Pediatr Nephrol (2016) 31:407418

DOI 10.1007/s00467-015-3143-1

EDUCATIONAL REVIEW

Pathophysiology and clinical presentations

of salt-losing tubulopathies
Hannsjrg 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
recommendation

Introduction
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
* Hannsjrg W. Seyberth
seyberth@staff.uni-marburg.de
1

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

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]. For more
in-depth studies on the tubular system, the excellent Clinical
Journal of the American Society of Nephrology series entitled
BRenal Physiology for the Clinician^, which has just been
published, is highly recommended [38].

Salt reabsorption
One of the key players in the active uptake of Na+ and Cl- into
tubular cells on the thick ascending limb of the loop of Henle
(TAL) is the furosemide-sensitive sodiumpotassium-2-chloride co-transporter NKCC2 expressed in the apical cell membrane [5]. Once intracellular, Na+ is then actively pumped out
of TAL tubular cells by basolateral Na-K-ATPase, whereas Clleaves the cells basolaterally through the specific chloride
channels ClC-Ka and ClC-Kb. The proper functioning of both
chloride channels is dependent on the -subunit barttin.
In contrast to Na+ and Cl-, K+ is recycled across the apical
cell membrane back into the tubular fluid through a potassium
permeable ion channel, called the renal outer medullary potassium channel ROMK or KIr 1.1. Thus, an intact ROMK is
essential to produce a lumen-positive transepithelial potential,
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.
The distal convoluted tubule (DCT), which starts a short
distance downstream from the macula densa (MD), plays an
important role in fine-tuning the renal excretion of sodium
chloride but also of calcium and magnesium [6]. The DCT
can be subdivided into an early segment (DCT1), a late segment (DCT2), and the connecting tubule (CNT) which leads
to the collecting duct (CD). These sub-segments are characterized by the expression of different ion transport proteins
responsible for salt and divalent cation reabsorption.
Just as in TAL, the energy for the active transcellular salt
transport in DCT is provided by the activity of the basolateral
Na-K-ATPase. 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 this part of the DCT the activity of the Na-K-ATPase
is complemented by the inwardly rectifying potassium channels Kir4.1/5.1 which facilitate the basolateral extrusion of
Na+ [9]. These potassium channels allow recirculation of
K+, 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- transport. After its intracellular uptake together with Na+, Clleaves the cell basolaterally through ClC-Kb. ClC-Ka is not
expressed in the DCT.

Pediatr Nephrol (2016) 31:407418

In the aldosterone-sensitive late distal tubule (ASDT), the

expression of NCC diminishes in the distal direction while
that of the amiloride-sensitive epithelial sodium channel
ENaC, the other key player in transepithelial Na+ transport
in the DCT, increases from the DCT2 to the CNT and finally
decreases in the CD [6, 7]. In this late part of the ASDT Na+ is
actively taken up into tubular cells by ENaC without Cl- and
Cl- is transported separately between the epithelial cells by a
passive process. 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.
For reasons of electroneutrality, each Na+ which enters the
tubular cell via ENaC requires secretion of the cation at the
luminal side [6, 7]. 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.
This voltage-dependent K+ secretion is not the only factor
which determines the rate of K+ secretion in the ASDT. In
the state of increased urine flow, 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 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 acidbase
homeostasis.
Not only K+ secretion but also H+ secretion is considered to
be essential for the maintenance of electroneutrality in the late
ASDT [7, 8]. 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. Another key player in salt reabsorption in the CD,
the chloridebicarbonate-exchanger (pendrin), is expressed at
the apical cell membrane of sub-type B intercalated cells. The
important role of pendrin in both acidbase and electrolyte
homeostasis becomes apparent in the state of extracellular
fluid volume (ECF) contraction and hyperaldosteronism. Under these circumstances Cl- is reabsorbed to a greater than
normal extent in the ASDT, causing insufficient Cl- delivery
to pendrin in the downstream CD. As a consequence of persistent chloride depletion, insufficient chloride is available for
exchange with bicarbonate, with the resultant decrease of urinary bicarbonate excretion eventually leading to metabolic
alkalosis [10].

Water reabsorption
The primary function of TAL is to maintain an appropriate
high salt concentration in the interstitium of the medulla as a

Pediatr Nephrol (2016) 31:407418

prerequisite for countercurrent exchange and the urinary concentration and dilution mechanism. This segment is practically impermeable to water and actively pumps large portions of
sodium chloride out of the filtrate, generating hypertonicity in
the interstitium of the medulla that drives countercurrent exchange [5]. The terminal part of the nephron, which includes
the DCT2, CNT, and CD, is not only responsible for finetuning of the electrolyte balance, but also for fine-tuning of
the water balance [7]. In the presence of arginine vasopressin
(AVP) the osmotic water permeability of the CD epithelium
increases, and water subsequently moves from CDs into the
more concentrated interstitium. 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. Thus, AVP simultaneously increases the osmotic
gradient for water transport and the water permeability of the
CD. The renal effects of AVP can be inhibited by prostaglandin E2 (PGE2) [7, 11].
In primary inherited nephrogenic diabetes insipidus (NDI),
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, with the consequence
that the principal cells in the CD remain impermeable. 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]. Typically, primary NDI is associated with hyposthenuria (excretion of
hypotonic urine), 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, cationselective route in the TAL [6]. This process is driven by the
lumen-positive transepithelial potential established by active
salt reabsorption in this segment (see preceding text). However, salt reabsorption also plays an important role in the tubular
reabsorption and renal excretion of calcium and magnesium
further downstream in the DCT. In this part of the tubule,
reabsorption of Ca2+ and Mg2+ (approx. 810 % each) is an
active transcellular and highly regulated transport process.
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 intracellular decrease of Ca2+
concentration facilitates apical cell membrane Ca2+ entry
through the calcium selective channel TRPV5, a key player
in determining the final urinary calcium excretion. Thus, in

409

the DCT the transepithelial transport of Na+ is inversely proportional to that of Ca2+.
In the active transcellular transport of filtered magnesium
in the early DCT cells, the magnesium selective channel
TRPM6 plays the role of gatekeeper for the entry of Mg2+ into
the apical cell membrane [6, 13]. TRPM6 is primarily driven
by a luminal membrane potential established by the voltagegated K+ channel Kv1.1, but also by the activity of the
basolateral Na-K-ATPase. In contrast to Ca2+ reabsorption,
the transcellular transport of Mg2+ and Na+ in the DCT is
directly proportional to each other. Of note is that up- or downregulation of the transport function along the DCT segment is
accomplished not only by changes in the activity and the
number of NCC, but also by the number of TRM6 channels
at the luminal membrane.

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. However, due to the effect of environmental factors and compensatory mechanisms modulating urinary electrolyte and mineral excretion in the more distal tubular segments, the results obtained in these early clearance studies were difficult to interpret, and the results were not conclusive. A more promising strategy that quickly gained acceptance was to challenge the patient with diuretics having a welldefined action on tubular transport mechanisms [1416]. Diuretic response tests are still performed today, in combination
or not with clearance studies, to evaluate the functional status
of a specific segment of the distal nephron. 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 same
rationale was also behind the earlier introduction of the term
Bpharmacotype^ by Reinalter et al. [18]. 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]. 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, 2022].
According to the combined physiologic and pharmacologic
classification, 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). The two groups are subdivided further into
loop disorders caused by a defect in NKCC2 or ROMK (L1 or

410
Table 1

Pediatr Nephrol (2016) 31:407418

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, 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 4.1)

GS

Thiazide

DCT

TAL, CD

BS III
EAST/SeSAME

Thiazide (+ furosemide)
Thiazide

DCT (+ TAL)
DCT

(TAL) CD
TAL, 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, Distal convoluted tubule; NKCC2, furosemide-sensitive sodiumpotassium-2-chloride co-transporter; ROMK, renal outer medullary potassium
channel; NCCT, thiazide-sensitive sodium-chloride co-transporter; CIC-Kb, CIC-Ka + b, specific chloride channels; Kir4.1, inwardly rectifying potassium channel; BS, Bartter syndrome; GS, Gitelman syndrome; EAST/SeSAME syndrome, epilepsy, ataxia, sensorineural deafness, and tubulopathy;
BSDN Bartter syndrome with sensorineural deafness; TAL, thick ascending limb of Henles loop, CD cortical collecting duct
a

L1, L2, Loop disorders caused by a defect in NKCC2 or ROMK, respectively; DC1, DC2, or DC3, DCT disorders caused by a defect in NCC, ClC-Kb,
or Kir 4.1, respectively; L-DC, furosemidethiazide-like salt-losing tubulopathies (SLT). For more details, see text

L2 type, respectively) and into DCT disorders caused by a

defect in NCC, ClC-Kb, or Kir 4.1 (DC1, DC2, or DC3 type,
respectively). Genetically and eponymously, the loop disorders are also referred to as Bartter syndrome (BS) type I and
type II, and the DCT disorders as Gitelman syndrome, BS
type III, and EAST syndrome. The L1 type is a pure
furosemide-like SLT, whereas the L2 type is a mixed furosemideamiloride-like SLT. Combined loop and DCT dysfunction is the most severe category of SLT, and this condition
forms a third group, namely, the furosemidethiazide-like
SLTs (L-DC type). Genetically, this combined disorder is referred to as Bartter syndrome with sensorineuronal deafness
(BSDN). 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 -subunit barttin).

Clinical presentation and pathophysiological

mechanisms in SLTs
Loop disorders
Our current knowledge of the the pathophysiological
mechanisms underlying loop disorders has recently
reviewed [2]. Typically NKCC2 or ROMK is dysfunctional, with the consequence that the active reabsorption
of solutes in TAL breaks down, leading to severe salt,
mineral, and water wasting. 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). 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, such as
hyperactive PGE2 synthesis as indicated by
hyperprostaglandinuria, secondary NDI, hyperaldosteronism
with hypokalemic alkalosis, and hypercalciuria associated
with nephrocalcinosis (Table 2).
PGE2 plays a pivotal role in the pathogenesis of loop disorders, particularly during the life-threatening and polyuric
phase shortly after birth. At the beginning of a series of destructive steps stands the congenitally impaired salt reabsorption via the NKCC2 pathway, which leads to a decrease in
intracellular Na+ and Cl- concentration in the interstitium but
also, as part of TAL, in the MD. The inadequately low Clconcentration, with shrinkage of the MD cells, incorrectly
signals a low tubular salt concentration, leading to increased
PGE2 synthesis [2]. Overproduced PGE2 interferes with
tubuloglomerular feedback through the disinhibition of glomerular filtration, which is considered to be one of the most
prominent mechanisms underlying the severe salt and water
wasting in loop disorders. In parallel, PGE2 activates the reninangiotensinaldosterone system (RAAS) and inhibits
AVP action. Unfortunately, the mechanism by which increased systemic PGE2 activity causes fever, vomiting, diarrhea, osteopenia, and failure to thriveall typical features of a
hyperprostaglandin E syndrome in infancyremains unexplained [23]. Nevertheless, these disease symptoms can effectively be suppressed by indomethacin, a potent inhibitor of
PGE2 synthesis [24].

Pediatr Nephrol (2016) 31:407418

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)

(+)

(+)

+
+

- (+)

normal
() variable

()

DC3 type (Kir 4.1)

normal

++

++

- isosthenuria

()

++

++

- 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. Plus signs indicate
presence; minus signs indicate absence. 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, Polyhydramnios; HPU, hyperprostaglandinuria, NDI, nephrogenic diabetes insipidus; HAS, hyperaldosteronism; NC, nephrocalcinosis; DCT,
distal convolated tubule
a

Hypokalemia and alkalosis are typical manifestations of all disorders

Transient hypoaldosteronism in the postnatal period

Another leading pathophysiological feature of loop disorders is a paralyzed concentrating and diluting machinery,
which leads to secondary NDI. However, in patients with loop
disorders not only can isosthenuria be observed, but also frequently hyposthenuria [16, 25], which is not so typical for
secondary NDI [12]. It should, however, be noted that not
only the epithelium of TAL is water impermeable, but also
the early DCT (DCT1). In this latter segment, NCC is
expressed a short distance downstream from the MD which
can be upregulated through phosphorylation by AVP [26].
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].
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. In case of ROMK
failure, there is no recirculation of K+ across the apical cell
membrane of the epithelial cell into the lumen to feed the
NKCC2, leading to almost the same situation as that which
exists in NKCC2 failure. 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, at which
time an immaturity of ASDT causes transient hyperkalemia.
This phenomenon emphasizes that, in addition to the flowdependent BK channels, ROMK also contributes to distal
net potassium secretion. With maturation of the BK channels
and the massive polyuria, these channels can take over, at least
in part, the kaliuretic function of ROMK [9]. 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, severity of initial clinical presentation, and
absences of major urinary concentrating defect, as well in
terms of specific electrolyte and mineral abnormalities. During
the first years of life DCT disorders are considered to be relative benign variants of salt-wasting tubulopathies, with patients commonly not becoming symptomatic before reaching
school age. In contrast, adult DCT patients suffer from muscular weakness, fatigue, salt craving, and/or signs of increasing neuromuscular excitability, such as cramps and tetany.
In contrast to loop disorders, signs of NDI with excessive
polyuria are not typical of DCT disorders, as the concentration
machinery in TAL is more or less intact [2]. Moreover, signs of
increased PGE2 activity are not so prominent in DCT disorders
as in loop disorders, 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].
The molecular pathogenesis of DCT disorders is either
based on a defect of sodium and chloride uptake by the apical
membrane, such as in the DC1 type with dysfunction of the
thiazide-sensitive NCC, or based on a defect of basolateral
sodium and chloride extrusion, such as in the DC2 and DC3
type with dysfunction of ClC-Kb or Kir 4.1, respectively.

412

Whereas the DC1 type is thought to be the prototype of a DCT

disorder, the DC2 type can be seen as a mixed thiazidefurosemide type and the DC3 type can be viewed as the mixed
kidney brain type (Table 1).
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, the DC2 type disorder was initially been
assigned to the group of loop disorders [28]. However,
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]. This
mixed DCTTAL or thiazidefurosemide-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]. Expression of both of these
chloride channels occurs in the TAL, while that of CICKb is almost exclusively limited to the DCT. Thus, with
respect to the isolated ClC-Kb defect by ClC-Ka in TAL,
there is a potential for compensation, whereas no such
option exists in the DCT. For this reason, in contrast to
the eponymic terminology, BS III is primarily regarded as
a DCT disorder in the physiologic terminology.
Dysfunction of Kir 4.1 is the integral pathogenetic component of the EAST/SeSAME syndrome. As Kir 4.1 is
expressed in several parts of the brain as well as in the kidney,
this Bcerebro-renal syndrome^ is quite complex. Beginning in
early infancy, it manifests as epilepsy and severe ataxia,
sensorineuronal deafness, mental retardation, and a renal
SLT with hypokalemic metabolic alkalosis [9].
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. The cause is an impaired
basolateral chloride extrusion through the chloride channels ClC-Ka and ClC-Kb throughout the distal tubule [2].
This impairment is caused either by a digenic defect in
both ClC-Ka and ClC-Kb or by a defect in barttin, an
essential subunit of both chloride channels. As with most
SLTs with a loop defect, these disorders manifest themselves prenatally with the development of maternal
polyhydramnios due to fetal polyuria that is followed by
preterm labor and extreme prematurity. Infants subsequently exhibit excessive salt and water losses and
isosthenuric polyuria. However, in contrast to a disorder
with an isolated loop defect, the plasma chloride levels
decrease to rather low levels. Of note is that
hypochloremia can also be observed in patients with an
isolated defect in ClC-Kb.
Although this third group of SLTs is a combination of the
two categories of SLTs, not all features of the clinical

Pediatr Nephrol (2016) 31:407418

presentation will necessarily be aggravated by dysfunctions

that are located in both the TAL and the DCT. The overall
clinical presentation combines all single effects, which might
aggravate, mitigate, or even compensate each other
completely.

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. If the pathogenesis
starts either in the TAL or DCT, it is the function of the more
downstream ASDT (including the late DCT, the CNT, and the
CD) which contributes to the renal adaptation process in SLTs.
ECF volume depletion induces activation of RAAS, and the
release of angiotensin II and aldosterone are thought to be
major stimuli for the upregulation of NCC, ENaC, and
ROMK in CNT and CD [7]. In the case of an isolated TAL
defect, this upregulation of ASDT is further expanded by
(additional) upregulation by the DCT [1]. On the other hand,
a failing DCT is complemented by upregulation of the TAL
(Fig. 1). These adaptation processes in the intact segments,
when not the primary targets of diuretics, also play a key role
in development of diuretic resistance during long-term diuretic treatment [31].
When one part of the distal nephron is failing, the remaining segments can adapt via at least three basic modalities: (1)
activation of the ion transporter proteins, such as by posttranslational modification (e.g. phosphorylation as seen in NKCC2
in Fig. 1); (2) increase in the abundance of specific molecules,
such as the higher expression of transport proteins and channels, or by hypertrophy of the whole transport system in the
segment; (3) a combination of both (1) and (2), as occurs in the
adaptation process of the DCT in loop disorders [1]. The upregulation of different segments of the distal nephron can be
achieved systemically by hormonal stimulation or locally by
paracrine activities, as well as more mechanically by flowdependent effects, such as shear stress caused by marked polyuria. 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, 7, 32, 33].

Compensation, neutralization, and aggravation

Under physiologic conditions the up- and downregulation of
different segments of the distal nephron play important roles
in fine-tuning electrolyte, mineral, and water homeostasis.
This mechanism operates in the pathological situation as well.
In patients with either a defect in TAL or in DCT up- and
downregulation significantly influences the clinical

Pediatr Nephrol (2016) 31:407418

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

NCC

Na+

Na+

Na+
K+

Na+
2ClK+

CNT

DCT

K+

Cl-

TAL

Na+
2ClK+

NCC

K+
K+

NKCC2

Fig. 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). DCT disorders typically result from inactivation of sodium
chloride co-transporter (NCC), which leads to flooding of the connecting
tubule (CNT) with solutes and, subsequently, extracellular fluid volume
depletion. These effects lead to hypertrophy of the CNT and activation of
both the epithelial sodium channel (ENaC) and the potassium channel
(ROMK). These patients also have activation of the sodium-potassium-2-

chloride co-transporter (NKCC2), presumably via phosphorylation. In

contrast, patients with a defect in NKCC2 flood the entire distal nephron
with solute and water; these individuals develop hypertrophy throughout
the distal nephron with increases in the number and activity of salttransporting protein. 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. Eventually, it can lead to (over-)compensation and mitigation, but also to aggravation. This phenomenon will be illustrated with a number of examples.
The pathomechanism of hyperaldosteronism, which is an
integral part of the pathogenesis of all SLTs, can be viewed
from this perspective. Hyperaldosteronism is a direct reaction
to increased tubular salt delivery to the late distal tubule and to
contraction of the ECF volume, resulting in stimulation of the
RAAS, and can be considered an attempt of the distal nephron
to reduce sodium wastage and volume contraction [1, 33].
However, for reasons of electroneutrality this compensatory
mechanism leads to increased tubular K+ and H+ secretion
and consequently to hypokalemic metabolic alkalosis. This
metabolic imbalance in the Bmilieu intrieur^ can cause serious
effects on the function of various organ systems, such as the
cardiovascular and neuromuscular system. Thus, there is some
compensation through RAAS stimulation, but in view of the
metabolic situation, this compensation can aggravate the clinical presentation of the disease. One pathology replaces another.
Also in the latest part of the distal tubule, under pathological conditions mechanical factors can lead to the overreaction
of adaptation and eventually to worsening of the clinical presentation, as in polyuric diseases. 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. Stress directly enhances the activity of
(mechanosensitive) ENaC, BK channels, and H+-ATPase activity [6, 34, 35]. Thus, high urine flow on its own enhances
distal urinary acidification and aggravates hypokalemic metabolic alkalosis. Moreover, increased urine flow might also
stimulate the synthesis of tubular PGE2 and its release into

the tubular lumen. In animal studies, high tubular flow rates

in vivo, as a consequence of isotonic volume expansion, induce the expression of COX-2 activity and enhance PGE2
release in the cortical CD [36]. This paracrine stimulus further
aggravates sodium and water wastage through the inhibition
of sodium and water transport in the CD [7].
Comparing loop and DCT disorders is instructive for
studying various interactions between dysfunctional and
adapted segments. For example, in loop disorders with an
upregulated DCT, passive paracellular Mg2+ and Ca2+ reabsorption in the TAL is low due to a reduced luminal positive
transepithelial potential [1, 37]. Further downstream the two
cations are handled quite differently by the upregulated DCT
segment where the expression and activity of TRPM6, a
magnesium-specific channel, is increased, counteracting at
least in part urinary magnesium wasting in the upstream tubular segment [38]. Thus, hypomagnesemia is not commonly
observed in patients with loop disorders (Table 2). Unfortunately, no such compensatory mechanism exists for calcium.
Due to upregulated Na+ transport via NCC, intracellular Na+
concentration is high, which in turn inhibits Ca2+ extrusion
across the basolateral membrane via the Na+/Ca2+ exchanger
NCX1, resulting in a high intracellular Ca2+ concentration,
leading to reduced apical Ca2+entry through the calcium selective channel TRPV5. In this case, DCT adaptation aggravates urinary calcium wastage, which frequently leads to the
development of osteopenia and nephrocalcinosis even during
infancy. In summary, the combination of excessive hypercalciuria (with secondary nephrocalcinosis) and normal plasma
levels of magnesium is a characteristic signature of loop
disorders.

414

In contrast, in DCT disorders the TAL segment is upregulated [1, 39]. A major step in this adaptative process is the
activation of NKCC2 through phosphorylation of the transporter protein (Fig. 1). In addition to increased reabsorption
activity in the proximal tubule, the upregulated TAL segment
is responsible for enhanced sodium and chloride reabsorption,
and consequently also for mineral reabsorption, in the early
part of the distal nephron. These two compensating effects
result in much less salt and water wasting in DCT disorders
than in loop disorders. Moreover, increased Ca2+ uptake
through the activated TRPV5 channel selectively prevents hypercalciuria. Due to more severely reduced ECF volume, as in
situations of insufficient salt supplementation and/or concurrent extra-renal salt losses, a further increase in sodium reabsorption in the TAL will lead to prominent hypocalciuria, one
of the most characteristic signs of DCT disorders. On the other
hand, 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. Thus, hypocalcemia and hypomagnesemia, which
are frequently associated with convulsions, are considered to
be a strong signature of a DCT disorder.
There is another situation in which the compensation concept can be applied successfully. The clinical presentation of
the mixed DC2 type with a ClC-Kb defect might not always
have a strong DCT signature, and on occasion features can be
observed that are reminiscent of the phenotype of a loop disorder. These specific features include (1) reduced capability to
form highly concentrated urine; (2) development of a moderately enlarged amniotic fluid volume during late pregnancy
which, however, is rarely associated with preterm delivery
[27]; (3) urinary excretion of calcium can be quite variable,
ranging from hypo-/normo- to hypercalciuria [29]. All three
loop disorder-like features may coexist in the same patient.
Thus, 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. Fortunately, this partial dysfunction of TAL is only seen
in a minority of DCT patients with a ClC-Kb defect [27, 29].
Partial compensation of the ClC-Kb defect is also responsible for another specific feature of the D2 type SLTs, namely,
the combination of pronounced metabolic alkalosis and
hypochloremia [25, 40]. These two conditions arise because
the downstream chloridebicarbonate exchanger pendrin in
the CD cannot compensate completely for the loss of ClCKb function along the entire length of the distal tubule, leading
to decreased transcellular Cl- reabsorption.
The interaction between hypo- 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]. These

Pediatr Nephrol (2016) 31:407418

differences are (Table 2): (1) in disorders with a combination

of a loop and DCT defect, polyuria is exclusively isosthenuric
and almost never hyposthenuric as the very proximal part of
DCT with its ability to dilute urine is not functional; (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; (3) marked
hypochloremia, a major characteristic of the D2 type of SLTs,
is naturally also present in combined disorders as these disorders are a combination of loop dysfunction and ClC-Kb
defect.
In summary, 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- and
downregulation) of loop and DCT disorders in the very same
body. The phenotype of combined tubular disorders can be
considered to provide evidence for the concept underlying
the physiologic and pharmacologic classification system of
SLTs.

Diagnostic considerations
Urine osmolality, urinary calcium excretion, and magnesium
plasma levels are the most informative and easily accessible,
clinical parameters to differentiate between loop and DCT
disorders. When these laboratory data are complemented by
an accurate and comprehensive case history an almost definitive diagnosis can be made. This is particularly true when
there is either a maternal history of a pregnancy complicated
by development of a massive polyhydramnios, which has led
to premature birth, or clinical signs of symptomatic hypomagnesemia, such as a positive Chvosteks sign and/or carpopedal
spasm.
Therapeutic approaches
One common therapeutic approach in both loop and DCT
disorders is to replace as much of the urinary losses as possible. The goal should be to replenish the total body deficits of
electrolytes and minerals and the ECF volume. This is the
most effective way to treat metabolic alkalosis. Following this
strategy, the therapeutic management is quite different between loop and DCT disorders. In infants with a full-blown,
life-threatening loop disorder, 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]. However,
excessive fluid replacement aggravates polyuria, indicating
the need to include antidiuretic therapy with an inhibitor of
PGE2 synthesis, preferably indomethacin, in the overall postnatal management. 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

Pediatr Nephrol (2016) 31:407418

further rise in urinary output. In contrast to this acute postnatal

management, in older children and adult patients with a slowly developing and more or less accidently diagnosed DCT
disorder, a salt- and potassium-rich diet is the basis of shortand long-term treatment. However, it should be noted that
early treatment with magnesium supplementation is imperative for effective treatment and prevention of complicating
hypokalemia [34].
Although our understanding of tubular adaptation and upregulation has increased significantly over the last years,
pressing questions do remain. A comparison of the natural
history of SLTs leaves the impression that there must be additional adaptive mechanisms available. For example, in infants
with loop disorders, indomethacin treatment can be reduced or
even temporarily withdrawn as the patients grow older [2, 24,
42, 43]. Moreover, a special subset of infants experiences
extreme salt and water wasting only during the perinatal period and early infancy. Once a few years older, these patients
have recovered from their initial tubular dysfunction
completely [44, 45]. Unfortunately, the underlying mutation
of this transient loop disorder has not yet been identified.
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]. Unfortunately, these latter patients have the tendency to have worsening disease and the
need for more intensified therapy when they reach adulthood.
Such observations have led to the speculation that the ASDT
segment is more able to adapt to TAL dysfunction than to
DCT dysfunction. In this context, it is noteworthy to recall
that there is close functional interrelation between the NCC
and ENaCthe route concerned with Na+ reabsorption in the
overlapping part of the DCT and the ASDT [6, 7, 33]. 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.
For many years, the use of RAAS inhibitors, such as aldosterone antagonists, angiotensin-converting enzyme inhibitors, and angiotensin-II-receptor blockers, has been considered as first-line treatment of SLTs, particularly of DCT disorders. Moreover, potassium-sparing diuretics (ENaC
blockers) had been recommended to be included in the treatment of DCT disorders. Based on our present understanding
of the pathophysiology of SLTs, however, RAAS inhibitors
and diuretic drugs should be used with caution in SLTs [2].
This intervention might help drive the serum concentration of
potassium somewhat towards the normal range, but at the
expense of the adaptive capability of the ASDT. These concerns have been confirmed by a more recent well-controlled
clinical study [47] which compared amiloride, eplerenone,
and indomethacin in terms of tolerability and efficacy for
treating hypokalemia in type DC1 disorder (with NCC defect).
Eplerenone and amiloride treatment were able to raise the

415

serum level of potassium only marginally; simultaneously

however, plasma levels of aldosterone rose by a factor of
three, which is or might be of concern from a cardiovascular
and renal point of view [48]. Although prostaglandins play a
minor role in the pathogenesis of DCT disorders, indomethacin was found to be more effective in treating hypokalemia.
Unfortunately, this treatment was associated with gastrointestinal intolerance to such an extent that indomethacin not infrequently had to be discontinued.
To avoid serious gastrointestinal side effects and possible
under- or overdosing, indomethacin treatment should be carefully titrated in each patient. After the salt intake has reached
the limit of the patients tolerability, the urinary excretion rate
of chloride and plasma renin activity can be used to assess the
efficacy of the treatment [2, 49]. In critical cases, monitoring
indomethacin drug levels and assessment of the urinary excretion rate of PGE2 can be used as markers.
In summary, 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];
(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; (3) calcium-sparing thiazides have sometimes
been recommended to treat hypercalciuria. This treatment
should not be propagated in loop disorders, as these diuretics
seriously compromise DCT adaptation.

Key summary points

1. In isolated TAL defect (pure loop disorders) ASDT adaptation is supported by upregulation of DCT functions. In
DCT disorders, the ASDT is complemented by the upregulation of TAL functions.
2. The key features of loop disorders are hypo- or
isosthenuric polyuria and hypercalciuria, whereas the
most characteristic features of DCT disorders are
hypocalciuria and hypomagnesemia, which occasionally
are associated with episodic cramps and/or tetany.
3. The basis of the pathophysiology of SLTs is usually a
monogenetic defect in the distal tubule network, which
leads to a variety of secondary effects in this part of the
nephron.
4. The secondary effects in a loop disorder, which have a
major impact on the clinical presentation, comprise a
combination of hyperprostaglandinuria, nephrogenic diabetes insipidus, hyperaldosteronism, and hypercalciuria
associated with nephrocalcinosis.
5. When the symptoms and signs of the monogenetic tubular
defect are taken into account, as well as the secondary

416

Pediatr Nephrol (2016) 31:407418

associated with polyhydramnios. All infants failed to

thrive and had a vasopressin-insensitive urinary concentrating defect. Hypokalemia was not necessarily present
on initial presentation. Urine calcium was high in all patients, and nephrocalcinosis was a constant finding.
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, the clinical diagnosis, which leads

to the appropriate therapy, can be made with high degree
of certainty.

Questions (answers are provided following

the reference list)
1. 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, both patients, a 5-year-old
black boy and a 25-year-old black male patient, had
symptoms of tetany as indicated by positive Chvosteks
and Trousseaus sign as well as carpopedal spasm. The
boys urine osmolality rose after dehydration for 24 h to
717 mOsm per kilogram body weight. No other key
features are described in this patient. The key features
of the older patient were as follows isosthenuria, renal
calcified deposits, and serum levels of chloride down
to 41.3 mEq/l.
Which diagnosis is your first choice for both the
young boy and the adult patient when applying the
new physiologic classification?
a) boy: DC1; adult: L-DC1 type
b) boy: L2; adult: DC1 type
c) boy: DC1; adult: DC2 type
d) boy: DC2; adult: L1 type
2. 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, as follows. Besides
hypokemia and hypomagnesemia, 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). Despite documented
hypomagnesemia in all three patients, only the young female, who also had marked metabolic alkalosis with
hypochloremia, sometimes displayed signs of tetany, such
as carpopedal spasm and a positive sign of Trousseau.
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. When comparing different types of SLTs with each other,

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. 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.

References
1.
2.

3.

4.

5.
6.
7.

3. In 1974 McCredie and colleagues [53] published a series

of four pediatric case reports in which they described a
variant of Bartters syndrome with hypercalciuria in
potassium-losing nephropathy. All four children were
born prematurely, and in all cases pregnancy was

8.

Ellison DH (2012) Adaption in Gitelman syndrome: we just want

to pump you upB. Clin J Am Soc Nephrol 7:379382
Seyberth HW, Schlingmann KP (2011) Bartter- and Gitelman-like
syndromes: salt-losing tubulopathies with loop or DCT defects.
Pediatr Nephrol 26:17891802
Zeidel ML, Hoenig MP, Palevsky PM (2014) A new CJASN
series: renal physiology for the clinician. Clin J Am Soc
Nephrol 9:1271
Hoenig MP, Zeidel ML (2014) Homeostasis, the milieu intrieur,
and the wisdom of the nephron. Clin J Am Soc Nephrol 9:1272
1281
Mount DB (2014) Thick ascending limb of the loop of Henle. Clin J
Am Soc Nephrol 9:19741986
Subramanya AR, Ellison DH (2014) Distal convoluted tubule. Clin
J Am Soc Nephrol 9:21472163
Pearce D, Soundararajan R, Trimpert C, Kashlan OB, Deen
PM, Kohan DE (2015) Collecting duct principal cell transport processes and their regulation. Clin J Am Soc Nephrol
10:135146
Roy A, Al-Bataineh MM, Pastor-Soler NM (2015) Collecting duct
intercalated cell function and regulation. Clin J Am Soc Nephrol 10:
305324

Pediatr Nephrol (2016) 31:407418

9.

10.
11.
12.

13.

14.

15.

16.

17.

18.

19.
20.
21.

22.

23.

24.

25.

26.
27.

28.

Cheng CJ, Sung CC, Huang CL, Lin SH (2015) Inward-rectifying

potassium channelopathies: new insights into disorders of sodium
and potassium homeostasis. Pediatr Nephrol 30:373383
Luke RG, Galla JH (2012) It is chloride depletion alkalosis, not
contration alkalosis. J Am Soc Nephrol 23:204207
Olesen ET, Fenton RA (2013) Is there a role for PGE2 in urinary
concentration? J Am Soc Nephrol 24:169178
Bockenhauer D, Bichet DG (2013) Inherited secondary
nephrogenic diabetes insipidus: concentrating on humans. Am J
Physiol Ren Physiol 304:F1037F1042
van der Wijst J, Bindels RJ, Hoenderop JG (2014) Mg2+ homeostasis: the balancing act of TRPM6. Curr Opin Nephrol Hypertens 23:
361369
Chaimovitz C, Levi J, Better OS, Oslander L, Benderli A (1973)
Studies on the site of renal salt loss in a patient with Bartters
syndrome. Pediatr Res 7:8994
Uribarri J, Alveranga D, Oh MS, Kukar NM, Del Monte
ML, Carroll HJ (1985) Bartters syndrome due to a defect
in salt reabsorption in the distal convoluted tubule. Nephron
40:5256
Kckerling A, Reinalter SC, Seyberth HW (1996) Impaired
response to furosemide in hyperprostaglandin E syndrome:
evidence for a tubular defect in the loop of Henle. J
Pediatr 129:519528
Unwin RJ, Capasso G (2006) Bartters and Gitelmans syndromes:
their relationship to the actions of loop and thiazide diuretics. Curr
Opin Pharmacol 6:208213
Reinalter SC, Jeck N, Peters M, Seyberth HW (2004)
Pharmacotyping of hypokalaemic salt-losing tubular disorders.
Acta Physiol Scand 181:513521
Seyberth HW (2008) An improved terminology and classification
of Bartter-like syndromes. Nat Clin Pract Nephrol 4:560567
Chadha V, Alon US (2009) Hereditary renal tubular disorders.
Semin Nephrol 29:399411
Nozu K, Iijima K, Kanda K, Nakanishi K, Yoshikawa N, Satomura
K, Kaito H, Hashimura Y, Ninchoji T, Komatsu H, Kamei K,
Miyashita R, Kugo M, Ohashi H, Yamazaki H, Mabe H, Otsubo
A, Igarashi T, Matsuo M (2010) The pharmacological characteristics of molecular-based inherited salt-losing tubulopathies. J Clin
Endocrinol Metab 95:E511E518
Cruz AJ, Castro A (2013) Gitelman or Bartter type 3 syndrome? A
case of distal convoluted tubulopathy caused by CLCNKB gene
mutation. BMJ Case Rep. doi:10.1136/bcr-2012-007929
Nsing RM, Schaub TP, Klein T, Schweer H, Seyberth HW (1997)
Prostanoid biosynthesis by blood monocytes of children with
hyperprostagandin E syndrome. Pediatr Res 42:241246
Seyberth HW, Rascher W, Schweer H, Khl PG, Mehls O, Schrer
K (1985) Congentital hypokalemia with hypercalciuria in pretem
infants: a hyperprostaglandinuric tubular syndrome different from
Bartter syndrome. J Pediatr 107:694701
Jeck N, Schlingmann KP, Reinalter SC, Kmhoff M, Peters M,
Waldegger S, Seyberth HW (2005) Salt handling in distal nephron:
lessons learned from inherited human disorders. Am J Physiol
Regul Integr Comp Physiol 288:R782R795
Knepper MA, Kwon TH, Nielsen S (2015) Molecular physiology
of water balance. N Engl J Med 372:13491358
Peters M, Jeck N, Reinalter S, Leonhardt A, Tnshoff B, Klaus G,
G KM, Seyberth HW (2002) Clinical presentation of genetically
defined patients with hypokalemic salt-losing tubulopathies. Am J
Med 112:183190
Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C,
Mendonca E, Stone R, Schurman S, Nayir A, Alpay H,
Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA,
Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard
GA, John E, Lifton RP (1997) Mutations of the chloride channel

417

29.

30.

31.

32.
33.

34.
35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

gene, CLCNKB, cause Bartters syndrome type III. Nat Genet 17:
171178
Konrad M, Vollmer M, Lemmink HH, van den Heuvel LP, Jeck N,
Vargas- Poussou R, Lakings A, Ruf R, Deschnes G, Antignac C,
Guay-Woodford L, Knoers NV, Seyberth HW, Feldmann D,
Hildebrandt F (2000) Mutations in the chloride channel gene
CLCNKB as a cause of classic Bartter syndrome. J Am Soc
Nephrol 11:14491459
Krmer BK, Bergler T, Stoelcker B, Waldegger S (2008)
Mechanisms of disease: kidney-specific chloride channels
ClCKA and ClCKB, Barttin subunit; and their clinical relevance.
Nat Clin Pract Nephrol 4:3846
Ellison DH (1991) The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med
114:886894
Hoorn EJ, Ellison DH (2012) WNK kinases and the kidney. Exp
Cell Res 318:10201026
Moes AD, van der Lubbe N, Zietse R, Loffing J, Hoorn EJ (2014)
The sodium chloride cotransporteter SLC12A3: new roles in sodium, potasium, and blood pressure regulation. Pflugers Arch 466:
107118
Huang CL, Kuo E (2007) Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol 18:26492652
Liu W, Pastor-Soler NM, Schreck C, Zavilowitz B, Kleyman TR,
Satlin LM (2012) Luminal flow modulates H+-ATPase activity in
cortical collecting duct (CCD). Am J Physiol Ren Physiol 302:
F205F215
Liu Y, Flores D, Carrisoza-Gaytn R, Rohatgi R (2014)
Biochemical regulation of cyclooxygenase-2 in the renal collecting
duct. Am J Physiol Ren Physiol 306:F214F223
Colussi G, Bettinelli A, Tedeschi S, De Ferrari ME, Syrn ML,
Borsa N, Mattiello C, Casari G, Bianchetti MG (2007) A thiazide
test for the diagnosis of renal tubular hypokalemic disorders. Clin J
Am Soc Nephrol 2:454460
van Angelen AA, van der Kemp AMW, Hoenderop JG, Bindels RJ
(2012) Increased expression of renal TRPM6 compensates for
Mg2+ wasting during furosemide treatment. Clin Kidney J 5:535
544
Favre GA, Nau V, Kolb I, Vargas-Poussou R, Hannedouche
T, Moulin B (2012) Localization of tubular adaptation to
renal sodium loss in Gitelman syndrome. Clin J Am Soc
Nephrol 7:472478
Brochard K, Boyer O, Blanchard A, Loirat C, Niaudet P, Macher
MA, Deschenes G, Bensman A, Decramer S, Cochat P, Morin D,
Broux F, Caillez M, Guyot C, Novo R, Jeunematre X, VargasPoussou R (2009) Phenotype- genotype correleation in antenatal
and neonatal variants of Bartter syndrome. Nephrol Dial
Transplant 24:14551464
Kmhoff M, Tekesin I, Peters M, Leonhard A, Seyberth HW (2005)
Perinatal management of a preterm neonate affected by
hyperprostaglandin E2 syndrome (HPS). Acta Paediatr 94:1690
1693
Leonhardt A, Timmermanns G, Roth B, Seyberth HW (1992)
Calcium homeostasis and hypercalciuria in hyperprostaglandin E
syndrome. J Pediatr 120:546554
Reinalter SC, Grne HJ, Konrad M, Seyberth HW, Klaus G
(2001) Evaluation of long-term treatment with indomethacin
in hereditary hypokalemic salt-losing tubulopathies. J Pediatr
139:398406
Reinalter S, Devlieger H, Proesmans W (1998) Neonatal Bartter
syndrome: sponataneous resolution of all signs and symptoms.
Pediatr Nephrol 12:186188
Ishimori S, Kaito H, Matsunoshita N, Otsubo H, Hashimoto F,
Ninchoji T, Nozu K, Morisada N, Iijima K (2013) SLC26A3 gene
analysis in patients with Bartter and Gitleman syndromes and

418
clinical characteristics of patients with unidentified mutations.
Kobe J Med Sci 59:E36E43
46. Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB, Yale Gitelman's
and Bartter's Syndrome Collaborative Study Group (2001)
Gitelmans syndrome revisited: an evaluation of symptoms and
health-related qualitity of life. Kidney Int 59:710717
47. Blanchard A, Vargas-Poussou R, Vallet M, Caumont-Prim A,
Allard J, Desport E, Dubourg L, Monge M, Bergerot D, Baron S,
Essig M, Bridoux F, Tack I, Azizi M (2015) Indomethacin,
amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome. J Am Soc Nephrol 26:468475
48. Brown NJ (2013) Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol
9:459469
49. Bockenhauer D, Cruwys M, Kleta R, Halperin LF, Wildgoose P,
Souma T, Nukiwa N, Cheema-Dhadli S, Chong CK, Kamel KS,
Davids MR, Halperin ML (2008) Antenatal Bartters syndrome:
why ist this not a lethal condition? QJM 101:927942
50. Famularo G, Gasbarrone L, Minisola G (2013) Hypomagnesemia
and proton- pump inhibitors. Expert Opin Drug Saf 12:709716
51. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC (1962) Hyerplasia
of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33:811828
52. Gitelman HJ, Graham JB, Welt LG (1966) A new familie disorder
characterized by hypokalemia and hypomagnesemia. Trans Assoc
Am Phys 79:221235
53. McCredie DA, Rotenberg E, Williams AL (1974) Hypercalciuria in
potassium-losing nephropathy: a new variant of Bartters syndrome. Aust Paediatr J 10:286295

Pediatr Nephrol (2016) 31:407418

Answers
1: C. For the boy, the DC1 type of SLT is the most likely diagnosis based
on the combination of tetany with normal urine osmolality after dehydration. For the adult, the combination of tetany with isothenuria and
hypochloremia best fits the diagnosis of a tubular disorder of the DC2
type. A loop disorder can definitely be excluded.
2: B. The triad of hypokalemia, hypomagnesemia, and almost normal
specific gravity in a random urine specimen is characteristic for a DCTlike disorder in all three patients. However, the additional sign of
hypochloremia in the unrelated young woman leads to the diagnosis of
a DC2 type disorder.
3: A. Children with hypercalciuria and potassium-losing nephropathy
fulfill all of the critical criteria for the diagnosis of a loop disorder, particularly when they had been born prematurely after a pregnancy that had
been complicated by polyhydramnios. As hypokalemia was not necessarily present when the infants were first examined, 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.
4: B. 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).
5: E. Na-K-ATPase is the only functional protein that is expressed at
the basolateral and not at the apical/luminal cell membrane. Therefore it
cannot be stimulated directly by increased urine flow.