE: Carbonic anhydrase II de- 260–267, 2005 tubular acidosis in two brothers. Acta Pae- ficiency identified as the primary defect in 117. Gil H, Santos F, García E, Alvarez MV, diatr Scand 68: 861–868, 1979 the autosomal recessive syndrome of os- Ordóñez FA, Málaga S, Coto E: Distal RTA 129. Rodriguez Soriano J, Boichis H, Stark H, teopetrosis with renal tubular acidosis and with nerve deafness: clinical spectrum and Edelmann CM Jr: Proximal renal tubular cerebral calcification. Proc Natl Acad Sci U mutational analysis in five children. Pediatr acidosis. A defect in bicarbonate reabsorption SA80: 2752–2756, 1983 Nephrol 22: 825–828, 2007 with normal urinary acidification. Pediatr 106. Vainsel M, Fondu P, Cadranel S, Rocmans 118. Vargas-Poussou R, Cochat P, Le Pottier N, Res 1: 81–98, 1967 C, Gepts W: Osteopetrosis associated with Roncelin I, Liutkus A, Blanchard A, 130. Theodoropoulos DS, Shawker TH, Heinrichs C, proximal and distal tubular acidosis. Acta Jeunemaître X: Report of a family with two Gahl WA: Medullary nephrocalcinosis in Paediatr Scand 61: 429–434, 1972 different hereditary diseases leading to nephropathic cystinosis. Pediatr Nephrol 107. Whyte MP, Murphy WA, Fallon MD, Sly WS, early nephrocalcinosis. Pediatr Nephrol 23: 9: 412–418, 1995 Teitelbaum SL, McAlister WH, Avioli LV: 149–153, 2008 131. Saleem MA, Milford DV, Alton H, Osteopetrosis, renal tubular acidosis and 119. Feldman M, Prikis M, Athanasiou Y, Elia A, Chapman S, Winterborn MH: Hyper- basal ganglia calcification in three sisters. Pierides A, Deltas CC: Molecular in- calciuria and ultrasound abnormalities in Am J Med 69: 64–74, 1980 vestigation and long-term clinical progress children with cystinosis. Pediatr Nephrol 108. Ohlsson A, Stark G, Sakati N: Marble brain in Greek Cypriot families with recessive 9: 45–47, 1995 disease: recessive osteopetrosis, renal tu- distal renal tubular acidosis and sensori- 132. Claverie-Martín F, Ramos-Trujillo E, García- bular acidosis and cerebral calcification in neural deafness due to mutations in the Nieto V: Dent’s disease: clinical features three Saudi Arabian families. Dev Med ATP6V1B1 gene. Clin Genet 69: 135–144, and molecular basis. Pediatr Nephrol 26: Child Neurol 22: 72–84, 1980 2006 693–704, 2011 109. Rousselle AV, Heymann D: Osteoclastic 120. Tasic V, Korneti P, Gucev Z, Hoppe B, Blau 133. Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, acidification pathways during bone re- N, Cheong HI: Atypical presentation of Cheong HI: Renal manifestations of Dent sorption. Bone 30: 533–540, 2002 distal renal tubular acidosis in two siblings. disease and Lowe syndrome. Pediatr 110. Nykjaer A, Dragun D, Walther D, Vorum H, Pediatr Nephrol 23: 1177–1181, 2008 Nephrol 23: 243–249, 2008 Jacobsen C, Herz J, Melsen F, Christensen 121. Andreucci E, Bianchi B, Carboni I, Lavoratti 134. Bockenhauer D, Bokenkamp A, van’t Hoff EI, Willnow TE: An endocytic pathway essential G, Mortilla M, Fonda C, Bigozzi M, W, Levtchenko E, Kist-van Holthe JE, Tasic for renal uptake and activation of the steroid Genuardi M, Giglio S, Pela I: Inner ear ab- V, Ludwig M: Renal phenotype in Lowe

25-(OH) vitamin D3. Cell 96: 507–515, 1999 normalities in four patients with dRTA and Syndrome: a selective proximal tubular 111. Igarashi T, Inatomi J, Ohara T, Kuwahara T, SNHL: clinical and genetic heterogeneity. dysfunction. Clin J Am Soc Nephrol 3: Shimadzu M, Thakker RV: Clinical and Pediatr Nephrol 24: 2147–2153, 2009 1430–1436, 2008

3520 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 3511–3520, 2016