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Home , Bartter syndrome, EAST syndrome, Gitelman syndrome, Hypoaldosteronism, Pseudohypoaldosteronism, Tubulopathy

BRIEF REVIEW www.jasn.org

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

Robert Kleta and Detlef Bockenhauer

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

ABSTRACT Renal tubulopathies provide insights into the inner workings of the , yet also driving force for the passive reabsorption pose therapeutic challenges. Because of the central nature of in tubular of water. The price to pay for this powerful transport physiology, disorders of sodium handling may affect virtually all aspects system of filtration and reabsorption is a of the homeostatic functions of the kidney. Yet, owing to the rarity of these disor- high-energy demand: when adjusted ders, little clinical evidence regarding treatment exists. Consequently, treatment for organ weight, the kidneys, together can vary widely between individual physicians and centers and is based mainly on with the heart, have the highest resting understanding of renal physiology, reported clinical observations, and individual metabolic expenditure, approximately experiences. Salt-losing tubulopathies can affect all tubular segments, from the 440 kcal/kg per day, almost twice as proximal tubule to the collecting duct. But the more frequently observed disorders much as the brain, making the kidneys are Bartter and Gitelman , which affect salt transport in the thick ascend- susceptible to acute injury when the ing limb of Henle’s loop and/or the , and these disorders energy supply is impaired.3 generate the greatest controversies regarding management. Here, we review clin- The importance of tubular sodium ical and molecular aspects of salt-losing tubulopathies and discuss novel insights reabsorption becomes especially appar- provided mainly by genetic investigations and retrospective clinical reviews. Addition- ent when the system is disturbed, as in the ally, we discuss controversial topics in the management of these disorders to highlight salt-losing tubulopathies. areas of importance for future clinical trials. International collaboration will be required On the basis of anatomic and func- to perform clinical studies to inform the treatment of these rare disorders. tional characteristics, the tubules are typ- ically divided into four main segments: J Am Soc Nephrol 29: 727–739, 2018. doi: https://doi.org/10.1681/ASN.2017060600 proximal tubule (PT), thick ascending limb (TAL) of Henle’s loop, distal con- voluted tubule (DCT), and collecting The preservation of electrolyte, volume, containing an enormous load of solutes, duct (CD). Genetic or acquired defects and acid-base balance is vi- including about 20,000 mmol of sodium in salt transport in any of these segments tal to the functioning of our bodies. Be- per day (equivalent to the amount in lead to distinct tubulopathies, which cause life initially evolved in the ocean, 1.2 kg of cooking salt), only to laboriously have characteristic clinical and biochem- cellular function is dependent on the reabsorb virtually all of it back into circu- ical features (Figure 1). maintenance of the electrolyte concen- lation. In the original ocean environment, Interestingly, given the critical nature tration reflective of the original environ- a system of filtration was well suited given of sodium for the maintenance of volume ment. No idea could be thought, no the unlimited availability of salt and water. homeostasis, essentially all salt-losing tu- muscle moved, without the proper bal- Yet, in order to enable life on land, large bulopathies actually maintain normal ance of salts within our bodies.1 It is the losses of water and solutes had to be pre- responsibility of mainly the kidneys to vented, leading to the evolution of ever maintain this vital “milieu interieur.” more powerful tubules.2 Under physio- Published online ahead of print. Publication date The kidneys do so by the combination logic conditions, they are capable of re- available at www.jasn.org. of glomerular filtration and tubular absorbing .99% of filtered sodium and Correspondence: Dr. Detlef Bockenhauer, UCL reabsorption, a system that is best ex- water. This enormous task is accom- Centre for Nephrology and Department of Pediat- “ ric Nephrology, Great Ormond Street Hospital NHS plained by the evolutionary history. In- plished by a combination of distinct so- Trust, Great Ormond Street, London WC1N 3JH, telligent design” may not have devised a dium or sodium-coupled transport systems UK. Email: [email protected] system that, in an average adult, initially along the . It is the active reabsorp- Copyright © 2018 by the American Society of filters approximately 150 L of water daily, tion of sodium that generates the main Nephrology

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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 hydratase and 3-hydroxyacyl CoA dehydrogenase) impairs mitochondrial fatty acid oxida- tion.10,11 Although this defect is global it only manifests in the PT, because the PT does not utilize glucose for energy gener- ation, exposing the dependency on fatty acid oxidation.12 Patients typically pre- sent in childhood with rickets and the biochemical abnormalities. In contrast to FRTS1, however, no progressive CKD has been observed.13 FRTS4 is caused by a specific mutation (R76W, also anno- tated as R63W, depending on reference Figure 1. Sodium and water reabsorption along the nephron. Knockouts of distinctive sequence) in the proteins in particular nephron segments lead to distinctive disease in man, as indicated. HNF4A.14 Mutations in this gene are as- sociated with abnormalities in insulin sodium excretion in steady state, because place (Figure 2). Micropuncture studies secretion, typically hyperinsulinemic hy- persistent losses exceeding intake would suggest that between 60% and 80% of all poglycemia manifesting in the neonatal be incompatible with life. This normal filtered salt and water is reabsorbed in period and diabetes (MODY type 1) sodium excretion is achieved by a com- this segment.5 The “engine” for salt later in life. Consequently, patients with pensatory increase in absorption through transport, as in all tubular segments, is FRTS4 usually manifest shortly after birth other pathways. This explains the com- the basolateral Na+-K+-ATPase, which with hypoglycemia and subsequent inves- monly seen that establishes the electrochemical gradi- tigations then reveal the FRTS.15,16 The characterizes, for instance, Bartter and ent for sodium entry into the cell. The association of FRTS4 with only this one Gitelman (BS and GS, respec- Fanconi renotubular syndrome (FRTS) specificmutation(allotherdescribed tively), and that enhances sodium reab- represents global dysfunction of the PT HNF4A mutations are only associated sorption in the CD, primarily at the and, because of the high energy demand with altered insulin secretion) raises in- expense of secretion. Conse- of this transport process, is often associ- teresting questions over the specific quently, a key diagnostic feature for renal ated with disorders of impaired energy role of R76 for the function of HNF4A salt wasting is the fractional excretion supply, such as mitochondrial cytopa- in the maintenance of proximal tubular of chloride.4 thies.6 But, aside from being a secondary function,but,sofar,noinsightshave Here, we will review key advances in feature of systemic disorders, FRTS can been published. our understanding of the different renal also occur in primary form. Currently, The bulk of sodium in the PT is taken genetic disorders affecting salt (sodium OMIM lists three such forms of FRTS up by the apical Na+-H+ exchanger chloride) reabsorption with respect to (see Table 1): FRTS1 is dominantly inherit- NHE3, in this way linking sodium and both clinical phenotype and underlying ed and typically presents in childhood thus volume homeostasis with acid-base pathophysiology. An overview of these with rickets and the typical biochemi- homeostasis.17 Given this important disorders, the underlying genes, and cal abnormalities of FRTS. Progressive role, one might have expected a severe key clinical characteristics is given in Ta- CKD is typically observed with develop- form of a salt-losing and ble1.Inaddition,wewillhighlightsome ment of CKD stage 5 in adulthood. Al- proximal with loss of function clinical controversies around the treat- though the underlying gene has been of this transporter. Instead, recessive ment of salt-losing tubulopathies, which linked to a locus on chromosome 15, mutations in the encoding gene SLC9A3 need further clinical studies and which the identity of this gene remains to be are associated with congenital sodium are summarized in Table 2. revealed.7 FRTS2 previously referred to (OMIM #616868).18 Only two FRTS observed in two siblings with a ho- of the seven reported patients with avail- mozygous mutation in SLC34A1.8 Yet, able data exhibited acidosis. While also PT recessive mutations in this gene were presenting with diarrhea, mice lacking subsequently found to cause infantile hy- Nhe3 function do also show evidence The PT is the part of the nephron where percalciuria and the association with of salt wasting and acidosis.19 To better the most diverse action with respect to FRTS has been questioned.9 Aunique dissect the respective renal and/or intes- reabsorption (as well as secretion) takes aspect of PT energy utilization was tinal contribution to the acidosis, a renal

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Table 1. Genetics of primary renal salt-losing nephropathies and pertinent clinical characteristics Nephron Disorder OMIM Gene Protein Inheritance Typical Clinical Findings Segment PT Fanconi renotubular 134600 ? ? AD Rickets, progressive CKD syndrome type 1; FRTS1 Infantile 2a 613388 SLC34A1 NaPi-IIa AR Hypercalciuria, Hypophosphatemic rickets 241530 SLC34A3 NaPi-IIc AR/AD Hypercalciuria, with hypercalciuria nephrocalcinosis Fanconi renotubular syndrome 615605 EHHADH EHHADH AD Rickets, no type 3; FRTS3 Fanconi renotubular syndrome 600281 HNF4A HNF4A AD Congenital type 4; FRTS4 hyperinsulinism, later MODY, rickets Renal glucosuria 233100 SLC5A2 SGLT2 AR/AD Glucosuria Proximal renal tubular 604278 SLC4A4 KNBC AR , eye acidosis with eye findings abnormalities (corneal opacities, band keratopathy, , glaucoma), mental impairment with renal 259730 CA2 CA2 AR Osteopetrosis, cerebral tubular acidosis calcifications, metabolic acidosis TAL BS type 1 601678 SLC12A1 NKCC2 AR Prematurity, nephrocalcinosis, hypokalemic , iso- or hyposthenuria BS type 2b 241200 KCNJ1 ROMK1 AR Prematurity, polyhydramnios nephrocalcinosis, transient , then hypokalemic alkalosis, iso- or hyposthenuria BS type 3b 607364 CLCNKB ClC-Kb AR Severe hypokalemic hypochloremic alkalosis BS type 4Ab 602522 BSND Barttin AR Prematurity, BS type 4Bb CLCNKA, CLCNKB ClC-Ka, ClC-Kb AR polyhydramnios, sensorineural deafness, severe hypokalemic hypochloremic alkalosis, iso- or hyposthenuria BS type 5b 300971 MAGED2 MAGED2 XR Severe polyhydramnios, transient salt wasting AD hypocalcemic hypercalciuria CASR CASR AD Hypocalcemic hypercalciuria, that can be complicated by hypokalemic alkalosis DCT GS 263800 SLC12A3 NCC AR Hypokalemic alkalosis, hypocalciuria, hypomagnesemia EAST syndrome 612780 KCNJ10 Kir4.1 AR , , sensorineural deafness, hypokalemic alkalosis

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Table 1. Continued

Nephron Disorder OMIM Gene Protein Inheritance Typical Clinical Findings Segment Cortical AD 177735 NR3C2 MR AD Transient neonatal salt CD type I wasting with , hyperkalemia, acidosis AR pseudohypoaldosteronism 264350 SCNN1A ENaC a AR Hyponatremia, type I SCNN1B ENaC b hyperkalemia, acidosis, SCNN1G ENaC g pathologic sweat test, lung disease Listed are inherited salt-wasting disorders, including the underlying gene/protein and clinical characteristics. Note that most of these clinicaldisorderscanhavea wide 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. specific knock-out was generated, which hypophosphatemic nephrolithiasis have become major threats to public confirmed renal bicarbonate wasting, al- (OMIM # 612286),22 similar to the hy- health, the loss of sodium and glucose beit with only mild acidosis.20 These pophosphatemic rickets with hypercal- intheurinemaybebeneficial and studies confirm the important role of ciuria caused by heterozygous mutations SGLT2 thus became an attractive thera- NHE3;yet,atleastinPT,thelossof in SLC34A3, encoding NaPi-IIc (OMIM peutic target.25 Inhibitors of SGLT2, the function may be partially compen- #241530). Presumably, the hypophos- gliflozins, are now available and seem to sated by other NHE isoforms, such as phatemia-mediated suppression of provide substantial benefits in the man- NHE8.21 FGF23 leads to increased 1-a hydroxy- agement of diabetes, with not only im- Another important sodium trans- lation of cholecalciferol with resultant proved glucose control but also reduced 2 + 23 porter in PT is the Na -PO4 cotrans- hypercalcemia and hypercalciuria. cardiovascular mortality and diabetic ne- porter NaPi-IIa, encoded by SLC34A1. Of interest is also the sodium-glucose phropathy.27 Initially, a homozygous loss-of-function SGLT2, encoded by SLC5A2. Two further transporters affecting so- mutation was reported as the cause of Recessive mutations in this transporter dium reabsorption in the PT are associ- FRTS type 2 in two siblings.8 Yet, no fur- cause isolated renal glucosuria (OMIM ated with diseases: recessive mutations ther patients with FRTS and SLC34A1 #233100), which provides an example in SLC4A4, encoding basolateral Na- mutations have been identified since. of the enormous benefits the study of a bicarbonate cotransporter NBC1, cause Instead, recessive loss-of-function mu- rare disorder can have for common dis- proximal tubular acidosis with eye find- tations in this gene are recurrently orders. Patients with isolated renal gluco- ings (OMIM # 604278); and recessive found as the cause of infantile hypercal- suria can lose well over 100 g of glucose mutations in carbonic anhydrase 2, en- cemia with nephrocalcinosis (OMIM daily, yet with no apparent detrimental coded by CA2, cause proximal tubular #616963).9 Moreover, heterozygous consequences.24–26 In fact, in an era of acidosis with osteopetrosis (OMIM mutations have been associated with affluence in which obesity and diabetes #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 beneficial? Are antiproteinuric drugs indicated in patients who have developed proteinuria? What is the lower limit of plasma concentration that can be considered safe? DCT Is salt supplementation alone sufficient to normalize and levels? Listed are clinical controversies discussed in this review. These controversies need clarification through clinical trials and/or expert consensus. ACEi, - converting enzyme inhibitors, COXi, cyclooxygenase inhibitors.

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Although the exact amount of physio- logic tubular protein (including albumin) reabsorption remains controversial and may approach several grams per day,30 some patients also show evidence of glomerular damage.31,32 Should these patients 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 loss of volume homeostasis, are such treat- ments, which are generally recom- mended for proteinuria in CKD, of benefit to patients with rare tubular salt-losing disorders? 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-coupled transporters use the chemical and electrical gradient of sodium for the reabsorption of THICK ASCENDING LIMB molecules (X stands for, e.g., glucose, amino acids, phosphate). From the PT, the primary urine traverses into the thin limb of the . So far, no human disorders have been asso- ciated with altered salt transport here, so we will concentrate on the thick ascend- ing limb (TAL, Figure 3). The study of rare disease has greatly enhanced our understanding of this neph- ron segment, mainly through investiga- tionsintoBSandfamilialhypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC).Theelectroneutralfurosemide- 2 sensitive Na+-2Cl -K+ cotransporter (NKCC2), encoded by SLC12A1,isthe key apical sodium transporter. Mutations in this gene cause BS type 1 (OMIM #601678). Function of NKCC2 is depen- dent on apical recycling of potassium fi Figure 3. Simpli ed diagram of a TAL cell. Sodium is reabsorbed electroneutrally via through the ROMK, NKCC2 (defective in Bartter type 1), together with one potassium and two chloride ions. encoded by KCNJ1. Consequently, muta- The transporter can only function with all four ions bound and, because of its luminal tions in this channel are the cause of BS concentration, potassium binding becomes the rate-limiting step. Therefore, potassium is recycled through the potassium channel ROMK1 (defective in Bartter type 2) to ensure an type 2 (OMIM #241200). Together, these adequate luminal supply of potassium. This also generates a lumen positive transepithelial two transport proteins generate the lu- potential, providing the driving force for paracellular absorption of and magne- men positive transepithelial potential, sium. Sodium exits the cell on the basolateral (blood side) via the Na-K-ATPase, whereas which drives the paracellular absorption ++ ++ chloride exits through the chloride channels CLCNKB (defective in Bartter type 3) and of cations, including Ca and Mg ,a CLCNKA; both require Barttin (defective in Bartter type 4) for proper membrane locali- pathway lined by claudins 16 (CLDN16) zation. NKCC2 can be inhibited by loop diuretics, such as . and 19 (CLDN19). Mutations in these genes cause FHHNC (OMIM #248250 and #248190, respectively). Thus, reab- transport sodium directly, it clearly af- Clinical Controversies sorption of divalent cations in TAL is fects the availability of H+ for the apical Patients with FRTS exhibit proteinuria. linked to sodium transport via NKCC2. Na+-H+ exchange. However, except for This primarily reflects “tubular” pro- Yet, the claudins also facilitate paracellular occasional case reports and case series, teinuria, i.e., the impaired reabsorption sodium reabsorption and, at least in very little new data are available for these of filtered proteins, but in some patients the mouse model, FHHNC is associated very rare disorders.28,29 proteinuria reaches the nephrotic range. with renal salt wasting.33 Basolateral exit

J Am Soc Nephrol 29: 727–739, 2018 Pediatric Salt-Losing Tubulopathies 731 BRIEF REVIEW www.jasn.org of sodium and chloride is mediated by larger series of 115 patients an association of TGF, as chloride reabsorption is genet- the Na+-K+-ATPase and the chloride of complete loss-of-function mutations ically impaired in BS. Consequently, renin channel CLCNKB, respectively. Reces- with age at onset was seen.46 release and regulation of filtration are es- sive mutations in CLCNKB are the cause sentially uncoupled from volume status in of BS type 3 (OMIM #607364). It is likely Regulation by MAGED2 BS, because the volume sensor is defective. that the close homolog CLCNKA contrib- Previously, transient forms of antenatal PGE2 production appears be highest in BS utes to salt reabsorption in TAL, explain- BS have been described, but it was only types 1 and 2, which led to the proposal of ing the typically more severe phenotype recently that a genetic explanation for a the term “hyperprostaglandin E syn- in patients lacking Barttin (BSND), the subset of these patients was identified: loss- drome” for these BS subforms.37 Yet, de- obligate subunit for both CLCNK homo- of-function mutations in the melanoma- spite the lower PG levels, the hypokalemic logs, mutations in which cause BS type associated antigen-D2 (MAGED2).47 It alkalosis is typically much more pro- 4A (OMIM #602522). A similar severe appears that the encoded protein is an im- nounced in BS type 3 compared with phenotype occurs with loss-of-function portant regulator of tubular salt reabsorp- types 1 and 2.38,52 The reasons for this mutations in both chloride channels tion in TAL and DCT in the ante- and are not quite clear: is it, because CLCNKB (BS type 4B, OMIM #613090). In contrast perinatal period, but not thereafter. The is expressed also beyond TAL in the DCT, to these observations in patients, data gene maps to the X-chromosome and thus impairing salt transport in two neph- from mouse studies do not support the pregnancies with affected boys are prom- ron segments?35 But why then is it typi- notion of a substantial contribution of inently characterized by severe polyhy- cally the “milder” form with later onset? ClC-K1 (the mouse ortholog of CLCNKA) dramnios.47 After delivery, Do patients with BS type 3 have higher to salt reabsorption in TAL.34,35 It is im- persists with hypokalemic alkalosis, but aldosterone levels, despite lower PGE2? portant to note that CLCNKB and Bart- symptoms resolve spontaneously during If so, what triggers the aldosterone pro- tin constitute the key pathway for the first few months of life. Why there duction? Further investigations are basolateral chloride exit also in the seems to be separate regulation of tubular needed to better understand the often DCT (see below) and thus can phenotyp- transport before and after birth, and dramatic electrolyte abnormalities in ically resemble a mixed TAL/DCT what role exactly MAGED2 plays in this BS3. disorder.34,36 process, remain to be elucidated. Previously, a terminology had been Clinical Controversies proposed to separate BSs into so-called Macula Densa, Tubuloglomerular The wide spectrum of clinical severity in antenatal BS (BS types 1, 2, and 4) and Feedback, and Hyperreninism all types of BS has led to controversies “classic” BS (BS type 3) with presenta- Hypertrophy of the juxtaglomerular ap- regarding the terminology: should a clas- tion later in childhood.37 Indeed, retro- paratus (JGA) was already part of the sification system be on the basis of the spective reviews clearly show a trend for original description of BS.48 The JGA is clinical phenotype, distinguishing be- more severe antenatal presentation in BS at the interface of glomerular and tubu- tween “antenatal” BS (sometimes also types 1, 2, and 4 compared with type lar function and mediates tubuloglo- referred to as “hyperprostaglandin E 3.4,38 Yet, there is a wide spectrum of se- merular feedback (TGF) and essentially syndrome”)and“classic” BS?53 But verity in all forms of BS: some patients constitutes the “volume sensor” of the where exactly is the separation? Does a with BS type 1, 2, or 4 present only later kidney, where on the basis of tubular patient born at 36 weeks have antenatal in life, including adulthood, whereas sensing, renin release and glomerular fil- or classic BS? Or should it be on the basis some patients with BS type 3 have a se- tration are regulated.49 The tubular of the clinical similarity to the effects of vere antenatal presentation with prema- component of the JGA is the macula diuretics and thus the predominantly af- turity as early as 22 weeks of gestation densa and chloride transport is a key ini- fected nephron segment: loop versus and polyhydramnios treated with am- tial signaling pathway: decreased chlo- DCT disorder?37 But where do patients niocentesis.39–43There are some data ride availability indicates inadequate belong, who initially have a BS-like phe- for CLCNKB suggesting that mutation filtration and leads to activation of the notype but later fitaGStype,ascanbe type may influence the phenotype, with TGF with consequent renin release and seen in patients with CLCNKB muta- mutations affecting the Barttin-binding afferent arteriolar dilatation with hyperfil- tions?36 Do they switch classification site, the dimerization interface, or the tration through a number of intermediate and thus are told at some point that selectivity filter causing more severe steps, most prominently the production they have a different diagnosis then ini- dysfunction.44 Yet, the most common of PG E2 (PGE2) by cyclooxygenase-2 tially assigned? Or should we stick with mutation in CLCNKB is a whole-gene (COX2).50,51 This elevated COX2 activity the genetic classification,asinthisre- deletion, which can be associated with is the basis for treatment of BS with PG view? But even there is heterogeneity: the whole phenotypic spectrum. One synthesis inhibitors. Importantly, because BS type 5 is referred to by some authors recent review of 30 patients with BS macula densa cells are part of the TAL, as related to mutations in CASR, by oth- type 3 found no evidence for a genotype- mutational effects are present here as ers to combined mutations in CLCNKA phenotype association,45whereas in a well, leading in essence to a short-circuit and CLCNKB, and more recently it has

732 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 727–739, 2018 www.jasn.org BRIEF REVIEW been assigned by OMIM to the transient compounded by the use of K+-sparing NDI-like features, i.e., with a urine os- BS associated with mutations in diuretics, putting the patient at risk of molality ,200 mosm/kg and an inability MAGED2 (see Table 1).37,54 It gets even severe . Although we can to concentrate the urine after more confusing when clinical and genet- measure potassium very easily and thus administration of DDAVP.61,62 Misdiag- ic criteria are combined, so that antena- may feel prompted to treat abnormali- nosis of such patients with BS as tal BS becomes synonymous with BS ties, hypovolemia is much more difficult primary NDI has been reported and we types 1, 2, and 4, and classic BS with to express in exact numbers. Could therefore suggested the term “secondary type 3.37 In this system, a patient with some of the reported sudden collapses inherited NDI.”63 Presumably, the uri- adult presentation and mutations in in salt-losing tubulopathies be related nary dilution is mediated by a hypertro- SLC12A1 would be categorized as ante- to hypovolemia rather than hypokale- phied DCT, but the unresponsiveness to natal BS, whereas the premature baby mia; for instance, when the patient DDAVP remains to be clarified. Clini- with CLCNKB mutations would have develops vomiting and/or diarrhea, cally, these patients present a treatment classic BS. Similarly, a baby with BS compounding the renal with intestinal dilemma: salt supplementation is born prematurely after a pregnancy salt losses? However, given the above dis- usually a key component of the treat- complicated by polyhydramnios could cussed short-circuit of the JGA in BS, ment of BS, but contraindicated in be classified either as antenatal or classic where renin production appears to be NDI. In our own clinical experience, BS, depending on the underlying genetic uncoupled from volume status, the use salt supplements are poorly tolerated cause. Although such a classification of K+-sparing diuretics may be justified, by these patients, and often associated system captures well the majority of pa- as long as volume is sufficiently suppor- with hypernatremia and increased tients, in a substantial minority (includ- ted by fluid and pharmacologic salt sup- thirst (unpublished observations). ing the 20%–30% of patients with BS plementation. Further studies to assess Since the discovery of elevated renal type 3 with antenatal presentation) the the efficacy of these drugs are needed. production of PGs and their role in me- clinical and genetic criteria diverge.38,46 If used, may be preferable to diating elevated renin and aldosterone Potentially severe complications re- antagonists, such as levels, suppression of PGE2 production lated to the electrolyte abnormalities, , because the alkalosis by PG synthesis inhibitors is generally such as cardiac , have been may not only be mediated by H+ secre- accepted as beneficial in the treatment described in BS.55 We recently tion in the aldosterone-sensitive distal of BS, at least during the first few years described a case of BS type 4 with such nephron alone, but also by NHE3 in of life.64,65 Yet, during later childhood, dramatic alkalosis that not only TAL, which is also inhibited by amiloride, this effect appears to be less pronounced was there impaired breathing (“renal albeit with a much lower affinity compared and PG synthesis inhibitors are often apnea”), but there also seemed to be a with ENaC.59 weaned or withdrawn. Why is this? Is it more generalized enzyme dysfunc- Obviously, this controversy extends because patients can now self-regulate tion.56 Alkalosis is typically most severe beyond potassium-sparing diuretics, their salt and water intake and thus bet- in patients with BS types 3 and 4, poten- but also concerns the use of angiotensin ter self-maintain homeostasis? Or are tially related to chloride depletion, converting enzyme inhibitors and angio- there developmental changes in the reg- emphasizing the need to use chloride- tensin receptor blockers. Although not ulation of tubular salt reabsorption that containing salt supplementation.57 In- commonly used in BS, physicians may make PGs less relevant? The discovery of deed, stabilization of volume status be inclined to use them in those patients BS type 5 and the causative gene with salt and water should always be who develop proteinuria, especially if the MAGED2 clearly provide evidence for the first therapeutic aim. Yet, even the biopsy reveals .46 developmental changes in the first combined use of such supplementation Whether these medications at this stage months of life in the regulation of tubu- with PG synthesis inhibitors is often not can help protect kidney function that lar salt transport.66 sufficient to achieve sustained normali- could justify the risk of is In the infantile period, clinical obser- zation of electrolyte abnormalities. This yet another open question. vations demonstrate an often dramatic is most dramatically seen in BS type 4.58 Another treatment dilemma occurs in improvement from PGE2 inhibition: it So, what level of potassium can we con- patients with BS complicated by a neph- reduces polyuria, improves the electro- sider safe and should we aim for? Is a rogenic (NDI)–like lyte abnormalities, and ameliorates the wildly swinging potassium level associ- phenotype. The TAL is critical for uri- failure to thrive.64 However, which ated with large doses of intermittent nary dilution and the establishment of drug should be used? The most com- supplementation safer than a stable the interstitial concentration gradi- monly prescribed drug in BS is indo- but very low level? The hypokalemic ent.60 Consequently, isosthenuria, the methacin due to its described efficacy alkalosis can be improved with the use inability to either dilute or concentrate with respect to decreased polyuria, im- of K+-sparing diuretics, but this is con- the urine, would be expected in BS and proved growth, and electrolyte con- troversial: BS is primarily a salt-wasting is indeed present in many of them. trol.67,68 Yet, it can also be associated disorder and the salt wasting will be However, there are some patients with with severe side effects, especially

J Am Soc Nephrol 29: 727–739, 2018 Pediatric Salt-Losing Tubulopathies 733 BRIEF REVIEW www.jasn.org gastrointestinal, such as gastric ulcer, DCT The identificationofanimalmodelsof necrotizing enterocolitis, and gut perfo- EASTsyndrome may facilitate the gener- ration.69 Moreover, long-term use as Impaired salt reabsorption in the DCT ation of new treatments for this severe pain medication is associated with is associated with two disorders: GS multisystem disorder.88–90 CKD.70 The identification of the critical (OMIM #263800) and EAST syn- The discovery of EAST syndrome es- role of COX2 in the excess production of drome (also called SeSAME, OMIM tablished the critical role of KCNJ10 for PGs in BS established selective COX2 #612780).79–81 GS is probably the most the function of the DCT and prompted inhibitors, the so-called “coxibs,” as a common renal salt-wasting disorder the consideration for the DCTas the renal promising new treatment option.71 In- with an incidence of around 1:25,000 “K+-sensor” to maintain potassium deed, successful treatment with these and is often considered a mild disorder. homeostasis.91 leads to drugs has been recurrently report- It is typically diagnosed during adoles- hyperpolarization of the basolateral ed.69,72,73 However, with the realization cence or adulthood, often incidentally, membrane of DCT cells with conse- of the increased cardiovascular mortality when blood tests are obtained for other quent enhanced chloride exit through with selective compared with nonselec- reasons and hypokalemia is noted. CLCNKB. The resultant decreased intra- tive COX inhibitors, at least in adults, Yet, there are many patients who report cellular chloride concentration activates and the subsequent withdrawal of significant symptoms, such as severe fa- the WNK-SPAK pathway, which in turns rofecoxib from the market, the use of tigue, lack of stamina, and impaired leads to phosphorylation and thus the coxibs in BS has remained controver- quality of life.82 Interestingly, the severity increased activity of the NaCl cotrans- sial. In one retrospective review of 28 pa- of electrolyte abnormalities in these pa- porter NCC, so that little sodium tients with BS or GS, rofecoxib use was tients is not significantly different from remains to be delivered to the CD.92 associated with higher BP compared those with minor or no symptoms.83 Later Conversely, in hyperkalemia, sodium with indomethacin, although in both in life, patients may develop complica- uptake in DCT will be decreased and groups BP was still below the average.74 tions, such as chondrocalcinosis and scle- more sodium is delivered to the CD It remains to be determined what poses rochoroidal calcifications. Surprisingly, where sodium reabsorption can be bal- the greater threat to patients with BS: the the development of has anced by potassium secretion (see Fig- risk of gastrointestinal and/or renal side been reported in isolated adult patients ures 4 and 5). The WNK kinases WNK4 effects, or the potentially increased car- with GS and one large retrospective and WNK1 are important regulators for diovascular mortality. Yet, even with re- study suggests that there may also be an the relative abundance of sodium reab- gard to the renal side effects, there is increased risk of type 2 diabetes and sorption in DCT versus CD, and the in- some controversy: retrospective reviews CKD.83,84 terplay between sodium and potassium is have revealed that a substantial subset of From an isolated renal perspective, increasingly recognized as a key element patients (up to 25%) with BS develop EAST syndrome is essentially indistin- not only for potassium homeostasis, but CKD.46,52 The reasons for this may in- guishable from GS and the severity of also BP regulation.93,94 clude prematurity and indomethacin the disorder is primarily determined by The expression of CLCNKB in DCT nephrotoxicity. Yet, interestingly, if bi- the extrarenal manifestations: generalized also explains why patients with BS type 3 opsies are performed, these typically do seizuresare commonly the presenting syn- can phenotypically resemble GS.34,46 Pa- not reveal the tubulointerstitial changes drome in infancy, yet the epilepsy typically tients with HNF1B mutations can also expected from indomethacin toxicity, improves with time and many patients phenocopy GS, presenting the typical but often glomerulosclerosis.46,75 Con- have several years with little or no electrolyte profile, sometimes with only sequently, it has been speculated that activity, although with later emergence of minor radiologic abnormalities of the the persistent elevation of PGs with focal epilepsy.85 Although KCNJ10 is ex- kidneys, leading to a potential misdiag- consequent glomerular hyperfiltration pressed in the eye and patients have subtle, nosis.95,96 and elevated renin and aldosterone may but distinct, changes on electroretino- contribute to this glomerular damage, grams, these do not lead to any apparent Clinical Controversies and that life-long treatment with symptoms.86 It is the degree of ataxia, The same potentially serious complica- PG synthesis inhibitors may therefore especially with the associated speech tions of hypokalemic alkalosis reported actually protect, rather than impair, dyspraxia, that determines mostly the dis- in BS have also been associated with GS. long-term kidney function.71,75,76 ability of patients, with some patients vir- However, because GS does not involve Lastly, the antenatal treatment of BS tually unable to communicate because the JGA and thus TGF is intact, potential has been reported in isolated cases.77,78 both speech and written communication elevations of PGs, renin, and aldosterone Yet, whether there is true benefit from are impaired by the .87 should reflect physiologic compensation this early treatment which justifies the This decreased expressive ability may for the salt losses in the DCT. Following increased risk of potential complica- have contributed to the stigmatizing this understanding of the pathophys- tions such as necrotizing enterocolitis label of “mental retardation,” part of the iology, such activation of the renin- remains controversial. acronym “SeSAME.” angiotensin system should be suppressible

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is especially important in EAST syn- drome, because the may be at- tributed to hypomagnesemia. Yet, in our experience, seizures occur in EAST syn- drome independent of plasma magne- sium levels and, similarly, symptoms of GS cannot be correlated with the degree of electrolyte abnormalities.83,85 An increase in plasma levels after oral supplementation results in increased glomerular filtration and thus increased renal losses, leading to a virtual impos- sibility in many patients to normalize plasma levels with oral supplementation.

Figure 4. Simplified diagram of a DCT cell. Sodium is reabsorbed electroneutrally via a sodium-chloride cotransporter (NCC) and can then exit toward the blood side via the Na-K- CD ATPase, whereas chloride can pass through the basolateral CLCKNB. KCNJ10 indirectly regulates Na-K-ATPase activity by providing a supply of potassium The CD is the final part of the nephron dependent on basolateral potassium concentration. NCC can be inhibited by . and, although quantitatively the smallest Impaired salt reabsorption in DCT indirectly affects magnesium uptake via TRPM6, ex- proportionoffilteredsodiumisreabsorbed plaining the renal magnesium wasting for salt-losing disorders of the DCT. here, this is the tubular segment where final decisions about sodium and water reab- sorption are being made and reabsorption is most highly regulated. Because there is no further segment downstream to com- pensate, dysfunction in this segment can be most devastating, as seen in the autosomal recessive form of pseudohypoaldosteron- ism type 1 (arPHA1, OMIM #264350), caused by loss-of-function mutations in any of the subunits of the epithelial so- dium channel ENaC. Affected infants typically present in the first few days with excessive weight loss and are found to have life-threatening hypovolemia with hyperkalemia and acidosis. Inter- estingly, PHA1 is the only salt-losing tubulopathy that typically presents with Figure 5. Simplified diagram of a principal cell and type 1 intercalated cell in the cortical hyponatremia, presumably because the CD. Sodium reabsorption occurs electrogenically through ENaC and Na-K-ATPase and severe hypovolemia leads to release of an- thus facilitates potassium and proton secretion through ROMK and the H+-ATPase, re- tidiuretic . Because ENaC is also spectively. Aldosterone indirectly affects the activity of these proteins via the mineralo- expressed in lungs and skin, patients corticoid receptor MRCR. ENaC can be inhibited by amiloride. with arPHA1 can also suffer from cystic fibrosis–like lung disease, as well as from a miliary skin rash. In contrast, the auto- by sufficient salt supplementation and, augmented salt wasting with amiloride somal dominant form (adPHA1, OMIM consequently, treatment with PG synthesis and the potential nephrotoxic and gastro- #177735) has exclusive renal manifesta- inhibitors and/or K+-sparing diuretics intestinal side effects of PG synthesis in- tions. It is caused by heterozygous mu- should be avoided in GS. Nevertheless, a hibitors, their use has been cautioned in tations in NR3C2, the gene encoding the beneficial effect of such drugs in GS has an expert consensus statement on GS.83 mineralocorticoid receptor. Affected been reported.97 Apparently, despite our As in BS, it remains controversial what patients typically present in the first insights into renal pathophysiology, we level of plasma potassium is acceptable in month of life with insufficient weight still do not fully understand the develop- GS. Similarly, to what degree should gain and subsequent blood tests ment of symptoms in GS. Yet, given the magnesium levels be normalized? This show hyponatremia, hyperkalemia, and

J Am Soc Nephrol 29: 727–739, 2018 Pediatric Salt-Losing Tubulopathies 735 BRIEF REVIEW www.jasn.org metabolic acidosis. Although manifesta- could inform the development of future Hernando N, Jones G, Wagner CA, Konrad tions are usually not as severe as in ar- clinical trials. M: Autosomal-recessive mutations in 98 SLC34A1 encoding sodium-phosphate co- PHA1, they can also be life-threatening. transporter 2A cause idiopathic infantile hy- Interestingly, symptoms resolve spontane- percalcemia. J Am Soc Nephrol 27: 604– ously later on, and in our own experience ACKNOWLEDGMENTS 614, 2016 even as early as during infancy. The reasons 10. Klootwijk ED, Reichold M, Helip-Wooley for this spontaneous improvement remain A, Tolaymat A, Broeker C, Robinette SL, This work was supported by the European Reinders J, Peindl D, Renner K, Eberhart K, to be elucidated. Studies of adult carriers Union, FP7 (grant agreement 2012-305608 Assmann N, Oefner PJ, Dettmer K, Sterner of adPHA1, however, show elevated re- “European Consortium for High-Through- C, Schroeder J, Zorger N, Witzgall R, nin and aldosterone, as well as levels, put Research in Rare Kidney Diseases Reinhold SW, Stanescu HC, Bockenhauer D, Jaureguiberry G, Courtneidge H, Hall compared with unaffected family mem- [EURenOmics]”). bers, suggesting that despite the absence AM, Wijeyesekera AD, Holmes E, Nicholson JK, O’Brien K, Bernardini I, Krasnewich DM, of overt symptoms, haploinsufficiency NR3C2 Arcos-Burgos M, Izumi Y, Nonoguchi H, Jia Y, of mayhavesubtlelifelong DISCLOSURES Reddy JK, Ilyas M, Unwin RJ, Gahl WA, Warth R, consequences.99,100 Kleta R: Mistargeting of peroxisomal EHHADH None. and inherited renal Fanconi’ssyndrome.NEngl JMed370: 129–138, 2014 11. 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