Pediatr Nephrol (2016) 31:407–418

DOI 10.1007/s00467-015-3143-1


Pathophysiology and clinical presentations
of salt-losing tubulopathies
Hannsjörg W. Seyberth 1,2

Received: 19 April 2015 / Revised: 1 June 2015 / Accepted: 5 June 2015 / Published online: 16 July 2015
# IPNA 2015

Abstract At least three renal tubular segments are involved in
the pathophysiology of salt-losing tubulopathies (SLTs).
Whether the pathogenesis starts either in the thick ascending
limb of the loop of Henle (TAL) or in the distal convoluted
tubule (DCT), it is the function of the downstream-localized
aldosterone sensitive distal tubule (ASDT) to contribute to the
adaptation process. In isolated TAL defects (loop disorders)
ASDT adaptation is supported by upregulation of DCT,
whereas in DCT disorders the ASDT is complemented by
upregulation of TAL function. This upregulation has a major
impact on the clinical presentation of SLT patients. Taking
into account both the symptoms and signs of primary tubular
defect and of the secondary reactions of adaptation, a clinical
diagnosis can be made that eventually leads to an appropriate
therapy. In addition to salt wasting, as occurs in all SLTs,
characteristic features of loop disorders are hypo- or
isosthenuric polyuria and hypercalciuria, whereas characteristics of DCT disorders are hypokalemia and (symptomatic)
hypomagnesemia. In both SLT categories, replacement of urinary losses is the primary goal of treatment. In loop disorders
COX inhibitors are also recommended to mitigate polyuria,
and in DCT disorders magnesium supplementation is essential
for effective treatment. Of note, the combination of a salt- and
potassium-rich diet together with an adequate fluid intake is
always the basis of long-term treatment in all SLTs.

Keywords Loop disorders . DCT disorders .
Pathophysiology . Physiologic classification . Tubular
adaptation processes . Clinical diagnostics . Therapeutic

A careful evaluation of the clinical presentation and medical
history (phenotype evaluation) of a patient with a salt-losing
tubulopathy with secondary hyperaldosteronism (SLT) often leads
to the underlying renal pathophysiology. Once the specific pathophysiology is known and understood, the odds on developing the
most appropriate therapeutic approach are greatly improved.
In this review the physiologic and clinically more meaningful term Bsalt-losing tubulopathy with secondary
hyperaldosteronism^ (SLT) has been chosen. This terminology
is based on the pathophysiology and the clinical presentation
of SLTs that are fundamental to an understanding of the underlying pathomechanisms [1]. With this knowledge, the young
physician is also better able to interpret the clinical presentation
of index patients with specific SLTs reported in earlier publications, when genetic analysis was not yet available.

Physiology of salt and water reabsorption
in the distal nephron
* Hannsjörg W. Seyberth

Department of Pediatrics and Adolescent Medicine, Philipps
University, Marburg, Germany


Lazarettgarten 23, 76829 Landau, Germany

In this section I briefly review the principal mechanisms of
salt, water, and mineral reabsorption in the distal nephron
before moving on to discuss the pathophysiology and clinical
presentations of SLTs. Only the key players in the
transepithelial transport in the distal nephron that obviously
are important in the context of this review are mentioned. For
the reader who wishes additional information, the

Under these circumstances Cl. Clleaves the cell basolaterally through ClC-Kb. causing insufficient Cl. a late segment (DCT2).into tubular cells on the thick ascending limb of the loop of Henle (TAL) is the furosemide-sensitive sodium–potassium-2-chloride co-transporter NKCC2 expressed in the apical cell membrane [5]. thus feeding the Na-K-ATPase pump necessary for continuous transport of Na+ and thereby also generating an electrochemical gradient which also favors transcellular Cl. K+ secretion can be reinforced by large flow-dependent high-conductance potassium channels (BK) which are expressed at the apical cell membrane of both the principal and intercalated cells (sub-type A) in the ASDT. The lumen-negative transepithelial voltage that is created by the Na-K-ATPase is not only the prerequisite for the electrogenic extrusion of Na+ at the basolateral cell membrane but also the driving force for this paracellular Cltransport. thereby clarifying why this electrogenic Na+ transport is coupled to the secretion of K+ via ROMK potassium channels at the apical cell membrane of the (segment-specific) principal cells in the late part of the ASDT. and the connecting tubule (CNT) which leads to the collecting duct (CD). is highly recommended [3–8]. The proper functioning of both chloride channels is dependent on the ß-subunit barttin. whereas Clleaves the cells basolaterally through the specific chloride channels ClC-Ka and ClC-Kb. The intercalated cells are grouped together between the principal cells in the CD and play an important role not only in K+ secretion but also in the regulation of acid–base homeostasis. called the renal outer medullary potassium channel ROMK or KIr 1. the excellent Clinical Journal of the American Society of Nephrology series entitled BRenal Physiology for the Clinician^.and Cl. Na+ is then actively pumped out of TAL tubular cells by basolateral Na-K-ATPase. Pediatr Nephrol (2016) 31:407–418 In the aldosterone-sensitive late distal tubule (ASDT).transport. Once intracellular. 7]. Another key player in salt reabsorption in the CD. K+ is recycled across the apical cell membrane back into the tubular fluid through a potassium permeable ion channel. the energy for the active transcellular salt transport in DCT is provided by the activity of the basolateral to pendrin in the downstream reabsorbed to a greater than normal extent in the ASDT. The distal convoluted tubule (DCT).1/5. After its intracellular uptake together with Na+. The key player in the active uptake of Na+ into the cells in the early DCT is the thiazide-sensitive sodium chloride co-transporter NCC expressed in the apical cell membrane. In contrast to Na+ and Cl-. an intact ROMK is essential to produce a lumen-positive transepithelial potential. The DCT can be subdivided into an early segment (DCT1). insufficient chloride is available for exchange with bicarbonate. ClC-Ka is not expressed in the DCT. increases from the DCT2 to the CNT and finally decreases in the CD [6.408 fundamentals of salt reabsorption in the distal tubule are discussed more extensively in the review by Seyberth and Schlingmann published in Pediatric Nephrology [2]. plays an important role in fine-tuning the renal excretion of sodium chloride but also of calcium and magnesium [6]. the other key player in transepithelial Na+ transport in the DCT. The important role of pendrin in both acid–base and electrolyte homeostasis becomes apparent in the state of extracellular fluid volume (ECF) contraction and transported separately between the epithelial cells by a passive process. Thus. which is needed for active transcellular salt reabsorption as well as for the driving force for the passive paracellular transport of Ca2+ and Mg2+ in the TAL segment. 8]. Water reabsorption The primary function of TAL is to maintain an appropriate high salt concentration in the interstitium of the medulla as a . which has just been published. 7]. The secretion of H+ is also localized in the CD where H+ is secreted through the H+-ATPase and the H+/ K+ATPase at the apical cell membrane of sub-type A intercalated cells. the chloride–bicarbonate-exchanger (pendrin). each Na+ which enters the tubular cell via ENaC requires secretion of the cation at the luminal side [6.1 which facilitate the basolateral extrusion of Na+ [9]. These potassium channels allow recirculation of K+. with the resultant decrease of urinary bicarbonate excretion eventually leading to metabolic alkalosis [10]. Just as in TAL. which starts a short distance downstream from the macula densa (MD). This voltage-dependent K+ secretion is not the only factor which determines the rate of K+ secretion in the ASDT. As a consequence of persistent chloride depletion. Not only K+ secretion but also H+ secretion is considered to be essential for the maintenance of electroneutrality in the late ASDT [7.1. For more in-depth studies on the tubular system. For reasons of electroneutrality. In this part of the DCT the activity of the Na-K-ATPase is complemented by the inwardly rectifying potassium channels Kir4. is expressed at the apical cell membrane of sub-type B intercalated cells. Salt reabsorption One of the key players in the active uptake of Na+ and Cl. In this late part of the ASDT Na+ is actively taken up into tubular cells by ENaC without Cl. In the state of increased urine flow. These sub-segments are characterized by the expression of different ion transport proteins responsible for salt and divalent cation reabsorption. the expression of NCC diminishes in the distal direction while that of the amiloride-sensitive epithelial sodium channel ENaC.

but also by the activity of the basolateral Na-K-ATPase. 8–10 % each) is an active transcellular and highly regulated transport process. but also by the number of TRM6 channels at the luminal membrane. AVP also increases a cAMPdependent stimulation of NaCl transport via NKCC2 in TAL and thereby induces an even further rise in hyperonicity in the interstitium. a key player in determining the final urinary calcium excretion. However. Classification of SLTs Early attempts to stratify and to classify the heterogeneous group of entities referred to as SLTs included comprehensive clearance measurements as these were believed to be helpful for identifying the very specific dysfunctional segments of the distal nephron responsible for salt and water wasting in different variants of SLTs. and water subsequently moves from CDs into the more concentrated interstitium. In the active transcellular transport of filtered magnesium in the early DCT cells. This intracellular decrease of Ca2+ concentration facilitates apical cell membrane Ca2+ entry through the calcium selective channel TRPV5. generating hypertonicity in the interstitium of the medulla that drives countercurrent exchange [5]. but also for fine-tuning of the water balance [7]. salt reabsorption also plays an important role in the tubular reabsorption and renal excretion of calcium and magnesium further downstream in the DCT. Of note is that up. the transcellular transport of Mg2+ and Na+ in the DCT is directly proportional to each other. 20–22]. This process is driven by the lumen-positive transepithelial potential established by active salt reabsorption in this segment (see preceding text). the results obtained in these early clearance studies were difficult to interpret. cationselective route in the TAL [6].1. reabsorption of Ca2+ and Mg2+ (approx. In primary inherited nephrogenic diabetes insipidus (NDI). AVP simultaneously increases the osmotic gradient for water transport and the water permeability of the CD. The results of such tests have led to the classification of SLTs based on the striking similarities between various phenotypes of SLTs and the action profiles of loop and thiazide diuretics [17]. The renal effects of AVP can be inhibited by prostaglandin E2 (PGE2) [7. the AVP receptor AVPR2 or the apical cell membrane water channel aquaporin 2 (AQP2) in the terminal part of the nephron (CD) are absent or dysfunctional. Typically. In this part of the tubule. which includes the DCT2. in 409 the DCT the transepithelial transport of Na+ is inversely proportional to that of Ca2+. In contrast to Ca2+ reabsorption. the magnesium selective channel TRPM6 plays the role of gatekeeper for the entry of Mg2+ into the apical cell membrane [6. in combination or not with clearance studies. while secondary NDI is usually associated with isosthenuria. Calcium and magnesium reabsorption About 20 % of the filtered load of Ca2+ and 70 % of that of Mg2+ are reabsorbed passively via the paracellular. SLTs can be divided initially into two major groups of tubular disorders: the furosemide-like loop disorder (L type) or the less severe thiazide-like DCT disorder (DC type) (Table 1).Pediatr Nephrol (2016) 31:407–418 prerequisite for countercurrent exchange and the urinary concentration and dilution mechanism. to evaluate the functional status of a specific segment of the distal nephron. The same rationale was also behind the earlier introduction of the term Bpharmacotype^ by Reinalter et al. According to the combined physiologic and pharmacologic classification. A physiologic classification of SLTs based on the anatomy and physiology of the distal nephron as well as on the pharmacotyping of diuretics was subsequently proposed by Seyberth [19]. Thus. Thus. there are two forms of NDI: a primary form that is due to impaired AQP2 function or expression in the CD (aquaporin deficiency NDI) and a secondary form that is due to impaired medullary concentration gradient in the medulla [12]. CNT. However.or downregulation of the transport function along the DCT segment is accomplished not only by changes in the activity and the number of NCC. and CD. due to the effect of environmental factors and compensatory mechanisms modulating urinary electrolyte and mineral excretion in the more distal tubular segments. The advantages of this type of classification for facilitating the characterization of patients with SLT on the basis of their renal pathophysiology and for selecting the appropriate therapeutic management have been noted by other researchers [1. The terminal part of the nephron. A more promising strategy that quickly gained acceptance was to challenge the patient with diuretics having a welldefined action on tubular transport mechanisms [14–16]. In the presence of arginine vasopressin (AVP) the osmotic water permeability of the CD epithelium increases. Thus. with the consequence that the principal cells in the CD remain impermeable. [18]. TRPM6 is primarily driven by a luminal membrane potential established by the voltagegated K+ channel Kv1. 11]. is not only responsible for finetuning of the electrolyte balance. 13]. The two groups are subdivided further into loop disorders caused by a defect in NKCC2 or ROMK (L1 or . and the results were not conclusive. The consequence of impaired Na+ transport (e.g. inhibition of NCC expression) is a low intracellular Na+ concentration which favors increased Na+ uptake and increased Ca2+ extrusion across the basolateral membrane via the Na + / Ca2+exchanger NCX1. This segment is practically impermeable to water and actively pumps large portions of sodium chloride out of the filtrate. Diuretic response tests are still performed today. primary NDI is associated with hyposthenuria (excretion of hypotonic urine).

see text L2 type.1. which is considered to be one of the most prominent mechanisms underlying the severe salt and water wasting in loop disorders. this combined disorder is referred to as Bartter syndrome with sensorineuronal deafness (BSDN). DCT disorders caused by a defect in NCC. and failure to thrive—all typical features of a hyperprostaglandin E syndrome in infancy—remains unexplained [23]. EAST/SeSAME syndrome. thiazide-sensitive sodium-chloride co-transporter. DC2. osteopenia. CIC-Kb. The L1 type is a pure furosemide-like SLT. CD BSDN BSDN Furosemide+thiazide Furosemide+thiazide TAL+DCT TAL+DCT CD CD Combined disorders L-DC1 type (ClC-Ka+b) L-DC2 type (barttin) The segment in parentheses is of secondary importance to the clinical presentation DCT. Genetically. CD BS III EAST/SeSAME Thiazide (+ furosemide) Thiazide DCT (+ TAL) DCT (TAL) CD TAL.410 Table 1 Pediatr Nephrol (2016) 31:407–418 Physiologic and pharmacologic classification (including the upregulated segments) Type of disorder (gene product)a Genetic/eponymous terminology Pharmacotype Affected segment Upregulated segment(s) L1 type (NKCC2) BS I Furosemide TAL DCT. ClC-Kb. respectively) and into DCT disorders caused by a defect in NCC. inwardly rectifying potassium channel. Genetically and eponymously. This third group is subdivided further into L-DC1 (caused by combined defects in ClC-Ka and ClC-Kb) and LDC2 type (caused by a defect in ß-subunit barttin). In parallel. particularly during the life-threatening and polyuric phase shortly after birth. DC1. NCCT. furosemide-sensitive sodium–potassium-2-chloride co-transporter. BS type III. as part of TAL. diarrhea. PGE2 plays a pivotal role in the pathogenesis of loop disorders. CIC-Ka + b. The inadequately low Clconcentration. epilepsy. or DC3 type. Overproduced PGE2 interferes with tubuloglomerular feedback through the disinhibition of glomerular filtration. and the DCT disorders as Gitelman syndrome. namely. specific chloride channels. incorrectly signals a low tubular salt concentration. whereas the L2 type is a mixed furosemide–amiloride-like SLT. or DC3. BS. hyperaldosteronism with hypokalemic alkalosis. BSDN Bartter syndrome with sensorineural deafness. . mineral. L2. respectively). sensorineural deafness. respectively. renal outer medullary potassium channel. with shrinkage of the MD cells.1. in the MD. and hypercalciuria associated with nephrocalcinosis (Table 2). thick ascending limb of Henle’s loop. TAL.1 (DC1.1) GS Thiazide DCT TAL. CD cortical collecting duct a L1. Unfortunately. L-DC. and water wasting. CD L2 type (ROMK) BS II Furodemide (+amiloride) TAL (+ CD) DCT (CD) Loop disorders DCT disorders DC1 type (NCCT) DC2 type (ClC-Kb) DC3 type (Kir 4. leading to severe salt. The earliest manifestation of this tubular dysfunction is fetal polyuria that leads in the last trimester of pregnancy to the development of severe polyhydramnios (up to 10 l). such as hyperactive PGE2 synthesis as indicated by hyperprostaglandinuria. DC2. Gitelman syndrome. a potent inhibitor of PGE2 synthesis [24]. Typically NKCC2 or ROMK is dysfunctional. leading to increased PGE2 synthesis [2]. or Kir 4. Kir4. secondary NDI. ROMK. Combined loop and DCT dysfunction is the most severe category of SLT. furosemide–thiazide-like salt-losing tubulopathies (SLT). GS. Clinical presentation and pathophysiological mechanisms in SLTs Loop disorders Our current knowledge of the the pathophysiological mechanisms underlying loop disorders has recently reviewed [2]. vomiting. NKCC2. these disease symptoms can effectively be suppressed by indomethacin. As a consequence of excessive diuresis with an urinary output of up to 50 ml/kg/h. several secondary pathophysiological features of a loop disorder can be observed in the postnatal period. with the consequence that the active reabsorption of solutes in TAL breaks down. the furosemide–thiazide-like SLTs (L-DC type). Nevertheless. Bartter syndrome. and this condition forms a third group. ClC-Kb. At the beginning of a series of destructive steps stands the congenitally impaired salt reabsorption via the NKCC2 pathway. ataxia. For more details. Loop disorders caused by a defect in NKCC2 or ROMK. and EAST syndrome. or Kir 4. Distal convoluted tubule. the mechanism by which increased systemic PGE2 activity causes fever. which leads to a decrease in intracellular Na+ and Cl. respectively.concentration in the interstitium but also. the loop disorders are also referred to as Bartter syndrome (BS) type I and type II. PGE2 activates the renin–angiotensin–aldosterone system (RAAS) and inhibits AVP action. and tubulopathy.

ROMK also contributes to distal net potassium secretion.Pediatr Nephrol (2016) 31:407–418 Table 2 411 Pathophysiology and clinical featuresa Type of disorder (gene product affected) PH Secondary pathophysiology Urinary analysis Plasma levels Cl- Mg2+ HPU NDI HAS NC Ca2+ Osmolality Loop disorders L1 type (NKCC2) ++ + + + L2 type (ROMK) ++ + + (-) +b + + ↑↑ hypo-/isosthenuria ↑↑ hypo-/isosthenuria - - DC1 type (NCC) DC2 type (ClC-Kb) (+) (+) - + + . The signs in parenthesis indicate that either the secondary pathophysiology is mild and/or present only occasionally or that changes are infrequently present and/or marginally different from normal PH. as the concentration machinery in TAL is more or less intact [2]. in patients with loop disorders not only can isosthenuria be observed. The pathophysiology and clinical presentation of loop disorders of the L2-type with ROMK defect are almost identical to those of the L1-type with NKCC2 defect. severity of initial clinical presentation. the kaliuretic function of ROMK [9]. . such as in the DC2 and DC3 type with dysfunction of ClC-Kb or Kir 4. In contrast. In contrast to loop disorders. 25]. such as in the DC1 type with dysfunction of the thiazide-sensitive NCC. be noted that not only the epithelium of TAL is water impermeable. signs of NDI with excessive polyuria are not typical of DCT disorders. these channels can take over. distal convolated tubule a Hypokalemia and alkalosis are typical manifestations of all disorders b Transient hypoaldosteronism in the postnatal period Another leading pathophysiological feature of loop disorders is a paralyzed concentrating and diluting machinery. hyperprostaglandinuria. adult DCT patients suffer from muscular weakness. In case of ROMK failure. but also frequently hyposthenuria [16. fatigue. Plus signs indicate presence. as shown by the uneventful clinical presentation of the patients in infancy and early childhood as well as by low urinary excretion rates of PGE2 and its metabolites [27]. This phenomenon emphasizes that. NDI. Moreover. The molecular pathogenesis of DCT disorders is either based on a defect of sodium and chloride uptake by the apical membrane. HPU. which is not so typical for secondary NDI [12].1) - - - + - ↓ normal - ↓ ++ ++ + + - . or based on a defect of basolateral sodium and chloride extrusion. respectively. In this latter segment. such as cramps and tetany. however. with patients commonly not becoming symptomatic before reaching school age. nephrocalcinosis. During the first years of life DCT disorders are considered to be relative benign variants of salt-wasting tubulopathies. nephrogenic diabetes insipidus. and absences of major urinary concentrating defect. The DCT1 segment functions as the most distal portion of the diluting segment and therefore is able to compensate to some extent for the impaired diluting capability of TAL in loop disorders [12].1. Later in life these patients with the L2-type disorder and ROMK defect appear to have a lower tendency to become hypokalemic than those with other SLTs [27]. DCT disorders Disorders of the DCT markedly differ from loop disorders in terms of onset. salt craving. but also the early DCT (DCT1). there is no recirculation of K+ across the apical cell membrane of the epithelial cell into the lumen to feed the NKCC2. The only major difference in the clinical presentation between the L2 type and L1 type of SLT can be observed during the first weeks of life. as well in terms of specific electrolyte and mineral abnormalities. Polyhydramnios. NCC is expressed a short distance downstream from the MD which can be upregulated through phosphorylation by AVP [26]. NC. which leads to secondary NDI. With maturation of the BK channels and the massive polyuria.isosthenuria ↓ (↓) DCT disorders Combined disorders L-DC1 type (ClC-Ka+b) L-DC2 type (barttin) Arrows indicate an increase (upwardly pointing arrows) or a decrease (downwardly pointing arrows) in excretion or concentration. However. hyperaldosteronism. at least in part. in addition to the flowdependent BK channels. It should. leading to almost the same situation as that which exists in NKCC2 failure. HAS.(+) ↓ normal (↓↑) variable ↓ ↓ (↓) DC3 type (Kir 4. minus signs indicate absence. signs of increased PGE2 activity are not so prominent in DCT disorders as in loop disorders. and/or signs of increasing neuromuscular excitability. DCT. at which time an immaturity of ASDT causes transient hyperkalemia.isosthenuria ↓ (↓) ++ ++ + + - .

For this reason. and a renal SLT with hypokalemic metabolic alkalosis [9]. Dysfunction of Kir 4. such as the higher expression of transport proteins and channels. or by hypertrophy of the whole transport system in the segment. mitigate. BS III is primarily regarded as a DCT disorder in the physiologic terminology. 7. Adaptation processes in tubular function in SLTs Any or all of the three segments of major interest can be involved in the pathophysiology of SLTs. Beginning in early infancy. The cause is an impaired basolateral chloride extrusion through the chloride channels ClC-Ka and ClC-Kb throughout the distal tubule [2]. 33]. The overall clinical presentation combines all single effects. a failing DCT is complemented by upregulation of the TAL (Fig. Expression of both of these chloride channels occurs in the TAL. Combined disorders A combined defect of salt reabsorption in the TAL and DCT leads to the clinically most severe variant of tubular salt-wasting disorders.412 Whereas the DC1 type is thought to be the prototype of a DCT disorder. Infants subsequently exhibit excessive salt and water losses and isosthenuric polyuria. the DC2 type disorder was initially been assigned to the group of loop disorders [28].and downregulation of different segments of the distal nephron play important roles in fine-tuning electrolyte. neutralization. also play a key role in development of diuretic resistance during long-term diuretic treatment [31]. the CNT. mental retardation. or even compensate each other completely. This mechanism operates in the pathological situation as well. 32.and downregulation significantly influences the clinical . when not the primary targets of diuretics. However. and the CD) which contributes to the renal adaptation process in SLTs. which might aggravate. it manifests as epilepsy and severe ataxia. whereas no such option exists in the DCT. As with most SLTs with a loop defect.1 is expressed in several parts of the brain as well as in the kidney. an essential subunit of both chloride channels. mineral. the results of a large clinical study clearly demonstrated that the clinical presentation of most patients with loss of ClC-Kb function has a strong DCT signature [29]. sensorineuronal deafness.g. However. these disorders manifest themselves prenatally with the development of maternal polyhydramnios due to fetal polyuria that is followed by preterm labor and extreme prematurity. such as by posttranslational modification (e. the DC2 type can be seen as a mixed thiazide–furosemide type and the DC3 type can be viewed as the mixed kidney brain type (Table 1). If the pathogenesis starts either in the TAL or DCT. not all features of the clinical Pediatr Nephrol (2016) 31:407–418 presentation will necessarily be aggravated by dysfunctions that are located in both the TAL and the DCT. 1). the plasma chloride levels decrease to rather low levels. When one part of the distal nephron is failing. while that of CICKb is almost exclusively limited to the DCT. This mixed DCT–TAL or thiazide–furosemide-like presentation of the DC2 type can be explained by differences in the expression of the chloride channels ClC-Ka and ClCKb in the distal nephron [30]. Of note is that hypochloremia can also be observed in patients with an isolated defect in ClC-Kb. Compensation. and water homeostasis. as occurs in the adaptation process of the DCT in loop disorders [1]. in contrast to the eponymic terminology. there is a potential for compensation. (2) increase in the abundance of specific molecules. and the release of angiotensin II and aldosterone are thought to be major stimuli for the upregulation of NCC. This impairment is caused either by a digenic defect in both ClC-Ka and ClC-Kb or by a defect in barttin. in contrast to a disorder with an isolated loop defect. phosphorylation as seen in NKCC2 in Fig. In the case of an isolated TAL defect. as well as more mechanically by flowdependent effects. such as shear stress caused by marked polyuria. (3) a combination of both (1) and (2). As Kir 4. the remaining segments can adapt via at least three basic modalities: (1) activation of the ion transporter proteins.1 is the integral pathogenetic component of the EAST/SeSAME syndrome. Although this third group of SLTs is a combination of the two categories of SLTs. with respect to the isolated ClC-Kb defect by ClC-Ka in TAL. ECF volume depletion induces activation of RAAS. and ROMK in CNT and CD [7]. In patients with either a defect in TAL or in DCT up. and aggravation Under physiologic conditions the up. These adaptation processes in the intact segments. Following realization that chloride leaves cells basolaterally through the ClC-Ka and ClC-Kb while Na+ and K+ are actively taken up into tubular cells of the TAL via NCKK2. 1). On the other hand. ENaC. it is the function of the more downstream ASDT (including the late DCT. this upregulation of ASDT is further expanded by (additional) upregulation by the DCT [1]. Thus. The upregulation of different segments of the distal nephron can be achieved systemically by hormonal stimulation or locally by paracrine activities. For further details on the molecular machinery and the complex network of kinases and ubiquitinases that regulate the activity of the ion channels and transporters in the distal nephron the reader is referred to excellent reviews in the field [6. this Bcerebro-renal syndrome^ is quite complex.

Hyperaldosteronism is a direct reaction to increased tubular salt delivery to the late distal tubule and to contraction of the ECF volume. 33]. This phenomenon will be illustrated with a number of examples. One pathology replaces another. presumably via phosphorylation. patients with a defect in NKCC2 flood the entire distal nephron with solute and water. is increased. these individuals develop hypertrophy throughout the distal nephron with increases in the number and activity of salttransporting protein. such as the cardiovascular and neuromuscular system. this compensation can aggravate the clinical presentation of the disease. counteracting at least in part urinary magnesium wasting in the upstream tubular segment [38]. 34. DCT disorders typically result from inactivation of sodium chloride co-transporter (NCC). Further downstream the two cations are handled quite differently by the upregulated DCT segment where the expression and activity of TRPM6. Moreover. Due to upregulated Na+ transport via NCC. as in polyuric diseases. but also to aggravation. In summary. passive paracellular Mg2+ and Ca2+ reabsorption in the TAL is low due to a reduced luminal positive transepithelial potential [1. as a consequence of isotonic volume expansion. no such compensatory mechanism exists for calcium. Also in the latest part of the distal tubule. resulting in stimulation of the RAAS. Comparing loop and DCT disorders is instructive for studying various interactions between dysfunctional and adapted segments. This metabolic imbalance in the Bmilieu intérieur^ can cause serious effects on the function of various organ systems. there is some compensation through RAAS stimulation. which frequently leads to the development of osteopenia and nephrocalcinosis even during infancy. and H+-ATPase activity [6. Eventually. This paracrine stimulus further aggravates sodium and water wastage through the inhibition of sodium and water transport in the CD [7]. which leads to flooding of the connecting tubule (CNT) with solutes and. for reasons of electroneutrality this compensatory mechanism leads to increased tubular K+ and H+ secretion and consequently to hypokalemic metabolic alkalosis. which in turn inhibits Ca2+ extrusion across the basolateral membrane via the Na+/Ca2+ exchanger NCX1. resulting in a high intracellular Ca2+ concentration.Pediatr Nephrol (2016) 31:407–418 413 Normal CNT DCT DCT Disorder Loop Disorder (DC1 Type) (L1 Type) DCT CNT CD Na+ Cl- CD Na+ NCC Na+ K+ Cl X NCC - CD Na+ Na+ Cl- Na+ TAL NKCC2 TAL Na+ 2ClK+ NKCC2 P NCC P Na+ Na+ Na+ K+ Na+ 2ClK+ CNT DCT K+ Cl- TAL Na+ 2ClK+ NCC P K+ K+ X NKCC2 Fig. These patients also have activation of the sodium-potassium-2- chloride co-transporter (NKCC2). Thus. leading to reduced apical Ca2+entry through the calcium selective channel TRPV5. intracellular Na+ concentration is high. under pathological conditions mechanical factors can lead to the overreaction of adaptation and eventually to worsening of the clinical presentation. subsequently. However. BK channels. the combination of excessive hypercalciuria (with secondary nephrocalcinosis) and normal plasma levels of magnesium is a characteristic signature of loop disorders. An example of such an aggravating factor can be shear stress at the cell membrane of the epithelial cells of the cortical CD due to increased tubular flow. In animal studies. Thus. but in view of the metabolic situation. in loop disorders with an upregulated DCT. can be viewed from this perspective. high tubular flow rates in vivo. extracellular fluid volume depletion. increased urine flow might also stimulate the synthesis of tubular PGE2 and its release into the tubular lumen. These effects lead to hypertrophy of the CNT and activation of both the epithelial sodium channel (ENaC) and the potassium channel (ROMK). Stress directly enhances the activity of (mechanosensitive) ENaC. For example. This schematic representation is a modified version of a scheme that was originally published by Ellison [1] and the modified version is reused here with permission of the managing editor of Clinical Journal of the American Society of Nephrology. CD Collecting duct presentation of SLTs. which is an integral part of the pathogenesis of all SLTs. high urine flow on its own enhances distal urinary acidification and aggravates hypokalemic metabolic alkalosis. and can be considered an attempt of the distal nephron to reduce sodium wastage and volume contraction [1. induce the expression of COX-2 activity and enhance PGE2 release in the cortical CD [36]. . In this case. Unfortunately. hypomagnesemia is not commonly observed in patients with loop disorders (Table 2). DCT adaptation aggravates urinary calcium wastage. 1 Schematic representation comparing transporter activity and nephron structure in normal individuals with those of patients with distal convoluted tubule (DCT) disorder (DC1 Type) and loop disorder (L1 Type). Thus. it can lead to (over-)compensation and mitigation. In contrast. a magnesium-specific channel. 37]. 35]. The pathomechanism of hyperaldosteronism.

indicating the need to include antidiuretic therapy with an inhibitor of PGE2 synthesis. the therapeutic management is quite different between loop and DCT disorders. or clinical signs of symptomatic hypomagnesemia. urinary calcium excretion. one of the most characteristic signs of DCT disorders. clinical parameters to differentiate between loop and DCT disorders. The clinical presentation of the mixed DC2 type with a ClC-Kb defect might not always have a strong DCT signature. Diagnostic considerations Urine osmolality. the upregulated TAL segment is responsible for enhanced sodium and chloride reabsorption. 39]. the combination of pronounced metabolic alkalosis and hypochloremia [25. namely. 29]. which has led to premature birth. the very first therapeutic step to prevent shock and acute renal failure is adequate replacement of salt and water via a central vein catheter [41]. On the other hand. These specific features include (1) reduced capability to form highly concentrated urine. However. All three loop disorder-like features may coexist in the same patient.and downregulation) of loop and DCT disorders in the very same body. Therapeutic approaches One common therapeutic approach in both loop and DCT disorders is to replace as much of the urinary losses as possible. The phenotype of combined tubular disorders can be considered to provide evidence for the concept underlying the physiologic and pharmacologic classification system of SLTs. This is the most effective way to treat metabolic alkalosis. a major characteristic of the D2 type of SLTs.reabsorption. is naturally also present in combined disorders as these disorders are a combination of loop dysfunction and ClC-Kb defect. There is another situation in which the compensation concept can be applied successfully. In addition to increased reabsorption activity in the proximal tubule. (3) urinary excretion of calcium can be quite variable. a further increase in sodium reabsorption in the TAL will lead to prominent hypocalciuria. such as a positive Chvostek’s sign and/or carpopedal spasm. The goal should be to replenish the total body deficits of electrolytes and minerals and the ECF volume. however. In infants with a full-blown. Following this strategy. These two compensating effects result in much less salt and water wasting in DCT disorders than in loop disorders. These two conditions arise because the downstream chloride–bicarbonate exchanger pendrin in the CD cannot compensate completely for the loss of ClCKb function along the entire length of the distal tubule. in DCT disorders the TAL segment is upregulated [1. hypocalcemia and hypomagnesemia. Moreover. Thus. loss of DCT function with impaired salt reabsorption and concomitant loss of TRPM6 activity leads to reduced Mg2+ transcellular uptake and thereby aggravates magnesium wasting. polyuria is exclusively isosthenuric and almost never hyposthenuric as the very proximal part of DCT with its ability to dilute urine is not functional. life-threatening loop disorder. as in situations of insufficient salt supplementation and/or concurrent extra-renal salt losses. A major step in this adaptative process is the activation of NKCC2 through phosphorylation of the transporter protein (Fig. Thus. In summary. in these cases it is assumed that ClC-Ka is only in part able to compensate for the loss of ClC-Kb function in the TAL. and consequently also for mineral reabsorption. the clinical presentation of the patient with a combined loop and DCT disorder can be seen as the net effect of all pathological changes (including all effects of up. in the overall postnatal management.414 In contrast. this partial dysfunction of TAL is only seen in a minority of DCT patients with a ClC-Kb defect [27. ranging from hypo-/normo. excessive fluid replacement aggravates polyuria. in the early part of the distal hypercalciuria [29]. and on occasion features can be observed that are reminiscent of the phenotype of a loop disorder. and magnesium plasma levels are the most informative and easily accessible. These Pediatr Nephrol (2016) 31:407–418 differences are (Table 2): (1) in disorders with a combination of a loop and DCT defect. which are frequently associated with convulsions. 40]. The appearance of polyuria in this context is most likely due to the fact that high infusion rates and urine flow by itself lead through excessive shear stress to an even . leading to decreased transcellular Cl. (2) urinary calcium excretion is in the normal range without any sign of the nephrocalcinosis that is also due to loss of DCT upregulation and its aggravating hypercalciuric effect. (2) development of a moderately enlarged amniotic fluid volume during late pregnancy which. Due to more severely reduced ECF volume. Fortunately. This is particularly true when there is either a maternal history of a pregnancy complicated by development of a massive polyhydramnios. are considered to be a strong signature of a DCT disorder.and hyperactive (upregulated) channels and transporter proteins in the same tubular disorder is another interesting situation which allows study of the principles of aggravation and compensation and how they affect the final clinical presentation. This integration accounts for the three distinct differences in clinical presentation between combined and pure loop disorders [25]. When these laboratory data are complemented by an accurate and comprehensive case history an almost definitive diagnosis can be made. Partial compensation of the ClC-Kb defect is also responsible for another specific feature of the D2 type SLTs. preferably indomethacin. is rarely associated with preterm delivery [27]. The interaction between hypo. increased Ca2+ uptake through the activated TRPV5 channel selectively prevents hypercalciuria. (3) marked hypochloremia. 1).

In isolated TAL defect (pure loop disorders) ASDT adaptation is supported by upregulation of DCT functions. pressing questions do remain. hyperaldosteronism. a special subset of infants experiences extreme salt and water wasting only during the perinatal period and early infancy. For example. These relatively benign courses of disease observed in all patients with loop disorders later in life are obviously in contrast to the experience with patients suffering from DCT disorders of the DC1 type [46]. Key summary points 1. which leads to a variety of secondary effects in this part of the nephron. In this context. however. in infants with loop disorders. the underlying mutation of this transient loop disorder has not yet been identified. In contrast to this acute postnatal management. and indomethacin in terms of tolerability and efficacy for treating hypokalemia in type DC1 disorder (with NCC defect). However.or isosthenuric polyuria and hypercalciuria. which have a major impact on the clinical presentation.Pediatr Nephrol (2016) 31:407–418 further rise in urinary output. Eplerenone and amiloride treatment were able to raise the 415 serum level of potassium only marginally. particularly of DCT disorders. nephrogenic diabetes insipidus. This treatment should not be propagated in loop disorders. these patients have recovered from their initial tubular dysfunction completely [44. and angiotensin-II-receptor blockers. this treatment was associated with gastrointestinal intolerance to such an extent that indomethacin not infrequently had to be discontinued. monitoring indomethacin drug levels and assessment of the urinary excretion rate of PGE2 can be used as markers. it should be noted that early treatment with magnesium supplementation is imperative for effective treatment and prevention of complicating hypokalemia [34]. whereas the most characteristic features of DCT disorders are hypocalciuria and hypomagnesemia. To avoid serious gastrointestinal side effects and possible under. Moreover. but at the expense of the adaptive capability of the ASDT. Unfortunately. In summary. Such observations have led to the speculation that the ASDT segment is more able to adapt to TAL dysfunction than to DCT dysfunction. 5. potassium-sparing diuretics (ENaC blockers) had been recommended to be included in the treatment of DCT disorders. a salt. it is noteworthy to recall that there is close functional interrelation between the NCC and ENaC—the route concerned with Na+ reabsorption in the overlapping part of the DCT and the ASDT [6. such as aldosterone antagonists. A genetic defect of NCC might reduce the capability of the early ASDT to adapt to a high salt flood in the distal nephron in the long term. Once a few years older. (2) RAAS inhibitors or ENaC blockers might be considered only in SLT patients as a second-line of approach when all the other therapeutic attempts had failed and indomethacin is not be indicated. A comparison of the natural history of SLTs leaves the impression that there must be additional adaptive mechanisms available. The basis of the pathophysiology of SLTs is usually a monogenetic defect in the distal tubule network. 3. 24. (3) calcium-sparing thiazides have sometimes been recommended to treat hypercalciuria. 42. When the symptoms and signs of the monogenetic tubular defect are taken into account. the use of RAAS inhibitors. Although our understanding of tubular adaptation and upregulation has increased significantly over the last years. angiotensin-converting enzyme inhibitors. in older children and adult patients with a slowly developing and more or less accidently diagnosed DCT disorder. 49]. these latter patients have the tendency to have worsening disease and the need for more intensified therapy when they reach adulthood.or overdosing. has been considered as first-line treatment of SLTs. simultaneously however. plasma levels of aldosterone rose by a factor of three. The secondary effects in a loop disorder. Based on our present understanding of the pathophysiology of SLTs. 33]. which occasionally are associated with episodic cramps and/or tetany. RAAS inhibitors and diuretic drugs should be used with caution in SLTs [2]. which is or might be of concern from a cardiovascular and renal point of view [48]. 7. as these diuretics seriously compromise DCT adaptation. 45]. the urinary excretion rate of chloride and plasma renin activity can be used to assess the efficacy of the treatment [2. Unfortunately. The key features of loop disorders are hypo. I present three caveats and reservations associated with the use of the (co-) medication in SLTs: (1) proton pump inhibitors (PIPs) are certainly not ideal for use in combination with indomethacin to prevent gastrointestinal intolerance as PIPs can cause hypomagnesemia on their own [50]. indomethacin was found to be more effective in treating hypokalemia. After the salt intake has reached the limit of the patient’s tolerability. Unfortunately. This intervention might help drive the serum concentration of potassium somewhat towards the normal range. These concerns have been confirmed by a more recent well-controlled clinical study [47] which compared amiloride. 43]. 4. and hypercalciuria associated with nephrocalcinosis. For many years. as well as the secondary . Moreover. Although prostaglandins play a minor role in the pathogenesis of DCT disorders. In critical cases. 2. the ASDT is complemented by the upregulation of TAL functions. In DCT disorders. indomethacin treatment should be carefully titrated in each patient. comprise a combination of hyperprostaglandinuria. indomethacin treatment can be reduced or even temporarily withdrawn as the patients grow older [2. eplerenone.and potassium-rich diet is the basis of shortand long-term treatment.

Clin J Am Soc Nephrol 9:1974–1986 Subramanya AR. Al-Bataineh MM.416 Pediatr Nephrol (2016) 31:407–418 associated with polyhydramnios. which leads to the appropriate therapy. the milieu intérieur. Ellison DH (2014) Distal convoluted tubule. Zeidel ML (2014) Homeostasis. 3. Hoenig MP. as follows. All four children were born prematurely. Which functional protein is not directly stimulated by increased urinary flow in the distal part of the nephron? a) ENaC b) BK channels c) H+-ATPase d) COX 2 e) Na-K-ATPase Conflict of interest The author declares no conflict of interest. had symptoms of tetany as indicated by positive Chvostek’s and Trousseau’s sign as well as carpopedal spasm. Deen PM. and serum levels of chloride down to 41. Trimpert C. The boy’s urine osmolality rose after dehydration for 24 h to 717 mOsm per kilogram body weight. Hypokalemia was not necessarily present on initial presentation. adult: L1 type 2. 6. all three white patients had normal specific gravity on random urine specimen (the two sisters) or a slightly reduced maximal urinary concentration (the young woman). adult: DC2 type d) boy: DC2.and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Besides hypokemia and hypomagnesemia. Clin J Am Soc Nephrol 10: 305–324 . which comparison demonstrates best the compensatory function of ClC-Ka (in TAL)? a) L1 with L2 type b) DC2 with L-DC1 type c) L1 with L-DC1 type d) DC1 with DC2 type 5. Pastor-Soler NM (2015) Collecting duct intercalated cell function and regulation. sometimes displayed signs of tetany. In 1966 Gitelman and colleagues [52] published the case reports of two sisters aged of 47 and 41 years and one unrelated 22-year-old woman. Clin J Am Soc Nephrol 7:379–382 Seyberth HW. Questions (answers are provided following the reference list) 1. 4. What is the most likely diagnosis of the two sisters and the unrelated young woman? a) sisters: DC3 and unrelated woman: DC2 type b) sisters: DC1 and unrelated woman: DC2 type c) sisters: DC2 and unrelated woman: DC1 type d) sisters: DC1 and unrelated woman: DC1 type 4. Kohan DE (2015) Collecting duct principal cell transport processes and their regulation. both patients. Ellison DH (2012) Adaption in Gitelman syndrome: „we just want to pump you upB. Clin J Am Soc Nephrol 9:1271 Hoenig MP. such as carpopedal spasm and a positive sign of Trousseau. and nephrocalcinosis was a constant finding. only the young female. What are the most likely diagnoses of these four children? a) L2 type b) L-DC2 type c) L-DC1 type d) L1 type reactions of adaptation. In 1974 McCredie and colleagues [53] published a series of four pediatric case reports in which they described a variant of Bartter’s syndrome with hypercalciuria in potassium-losing nephropathy. Kashlan OB. 7. Despite documented hypomagnesemia in all three patients. Clin J Am Soc Nephrol 10:135–146 Roy A. Clin J Am Soc Nephrol 9:2147–2163 Pearce D. and the wisdom of the nephron. The key features of the older patient were as follows isosthenuria. a 5-year-old black boy and a 25-year-old black male patient. In 1962 Bartter and colleagues [51] described their two index patients in the following way: besides hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. adult: L-DC1 type b) boy: L2. Clin J Am Soc Nephrol 9:1272– 1281 Mount DB (2014) Thick ascending limb of the loop of Henle. Palevsky PM (2014) A new CJASN series: renal physiology for the clinician. the clinical diagnosis. who also had marked metabolic alkalosis with hypochloremia. 3. Schlingmann KP (2011) Bartter. 5.3 mEq/l. can be made with high degree of certainty. 2. and in all cases pregnancy was 8. Soundararajan R. All infants failed to thrive and had a vasopressin-insensitive urinary concentrating defect. No other key features are described in this patient. Which diagnosis is your first choice for both the young boy and the adult patient when applying the new physiologic classification? a) boy: DC1. References 1. Pediatr Nephrol 26:1789–1802 Zeidel ML. adult: DC1 type c) boy: DC1. renal calcified deposits. When comparing different types of SLTs with each other. Urine calcium was high in all patients.

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Kleta R. However. Cruwys M. Simon DB. Halperin LF. Caumont-Prim A. particularly when they had been born prematurely after a pregnancy that had been complicated by polyhydramnios. Gasbarrone L. Bridoux F. Allard J. Cruz DN. Vallet M. one can assume that the most likely diagnosis is a L2 type disorder with ROMK defect. This SLT type is often associated with transient hypoaldosteronism in the postnatal period. Nukiwa N. Cheema-Dhadli S. 4: B. Minisola G (2013) Hypomagnesemia and proton. or eplerenone for treating hypokalemia in Gitelman syndrome. 2: B. Expert Opin Drug Saf 12:709–716 51. Baron S. . A new syndrome. Kobe J Med Sci 59:E36–E43 46. Davids MR. MacCardle RC (1962) Hyerplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. For the boy. Therefore it cannot be stimulated directly by increased urine flow. Gitelman HJ. hypomagnesemia. the additional sign of hypochloremia in the unrelated young woman leads to the diagnosis of a DC2 type disorder. For the adult. J Am Soc Nephrol 26:468–475 48. Am J Med 33:811–828 52. Bockenhauer D. 3: A. Aust Paediatr J 10:286–295 Pediatr Nephrol (2016) 31:407–418 Answers 1: C. Graham JB. the DC1 type of SLT is the most likely diagnosis based on the combination of tetany with normal urine osmolality after dehydration. Vargas-Poussou R. Dubourg L. Souma T. Children with hypercalciuria and potassium-losing nephropathy fulfill all of the critical criteria for the diagnosis of a loop disorder. Brown NJ (2013) Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. amiloride. Kidney Int 59:710–717 47. The (additional) function of ClC-Ka can be best demonstrated by comparing the clinical presentation of patients with isolated ClC-Kb defect (DC2 type) directly with the presentation of patients with a combined ClC-Ka and ClC-Kb defect (L-DC1 type). As hypokalemia was not necessarily present when the infants were first examined. Pronove P. Welt LG (1966) A new familie disorder characterized by hypokalemia and hypomagnesemia. Monge M. Tack I. Na-K-ATPase is the only functional protein that is expressed at the basolateral and not at the apical/luminal cell membrane. McCredie DA. Blanchard A. The triad of hypokalemia. Nat Rev Nephrol 9:459–469 49. Essig M. Trans Assoc Am Phys 79:221–235 53. Desport E. Azizi M (2015) Indomethacin. Chong CK. Gill JR Jr. Wildgoose P. Halperin ML (2008) Antenatal Bartter’s syndrome: why ist this not a lethal condition? QJM 101:927–942 50. Lifton RP. Shaer AJ. Yale Gitelman's and Bartter's Syndrome Collaborative Study Group (2001) Gitelman’s syndrome revisited: an evaluation of symptoms and health-related qualitity of life.pump inhibitors. and almost normal specific gravity in a random urine specimen is characteristic for a DCTlike disorder in all three patients. 5: E. Williams AL (1974) Hypercalciuria in potassium-losing nephropathy: a new variant of Bartter’s syndrome. Bergerot D. Rotenberg E. Bia MJ. Bartter FC. A loop disorder can definitely be excluded.418 clinical characteristics of patients with unidentified mutations. Famularo G. Kamel KS. the combination of tetany with isothenuria and hypochloremia best fits the diagnosis of a tubular disorder of the DC2 type.

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