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Salt-Losing Tubulopathies in Children: What’s New,What’s Controversial?

Robert Kleta and Detlef Bockenhauer

UCL Centre for Nephrology and Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom

ABSTRACTRenal tubulopathies provide insights into the inner workings of the kidney, yet alsopose therapeutic challenges. Because of the central nature of sodium in tubulartransport physiology, disorders of sodium handling may affect virtually all aspectsof the homeostatic functions of the kidney. Yet, owing to the rarity of these disor-ders, little clinical evidence regarding treatment exists. Consequently, treatmentcan vary widely between individual physicians and centers and is based mainly onunderstanding of renal physiology, reported clinical observations, and individualexperiences. Salt-losing tubulopathies can affect all tubular segments, from theproximal tubule to the collecting duct. But the more frequently observed disordersare Bartter and Gitelman syndrome, which affect salt transport in the thick ascend-ing limb of Henle’s loop and/or the distal convoluted tubule, and these disordersgenerate the greatest controversies regarding management. Here, we review clin-ical and molecular aspects of salt-losing tubulopathies and discuss novel insightsprovided mainly by genetic investigations and retrospective clinical reviews. Addition-ally, we discuss controversial topics in the management of these disorders to highlightareas of importance for future clinical trials. International collaboration will be requiredto perform clinical studies to inform the treatment of these rare disorders.

J Am Soc Nephrol 29: 727–739, 2018. doi: https://doi.org/10.1681/ASN.2017060600

The preservation of electrolyte, volume,and acid-base homeostasis balance is vi-tal to the functioning of our bodies. Be-cause life initially evolved in the ocean,cellular function is dependent on themaintenance of the electrolyte concen-tration reflective of the original environ-ment. No idea could be thought, nomuscle moved, without the proper bal-ance of salts within our bodies.1 It is theresponsibility of mainly the kidneys tomaintain this vital “milieu interieur.”The kidneys do so by the combinationof glomerular filtration and tubularreabsorption, a system that is best ex-plained by the evolutionary history. “In-telligent design” may not have devised asystem that, in an average adult, initiallyfilters approximately 150 L of water daily,

containing an enormous load of solutes,including about 20,000 mmol of sodiumper day (equivalent to the amount in1.2 kg of cooking salt), only to laboriouslyreabsorb virtually all of it back into circu-lation. In the original ocean environment,a system of filtration was well suited giventhe unlimited availability of salt and water.Yet, in order to enable life on land, largelosses of water and solutes had to be pre-vented, leading to the evolution of evermore powerful tubules.2 Under physio-logic conditions, they are capable of re-absorbing .99% of filtered sodium andwater. This enormous task is accom-plished by a combination of distinct so-diumor sodium-coupled transport systemsalong the nephron. It is the active reabsorp-tion of sodium that generates the main

driving force for the passive reabsorptionof water. The price to pay for this powerfulsystem of filtration and reabsorption is ahigh-energy demand: when adjustedfor organ weight, the kidneys, togetherwith the heart, have the highest restingmetabolic expenditure, approximately440 kcal/kg per day, almost twice asmuch as the brain, making the kidneyssusceptible to acute injury when theenergy supply is impaired.3

The importance of tubular sodiumreabsorption becomes especially appar-entwhen the system isdisturbed, as in thesalt-losing tubulopathies.

On the basis of anatomic and func-tional characteristics, the tubules are typ-ically divided into four main segments:proximal tubule (PT), thick ascendinglimb (TAL) of Henle’s loop, distal con-voluted tubule (DCT), and collectingduct (CD). Genetic or acquired defectsin salt transport in any of these segmentslead to distinct tubulopathies, whichhave characteristic clinical and biochem-ical features (Figure 1).

Interestingly, given the critical natureof sodium for themaintenanceof volumehomeostasis, essentially all salt-losing tu-bulopathies actually maintain normal

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Correspondence: Dr. Detlef Bockenhauer, UCLCentre for Nephrology and Department of Pediat-ric Nephrology, Great Ormond Street Hospital NHSTrust, Great Ormond Street, London WC1N 3JH,UK. Email: [email protected]

Copyright © 2018 by the American Society ofNephrology

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sodium excretion in steady state, becausepersistent losses exceeding intake wouldbe incompatible with life. This normalsodium excretion is achieved by a com-pensatory increase in absorption throughother pathways. This explains the com-monly seen hyperaldosteronism thatcharacterizes, for instance, Bartter andGitelman syndromes (BS and GS, respec-tively), and that enhances sodium reab-sorption in the CD, primarily at theexpense of potassium secretion. Conse-quently, a key diagnostic feature for renalsalt wasting is the fractional excretionof chloride.4

Here, we will review key advances inour understanding of the different renalgenetic disorders affecting salt (sodiumchloride) reabsorption with respect toboth clinical phenotype and underlyingpathophysiology. An overview of thesedisorders, the underlying genes, andkey clinical characteristics is given in Ta-ble 1. In addition, we will highlight someclinical controversies around the treat-ment of salt-losing tubulopathies, whichneed further clinical studies and whichare summarized in Table 2.

PT

The PT is the part of the nephron wherethe most diverse action with respect toreabsorption (as well as secretion) takes

place (Figure 2). Micropuncture studiessuggest that between 60% and 80% of allfiltered salt and water is reabsorbed inthis segment.5 The “engine” for salttransport, as in all tubular segments, isthe basolateral Na+-K+-ATPase, whichestablishes the electrochemical gradi-ent for sodium entry into the cell. TheFanconi renotubular syndrome (FRTS)represents global dysfunction of the PTand, because of the high energy demandof this transport process, is often associ-ated with disorders of impaired energysupply, such as mitochondrial cytopa-thies.6 But, aside from being a secondaryfeature of systemic disorders, FRTS canalso occur in primary form. Currently,OMIM lists three such forms of FRTS(see Table 1): FRTS1 is dominantly inherit-ed and typically presents in childhoodwith rickets and the typical biochemi-cal abnormalities of FRTS. ProgressiveCKD is typically observed with develop-ment of CKD stage 5 in adulthood. Al-though the underlying gene has beenlinked to a locus on chromosome 15,the identity of this gene remains to berevealed.7 FRTS2 previously referred toFRTS observed in two siblings with a ho-mozygous mutation in SLC34A1.8 Yet,recessive mutations in this gene weresubsequently found to cause infantile hy-percalciuria and the association withFRTS has been questioned.9 A uniqueaspect of PT energy utilization was

highlighted by our discovery of the mo-lecular basis of FRTS type 3, where a het-erozygous missense mutation in EH-HADH (encoding enoyl-CoA hydrataseand 3-hydroxyacyl CoA dehydrogenase)impairs mitochondrial fatty acid oxida-tion.10,11 Although this defect is global itonly manifests in the PT, because the PTdoes not utilize glucose for energy gener-ation, exposing the dependency on fattyacid oxidation.12 Patients typically pre-sent in childhood with rickets and thebiochemical abnormalities. In contrastto FRTS1, however, no progressive CKDhas been observed.13 FRTS4 is causedby a specific mutation (R76W, also anno-tated as R63W, depending on referencesequence) in the transcription factorHNF4A.14 Mutations in this gene are as-sociated with abnormalities in insulinsecretion, typically hyperinsulinemic hy-poglycemia manifesting in the neonatalperiod and diabetes (MODY type 1)later in life. Consequently, patients withFRTS4 usually manifest shortly after birthwith hypoglycemia and subsequent inves-tigations then reveal the FRTS.15,16 Theassociation of FRTS4 with only this onespecific mutation (all other describedHNF4A mutations are only associatedwith altered insulin secretion) raises in-teresting questions over the specificrole of R76 for the function of HNF4Ain the maintenance of proximal tubularfunction, but, so far, no insights havebeen published.

The bulk of sodium in the PT is takenup by the apical Na+-H+ exchangerNHE3, in this way linking sodium andthus volume homeostasis with acid-basehomeostasis.17 Given this importantrole, one might have expected a severeform of a salt-losing tubulopathy andproximal acidosis with loss of functionof this transporter. Instead, recessivemutations in the encoding gene SLC9A3are associated with congenital sodiumdiarrhea (OMIM #616868).18 Only twoof the seven reported patients with avail-able data exhibited acidosis. While alsopresenting with diarrhea, mice lackingNhe3 function do also show evidenceof salt wasting and acidosis.19 To betterdissect the respective renal and/or intes-tinal contribution to the acidosis, a renal

Figure 1. Sodium and water reabsorption along the nephron. Knockouts of distinctiveproteins in particular nephron segments lead to distinctive disease in man, as indicated.

728 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 727–739, 2018


Table 1. Genetics of primary renal salt-losing nephropathies and pertinent clinical characteristics

NephronSegment

Disorder OMIM Gene Protein Inheritance Typical Clinical Findings

PT Fanconi renotubularsyndrome type 1; FRTS1

134600 ? ? AD Rickets, progressive CKD

Infantile hypercalciuria 2a 613388 SLC34A1 NaPi-IIa AR Hypercalciuria,nephrocalcinosis

Hypophosphatemic ricketswith hypercalciuria

241530 SLC34A3 NaPi-IIc AR/AD Hypercalciuria,nephrocalcinosis

Fanconi renotubular syndrometype 3; FRTS3

615605 EHHADH EHHADH AD Rickets, no kidney failure

Fanconi renotubular syndrometype 4; FRTS4

600281 HNF4A HNF4A AD Congenitalhyperinsulinism, laterMODY, rickets

Renal glucosuria 233100 SLC5A2 SGLT2 AR/AD GlucosuriaProximal renal tubularacidosis with eye findings

604278 SLC4A4 KNBC AR Metabolic acidosis, eyeabnormalities(corneal opacities, bandkeratopathy, cataract,glaucoma), mentalimpairment

Osteopetrosis with renaltubular acidosis

259730 CA2 CA2 AR Osteopetrosis, cerebralcalcifications, metabolicacidosis

TAL BS type 1 601678 SLC12A1 NKCC2 AR Prematurity,polyhydramniosnephrocalcinosis,hypokalemic alkalosis,iso- or hyposthenuria

BS type 2b 241200 KCNJ1 ROMK1 AR Prematurity,polyhydramniosnephrocalcinosis,transient hyperkalemia,then hypokalemicalkalosis,iso- or hyposthenuria

BS type 3b 607364 CLCNKB ClC-Kb AR Severe hypokalemichypochloremic alkalosis

BS type 4Ab 602522 BSND Barttin AR Prematurity,polyhydramnios,sensorineural deafness,severe hypokalemichypochloremic alkalosis,iso- or hyposthenuria

BS type 4Bb CLCNKA, CLCNKB ClC-Ka, ClC-Kb AR

BS type 5b 300971 MAGED2 MAGED2 XR Severe polyhydramnios,transient salt wasting

AD hypocalcemic hypercalciuria CASR CASR AD Hypocalcemichypercalciuria, that canbe complicatedby hypokalemic alkalosis

DCT GS 263800 SLC12A3 NCC AR Hypokalemic alkalosis,hypocalciuria,hypomagnesemia

EAST syndrome 612780 KCNJ10 Kir4.1 AR Epilepsy, ataxia,sensorineural deafness,hypokalemicalkalosis

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specific knock-out was generated, whichconfirmed renal bicarbonate wasting, al-beit with only mild acidosis.20 Thesestudies confirm the important role ofNHE3; yet, at least in PT, the loss offunction may be partially compen-sated by other NHE isoforms, such asNHE8.21

Another important sodium trans-porter in PT is the Na+-PO4

2 cotrans-porter NaPi-IIa, encoded by SLC34A1.Initially, a homozygous loss-of-functionmutation was reported as the cause ofFRTS type 2 in two siblings.8 Yet, no fur-ther patients with FRTS and SLC34A1mutations have been identified since.Instead, recessive loss-of-function mu-tations in this gene are recurrentlyfound as the cause of infantile hypercal-cemia with nephrocalcinosis (OMIM#616963).9 Moreover, heterozygousmutations have been associated with

hypophosphatemic nephrolithiasis(OMIM # 612286),22 similar to the hy-pophosphatemic rickets with hypercal-ciuria caused by heterozygousmutationsin SLC34A3, encoding NaPi-IIc (OMIM#241530). Presumably, the hypophos-phatemia-mediated suppression ofFGF23 leads to increased 1-a hydroxy-lation of cholecalciferol with resultanthypercalcemia and hypercalciuria.23

Of interest is also the sodium-glucosecotransporterSGLT2,encodedbySLC5A2.Recessive mutations in this transportercause isolated renal glucosuria (OMIM#233100), which provides an exampleof the enormous benefits the study of arare disorder can have for common dis-orders. Patients with isolated renal gluco-suria can lose well over 100 g of glucosedaily, yet with no apparent detrimentalconsequences.24–26 In fact, in an era ofaffluence in which obesity and diabetes

have become major threats to publichealth, the loss of sodium and glucosein the urine may be beneficial andSGLT2 thus became an attractive thera-peutic target.25 Inhibitors of SGLT2, thegliflozins, are now available and seem toprovide substantial benefits in the man-agement of diabetes, with not only im-proved glucose control but also reducedcardiovascular mortality and diabetic ne-phropathy.27

Two further transporters affecting so-dium reabsorption in the PT are associ-ated with diseases: recessive mutationsin SLC4A4, encoding basolateral Na-bicarbonate cotransporter NBC1, causeproximal tubular acidosis with eye find-ings (OMIM # 604278); and recessivemutations in carbonic anhydrase 2, en-coded by CA2, cause proximal tubularacidosis with osteopetrosis (OMIM#259730). Although CA2 does not

Table 2. Clinical controversies in salt-losing tubulopathies

Tubular Segment Clinical Controversies

PT Do antiproteinuric drugs such as ACEi protect kidney function, if proteinuria is of tubular origin?TAL Is salt supplementation beneficial in patients with secondary NDI?

Which COXi provides best efficacy with least side effects: indomethacin, ibuprofen, or celexocib?Should COXi be weaned off during school age or should they be maintained life-long?Is antenatal treatment of BS beneficial?

TAL and DCT What is the best classification for BS and GS?What is the lower limit of plasma potassium concentration that can be considered safe?Are potassium-sparing diuretics beneficial?Are antiproteinuric drugs indicated in patients who have developed proteinuria?What is the lower limit of plasma magnesium concentration that can be considered safe?

DCT Is salt supplementation alone sufficient to normalize renin and aldosterone levels?Listed are clinical controversies discussed in this review. These controversies need clarification through clinical trials and/or expert consensus. ACEi, angiotensin-converting enzyme inhibitors, COXi, cyclooxygenase inhibitors.

Table 1. Continued

NephronSegment

Disorder OMIM Gene Protein Inheritance Typical Clinical Findings

CorticalCD

AD pseudohypoaldosteronismtype I

177735 NR3C2 MR AD Transient neonatal saltwasting withhyponatremia,hyperkalemia, acidosis

AR pseudohypoaldosteronismtype I

264350 SCNN1A ENaC a AR Hyponatremia,hyperkalemia, acidosis,pathologicsweat test, lung disease

SCNN1B ENaC b

SCNN1G ENaC g

Listed are inherited salt-wasting disorders, including the underlying gene/protein and clinical characteristics. Note that most of these clinical disorders can have awide spectrum of severity. Typical clinical findings listed thus reflect symptoms seen in most, but not necessarily all, patients. Data from OMIM, HUGO, and NCBI(build 35.1). ?, unknown; AD, autosomal dominant; AR, autosomal recessive.aRecessive mutations in SLC34A1 have also been reported as a cause of FRTS2 (OMIM 613388, see text).bThese forms of BS also affect salt reabsorption in the distal tubule.



transport sodium directly, it clearly af-fects the availability of H+ for the apicalNa+-H+ exchange. However, except foroccasional case reports and case series,very little new data are available for thesevery rare disorders.28,29

Clinical ControversiesPatients with FRTS exhibit proteinuria.This primarily reflects “tubular” pro-teinuria, i.e., the impaired reabsorptionof filtered proteins, but in some patientsproteinuria reaches the nephrotic range.

Although the exact amount of physio-logic tubular protein (including albumin)reabsorption remains controversial andmay approach several grams per day,30

some patients also show evidence ofglomerular damage.31,32 Should thesepatients be treated with so-called anti-proteinuric drugs, such as ACEi or ARB?Given the impaired sodium reabsorp-tion in FRTS and thus risk of lossof volume homeostasis, are such treat-ments, which are generally recom-mended for proteinuria in CKD, ofbenefit to patients with rare tubularsalt-losing disorders?

THICK ASCENDING LIMB

From the PT, the primary urine traversesinto the thin limbof the loop ofHenle. Sofar, no human disorders have been asso-ciated with altered salt transport here, sowe will concentrate on the thick ascend-ing limb (TAL, Figure 3).

The study of rare disease has greatlyenhanced our understanding of this neph-ron segment, mainly through investiga-tions intoBSandfamilialhypomagnesemiawith hypercalciuria and nephrocalcinosis(FHHNC).Theelectroneutral furosemide-sensitive Na+-2Cl2-K+ cotransporter(NKCC2), encoded by SLC12A1, is thekey apical sodium transporter.Mutationsin this gene cause BS type 1 (OMIM#601678). Function of NKCC2 is depen-dent on apical recycling of potassiumthrough the potassium channel ROMK,encoded by KCNJ1. Consequently, muta-tions in this channel are the cause of BStype 2 (OMIM #241200). Together, thesetwo transport proteins generate the lu-men positive transepithelial potential,which drives the paracellular absorptionof cations, including Ca++ and Mg++, apathway lined by claudins 16 (CLDN16)and 19 (CLDN19). Mutations in thesegenes cause FHHNC (OMIM #248250and #248190, respectively). Thus, reab-sorption of divalent cations in TAL islinked to sodium transport via NKCC2.Yet, the claudins also facilitate paracellularsodium reabsorption and, at least inthe mouse model, FHHNC is associatedwith renal salt wasting.33 Basolateral exit

Figure 3. Simplified diagram of a TAL cell. Sodium is reabsorbed electroneutrally viaNKCC2 (defective in Bartter type 1), together with one potassium and two chloride ions.The transporter can only function with all four ions bound and, because of its luminalconcentration, potassium binding becomes the rate-limiting step. Therefore, potassium isrecycled through the potassium channel ROMK1 (defective in Bartter type 2) to ensure anadequate luminal supply of potassium. This also generates a lumen positive transepithelialpotential, providing the driving force for paracellular absorption of calcium and magne-sium. Sodium exits the cell on the basolateral (blood side) via the Na-K-ATPase, whereaschloride exits through the chloride channels CLCNKB (defective in Bartter type 3) andCLCNKA; both require Barttin (defective in Bartter type 4) for proper membrane locali-zation. NKCC2 can be inhibited by loop diuretics, such as furosemide.

Figure 2. Simplified diagram of a PT cell. Sodium reabsorption in the PT is mainly ac-complished by NHE3, which exchanges sodium for protons. Other sodium-coupledtransporters use the chemical and electrical gradient of sodium for the reabsorption ofmolecules (X stands for, e.g., glucose, amino acids, phosphate).



of sodium and chloride is mediated bythe Na+-K+-ATPase and the chloridechannel CLCNKB, respectively. Reces-sive mutations in CLCNKB are the causeof BS type 3 (OMIM #607364). It is likelythat the close homolog CLCNKA contrib-utes to salt reabsorption in TAL, explain-ing the typically more severe phenotypein patients lacking Barttin (BSND), theobligate subunit for both CLCNK homo-logs, mutations in which cause BS type4A (OMIM #602522). A similar severephenotype occurs with loss-of-functionmutations in both chloride channels(BS type 4B, OMIM#613090). In contrastto these observations in patients, datafrom mouse studies do not support thenotion of a substantial contribution ofClC-K1 (themouse ortholog ofCLCNKA)to salt reabsorption in TAL.34,35 It is im-portant to note that CLCNKB and Bart-tin constitute the key pathway forbasolateral chloride exit also in theDCT (see below) and thus can phenotyp-ically resemble a mixed TAL/DCTdisorder.34,36

Previously, a terminology had beenproposed to separate BSs into so-calledantenatal BS (BS types 1, 2, and 4) and“classic” BS (BS type 3) with presenta-tion later in childhood.37 Indeed, retro-spective reviews clearly show a trend formore severe antenatal presentation in BStypes 1, 2, and 4 compared with type3.4,38 Yet, there is a wide spectrum of se-verity in all forms of BS: some patientswith BS type 1, 2, or 4 present only laterin life, including adulthood, whereassome patients with BS type 3 have a se-vere antenatal presentation with prema-turity as early as 22 weeks of gestationand polyhydramnios treated with am-niocentesis.39–43There are some datafor CLCNKB suggesting that mutationtype may influence the phenotype, withmutations affecting the Barttin-bindingsite, the dimerization interface, or theselectivity filter causing more severedysfunction.44 Yet, the most commonmutation in CLCNKB is a whole-genedeletion, which can be associated withthe whole phenotypic spectrum. Onerecent review of 30 patients with BStype 3 found no evidence for a genotype-phenotype association,45whereas in a

larger series of 115 patients an associationof complete loss-of-function mutationswith age at onset was seen.46

Regulation by MAGED2Previously, transient forms of antenatalBS have been described, but it was onlyrecently that a genetic explanation for asubset of these patients was identified: loss-of-function mutations in the melanoma-associated antigen-D2 (MAGED2).47 Itappears that the encoded protein is an im-portant regulator of tubular salt reabsorp-tion in TAL and DCT in the ante- andperinatal period, but not thereafter. Thegene maps to the X-chromosome andpregnancies with affected boys are prom-inently characterized by severe polyhy-dramnios.47 After delivery, polyuriapersists with hypokalemic alkalosis, butsymptoms resolve spontaneously duringthe first few months of life. Why thereseems to be separate regulation of tubulartransport before and after birth, andwhat role exactly MAGED2 plays in thisprocess, remain to be elucidated.

Macula Densa, TubuloglomerularFeedback, and HyperreninismHypertrophy of the juxtaglomerular ap-paratus (JGA) was already part of theoriginal description of BS.48 The JGA isat the interface of glomerular and tubu-lar function and mediates tubuloglo-merular feedback (TGF) and essentiallyconstitutes the “volume sensor” of thekidney, where on the basis of tubularsensing, renin release and glomerular fil-tration are regulated.49 The tubularcomponent of the JGA is the maculadensa and chloride transport is a key ini-tial signaling pathway: decreased chlo-ride availability indicates inadequatefiltration and leads to activation of theTGF with consequent renin release andafferent arteriolar dilatationwith hyperfil-tration through a number of intermediatesteps, most prominently the productionof PG E2 (PGE2) by cyclooxygenase-2(COX2).50,51 This elevated COX2 activityis the basis for treatment of BS with PGsynthesis inhibitors. Importantly, becausemacula densa cells are part of the TAL,mutational effects are present here aswell, leading in essence to a short-circuit

of TGF, as chloride reabsorption is genet-ically impaired in BS. Consequently, reninrelease and regulation of filtration are es-sentially uncoupled fromvolume status inBS, because the volume sensor is defective.PGE2production appears behighest inBStypes 1 and 2, which led to the proposal ofthe term “hyperprostaglandin E syn-drome” for these BS subforms.37 Yet, de-spite the lower PG levels, the hypokalemicalkalosis is typically much more pro-nounced in BS type 3 compared withtypes 1 and 2.38,52 The reasons for thisare not quite clear: is it, because CLCNKBis expressed also beyond TAL in the DCT,thus impairing salt transport in two neph-ron segments?35 But why then is it typi-cally the “milder” form with later onset?Do patients with BS type 3 have higheraldosterone levels, despite lower PGE2?If so, what triggers the aldosterone pro-duction? Further investigations areneeded to better understand the oftendramatic electrolyte abnormalities inBS3.

Clinical ControversiesThe wide spectrum of clinical severity inall types of BS has led to controversiesregarding the terminology: should a clas-sification system be on the basis of theclinical phenotype, distinguishing be-tween “antenatal” BS (sometimes alsoreferred to as “hyperprostaglandin Esyndrome”) and “classic” BS?53 Butwhere exactly is the separation? Does apatient born at 36 weeks have antenatalor classic BS? Or should it be on the basisof the clinical similarity to the effects ofdiuretics and thus the predominantly af-fected nephron segment: loop versusDCT disorder?37 But where do patientsbelong, who initially have a BS-like phe-notype but later fit a GS type, as can beseen in patients with CLCNKB muta-tions?36 Do they switch classificationand thus are told at some point thatthey have a different diagnosis then ini-tially assigned? Or should we stick withthe genetic classification, as in this re-view? But even there is heterogeneity:BS type 5 is referred to by some authorsas related to mutations in CASR, by oth-ers to combined mutations in CLCNKAand CLCNKB, and more recently it has



been assigned by OMIM to the transientBS associated with mutations inMAGED2 (see Table 1).37,54 It gets evenmore confusing when clinical and genet-ic criteria are combined, so that antena-tal BS becomes synonymous with BStypes 1, 2, and 4, and classic BS withtype 3.37 In this system, a patient withadult presentation and mutations inSLC12A1 would be categorized as ante-natal BS, whereas the premature babywith CLCNKB mutations would haveclassic BS. Similarly, a baby with BSborn prematurely after a pregnancycomplicated by polyhydramnios couldbe classified either as antenatal or classicBS, depending on the underlying geneticcause. Although such a classificationsystem captures well the majority of pa-tients, in a substantial minority (includ-ing the 20%–30% of patients with BStype 3 with antenatal presentation) theclinical and genetic criteria diverge.38,46

Potentially severe complications re-lated to the electrolyte abnormalities,such as cardiac arrhythmias, have beendescribed in BS.55 We recentlydescribed a case of BS type 4 with suchdramatic alkalosis that not onlywas there impaired breathing (“renalapnea”), but there also seemed to be amore generalized enzyme dysfunc-tion.56 Alkalosis is typically most severein patients with BS types 3 and 4, poten-tially related to chloride depletion,emphasizing the need to use chloride-containing salt supplementation.57 In-deed, stabilization of volume statuswith salt and water should always bethe first therapeutic aim. Yet, even thecombined use of such supplementationwith PG synthesis inhibitors is often notsufficient to achieve sustained normali-zation of electrolyte abnormalities. Thisis most dramatically seen in BS type 4.58

So, what level of potassium can we con-sider safe and should we aim for? Is awildly swinging potassium level associ-ated with large doses of intermittentsupplementation safer than a stablebut very low level? The hypokalemicalkalosis can be improved with the useof K+-sparing diuretics, but this is con-troversial: BS is primarily a salt-wastingdisorder and the salt wasting will be

compounded by the use of K+-sparingdiuretics, putting the patient at risk ofsevere hypovolemia. Although we canmeasure potassium very easily and thusmay feel prompted to treat abnormali-ties, hypovolemia is much more difficultto express in exact numbers. Couldsome of the reported sudden collapsesin salt-losing tubulopathies be relatedto hypovolemia rather than hypokale-mia; for instance, when the patientdevelops vomiting and/or diarrhea,compounding the renal with intestinalsalt losses? However, given the above dis-cussed short-circuit of the JGA in BS,where renin production appears to beuncoupled from volume status, the useof K+-sparing diuretics may be justified,as long as volume is sufficiently suppor-ted by fluid and pharmacologic salt sup-plementation. Further studies to assessthe efficacy of these drugs are needed.If used, amiloride may be preferable tomineralocorticoid antagonists, such asspironolactone, because the alkalosismay not only be mediated by H+ secre-tion in the aldosterone-sensitive distalnephron alone, but also by NHE3 inTAL, which is also inhibited by amiloride,albeitwith amuch lower affinity comparedwith ENaC.59

Obviously, this controversy extendsbeyond potassium-sparing diuretics,but also concerns the use of angiotensinconverting enzyme inhibitors and angio-tensin receptor blockers. Although notcommonly used in BS, physicians maybe inclined to use them in those patientswho develop proteinuria, especially if thebiopsy reveals glomerulosclerosis.46

Whether these medications at this stagecan help protect kidney function thatcould justify the risk of hypotension isyet another open question.

Another treatment dilemmaoccurs inpatients with BS complicated by a neph-rogenic diabetes insipidus (NDI)–likephenotype. The TAL is critical for uri-nary dilution and the establishment ofthe interstitial concentration gradi-ent.60 Consequently, isosthenuria, theinability to either dilute or concentratethe urine, would be expected in BS andis indeed present in many of them.However, there are some patients with

NDI-like features, i.e., with a urine os-molality,200mosm/kg and an inabilityto concentrate the urine afteradministration of DDAVP.61,62 Misdiag-nosis of such patients with BS asprimary NDI has been reported and wetherefore suggested the term “secondaryinherited NDI.”63 Presumably, the uri-nary dilution is mediated by a hypertro-phied DCT, but the unresponsiveness toDDAVP remains to be clarified. Clini-cally, these patients present a treatmentdilemma: salt supplementation isusually a key component of the treat-ment of BS, but contraindicated inNDI. In our own clinical experience,salt supplements are poorly toleratedby these patients, and often associatedwith hypernatremia and increasedthirst (unpublished observations).

Since the discovery of elevated renalproduction of PGs and their role in me-diating elevated renin and aldosteronelevels, suppression of PGE2 productionby PG synthesis inhibitors is generallyaccepted as beneficial in the treatmentof BS, at least during the first few yearsof life.64,65 Yet, during later childhood,this effect appears to be less pronouncedand PG synthesis inhibitors are oftenweaned or withdrawn. Why is this? Is itbecause patients can now self-regulatetheir salt and water intake and thus bet-ter self-maintain homeostasis? Or arethere developmental changes in the reg-ulation of tubular salt reabsorption thatmake PGs less relevant? The discovery ofBS type 5 and the causative geneMAGED2 clearly provide evidence fordevelopmental changes in the firstmonths of life in the regulation of tubu-lar salt transport.66

In the infantile period, clinical obser-vations demonstrate an often dramaticimprovement from PGE2 inhibition: itreduces polyuria, improves the electro-lyte abnormalities, and ameliorates thefailure to thrive.64 However, whichdrug should be used? The most com-monly prescribed drug in BS is indo-methacin due to its described efficacywith respect to decreased polyuria, im-proved growth, and electrolyte con-trol.67,68 Yet, it can also be associatedwith severe side effects, especially



gastrointestinal, such as gastric ulcer,necrotizing enterocolitis, and gut perfo-ration.69 Moreover, long-term use aspain medication is associated withCKD.70 The identification of the criticalrole of COX2 in the excess production ofPGs in BS established selective COX2inhibitors, the so-called “coxibs,” as apromising new treatment option.71 In-deed, successful treatment with thesedrugs has been recurrently report-ed.69,72,73 However, with the realizationof the increased cardiovascular mortalitywith selective compared with nonselec-tive COX inhibitors, at least in adults,and the subsequent withdrawal ofrofecoxib from the market, the use ofthe coxibs in BS has remained controver-sial. In one retrospective review of 28 pa-tients with BS or GS, rofecoxib use wasassociated with higher BP comparedwith indomethacin, although in bothgroups BP was still below the average.74

It remains to be determined what posesthe greater threat to patients with BS: therisk of gastrointestinal and/or renal sideeffects, or the potentially increased car-diovascular mortality. Yet, even with re-gard to the renal side effects, there issome controversy: retrospective reviewshave revealed that a substantial subset ofpatients (up to 25%) with BS developCKD.46,52 The reasons for this may in-clude prematurity and indomethacinnephrotoxicity. Yet, interestingly, if bi-opsies are performed, these typically donot reveal the tubulointerstitial changesexpected from indomethacin toxicity,but often glomerulosclerosis.46,75 Con-sequently, it has been speculated thatthe persistent elevation of PGs withconsequent glomerular hyperfiltrationand elevated renin and aldosterone maycontribute to this glomerular damage,and that life-long treatment withPG synthesis inhibitors may thereforeactually protect, rather than impair,long-term kidney function.71,75 ,76

Lastly, the antenatal treatment of BShas been reported in isolated cases.77,78

Yet, whether there is true benefit fromthis early treatment which justifies theincreased risk of potential complica-tions such as necrotizing enterocolitisremains controversial.

DCT

Impaired salt reabsorption in the DCTis associated with two disorders: GS(OMIM #263800) and EAST syn-drome (also called SeSAME, OMIM#612780).79–81 GS is probably the mostcommon renal salt-wasting disorderwith an incidence of around 1:25,000and is often considered a mild disorder.It is typically diagnosed during adoles-cence or adulthood, often incidentally,when blood tests are obtained for otherreasons and hypokalemia is noted.Yet, there are many patients who reportsignificant symptoms, such as severe fa-tigue, lack of stamina, and impairedquality of life.82 Interestingly, the severityof electrolyte abnormalities in these pa-tients is not significantly different fromthosewithminoror no symptoms.83 Laterin life, patients may develop complica-tions, such as chondrocalcinosis and scle-rochoroidal calcifications. Surprisingly,the development of hypertension hasbeen reported in isolated adult patientswith GS and one large retrospectivestudy suggests that there may also be anincreased risk of type 2 diabetes andCKD.83,84

From an isolated renal perspective,EAST syndrome is essentially indistin-guishable from GS and the severity ofthe disorder is primarily determined bythe extrarenal manifestations: generalizedseizures are commonly thepresenting syn-drome in infancy, yet the epilepsy typicallyimproves with time and many patientshave several years with little or no seizureactivity, although with later emergence offocal epilepsy.85 Although KCNJ10 is ex-pressed in the eye and patients have subtle,but distinct, changes on electroretino-grams, these do not lead to any apparentsymptoms.86 It is the degree of ataxia,especially with the associated speechdyspraxia, that determines mostly the dis-ability of patients, with some patients vir-tually unable to communicate becauseboth speech and written communicationare impaired by themovement disorder.87

This decreased expressive ability mayhave contributed to the stigmatizinglabel of “mental retardation,” part of theacronym “SeSAME.”

The identificationof animalmodels ofEASTsyndromemay facilitate the gener-ation of new treatments for this severemultisystem disorder.88–90

The discovery of EAST syndrome es-tablished the critical role of KCNJ10 forthe function of the DCT and promptedthe consideration for theDCTas the renal“K+-sensor” to maintain potassiumhomeostasis.91 Hypokalemia leads tohyperpolarization of the basolateralmembrane of DCT cells with conse-quent enhanced chloride exit throughCLCNKB. The resultant decreased intra-cellular chloride concentration activatestheWNK-SPAK pathway, which in turnsleads to phosphorylation and thusincreased activity of the NaCl cotrans-porter NCC, so that little sodiumremains to be delivered to the CD.92

Conversely, in hyperkalemia, sodiumuptake in DCT will be decreased andmore sodium is delivered to the CDwhere sodium reabsorption can be bal-anced by potassium secretion (see Fig-ures 4 and 5). The WNK kinases WNK4and WNK1 are important regulators forthe relative abundance of sodium reab-sorption in DCT versus CD, and the in-terplay between sodium and potassium isincreasingly recognized as a key elementnot only for potassium homeostasis, butalso BP regulation.93,94

The expression of CLCNKB in DCTalso explains why patients with BS type 3can phenotypically resemble GS.34,46 Pa-tients with HNF1B mutations can alsophenocopy GS, presenting the typicalelectrolyte profile, sometimes with onlyminor radiologic abnormalities of thekidneys, leading to a potential misdiag-nosis.95,96

Clinical ControversiesThe same potentially serious complica-tions of hypokalemic alkalosis reportedin BS have also been associated with GS.However, because GS does not involvethe JGA and thus TGF is intact, potentialelevations of PGs, renin, and aldosteroneshould reflect physiologic compensationfor the salt losses in the DCT. Followingthis understanding of the pathophys-iology, such activation of the renin-angiotensin system should be suppressible



by sufficient salt supplementation and,consequently, treatmentwithPG synthesisinhibitors and/or K+-sparing diureticsshould be avoided in GS. Nevertheless, abeneficial effect of such drugs in GS hasbeen reported.97 Apparently, despite ourinsights into renal pathophysiology, westill do not fully understand the develop-ment of symptoms in GS. Yet, given the

augmented salt wasting with amilorideand the potential nephrotoxic and gastro-intestinal side effects of PG synthesis in-hibitors, their use has been cautioned inan expert consensus statement on GS.83

As inBS, it remains controversialwhatlevel of plasma potassium is acceptable inGS. Similarly, to what degree shouldmagnesium levels be normalized? This

is especially important in EAST syn-drome, because the seizures may be at-tributed to hypomagnesemia. Yet, in ourexperience, seizures occur in EAST syn-drome independent of plasma magne-sium levels and, similarly, symptomsof GS cannot be correlated with thedegree of electrolyte abnormalities.83,85

An increase in plasma levels after oralsupplementation results in increasedglomerular filtration and thus increasedrenal losses, leading to a virtual impos-sibility in many patients to normalizeplasma levels with oral supplementation.

CD

The CD is the final part of the nephronand, although quantitatively the smallestproportionoffilteredsodiumisreabsorbedhere, this is the tubular segmentwherefinaldecisions about sodium and water reab-sorption are being made and reabsorptionis most highly regulated. Because there isno further segment downstream to com-pensate,dysfunction in this segmentcanbemost devastating, as seen in the autosomalrecessive form of pseudohypoaldosteron-ism type 1 (arPHA1, OMIM #264350),caused by loss-of-function mutations inany of the subunits of the epithelial so-dium channel ENaC. Affected infantstypically present in the first few dayswith excessive weight loss and are foundto have life-threatening hypovolemiawith hyperkalemia and acidosis. Inter-estingly, PHA1 is the only salt-losingtubulopathy that typically presents withhyponatremia, presumably because thesevere hypovolemia leads to release of an-tidiuretic hormone. Because ENaC is alsoexpressed in lungs and skin, patientswith arPHA1 can also suffer from cysticfibrosis–like lung disease, as well as from amiliary skin rash. In contrast, the auto-somal dominant form (adPHA1, OMIM#177735) has exclusive renal manifesta-tions. It is caused by heterozygous mu-tations inNR3C2, the gene encoding themineralocorticoid receptor. Affectedpatients typically present in the firstmonth of life with insufficient weightgain and subsequent blood testsshow hyponatremia, hyperkalemia, and

Figure 5. Simplified diagram of a principal cell and type 1 intercalated cell in the corticalCD. Sodium reabsorption occurs electrogenically through ENaC and Na-K-ATPase andthus facilitates potassium and proton secretion through ROMK and the H+-ATPase, re-spectively. Aldosterone indirectly affects the activity of these proteins via the mineralo-corticoid receptor MRCR. ENaC can be inhibited by amiloride.

Figure 4. Simplified diagram of a DCT cell. Sodium is reabsorbed electroneutrally via asodium-chloride cotransporter (NCC) and can then exit toward the blood side via theNa-K-ATPase, whereas chloride can pass through the basolateral chloride channel CLCKNB.KCNJ10 indirectly regulates Na-K-ATPase activity by providing a supply of potassiumdependent on basolateral potassium concentration. NCC can be inhibited by thiazides.Impaired salt reabsorption in DCT indirectly affects magnesium uptake via TRPM6, ex-plaining the renal magnesium wasting for salt-losing disorders of the DCT.



metabolic acidosis. Although manifesta-tions are usually not as severe as in ar-PHA1, they can also be life-threatening.98

Interestingly, symptoms resolve spontane-ously later on, and in our own experienceeven as early as during infancy. The reasonsfor this spontaneous improvement remainto be elucidated. Studies of adult carriersof adPHA1, however, show elevated re-ninandaldosterone, aswell as cortisol levels,compared with unaffected family mem-bers, suggesting that despite the absenceof overt symptoms, haploinsufficiencyof NR3C2 may have subtle lifelongconsequences.99,100

SUMMARY

Much has been learned about salt-losingtubulopathies, catalyzedby the recent ad-vances in genetics, which has led to theidentification of most of the underlyinggenes. However, clinical observations ingenotyped patients continue to raisequestions about specific aspects of theroles of these genes. Most importantly,despite the ever more detailed insightsinto human physiology, treatment formost these disorders is highly variablebetween physicians and sometimeseven controversial. Fundamental ques-tions, such as whether hypokalemia orhypovolemia pose a graver threat to pa-tients with BS and GS, remain open. Be-cause of the rarityof these disorders, solidclinical evidence is usually not availableand it is the anecdotal experience thatoften influences the individual physi-cian.101 National and internationalefforts, such as the United Kingdomregistry for rare renal diseases (www.rarerenal.org), the Kidney Disease Im-proving Global Outcomes expert consen-sus conference onGS,83 and the EuropeanReference Network for rare diseases(http://ec.europa.eu/health/rare_diseases/european_reference_networks/erf_en),are important initiatives to improve thesystematic collection of evidence andprovide a framework for the develop-ment of rational and improved treat-ments. In this review, we have tried tohighlight controversial topics in themanagement of these disorders, which

could inform the development of futureclinical trials.

ACKNOWLEDGMENTS

This work was supported by the European

Union, FP7 (grant agreement 2012-305608

“European Consortium for High-Through-

put Research in Rare Kidney Diseases

[EURenOmics]”).

DISCLOSURESNone.

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