ACKD

Hyperkalemic Forms of Renal Tubular

Acidosis: Clinical and Pathophysiological
Aspects
Daniel Batlle and Jose Arruda

In contrast to distal type I or classic renal tubular acidosis (RTA) that is associated with hypokalemia, hyperkalemic forms of RTA
also occur usually in the setting of mild-to-moderate CKD. Two pathogenic types of hyperkalemic metabolic acidosis are
frequently encountered in adults with underlying CKD. One type, which corresponds to some extent to the animal model of se-
lective aldosterone deficiency (SAD) created experimentally by adrenalectomy and glucocorticoid replacement, is manifested in
humans by low plasma and urinary aldosterone levels, reduced ammonium excretion, and preserved ability to lower urine pH
below 5.5. This type of hyperkalemic RTA is also referred to as type IV RTA. It should be noted that the mere deficiency of aldo-
sterone when glomerular filtration rate is completely normal only causes a modest decline in plasma bicarbonate which empha-
sizes the importance of reduced glomerular filtration rate in the development of the hyperchloremic metabolic acidosis
associated with SAD. Another type of hyperkalemic RTA distinctive from SAD in which plasma aldosterone is not reduced is
referred to as hyperkalemic distal renal tubular acidosis because urine pH cannot be reduced despite acidemia or after provoc-
ative tests aimed at increasing sodium-dependent distal acidification such as the administration of sodium sulfate or loop di-
uretics with or without concurrent mineralocorticoid administration. This type of hyperkalemic RTA (also referred to as
voltage-dependent distal renal tubular acidosis) has been best described in patients with obstructive uropathy and resembles
the impairment in both hydrogen ion and potassium secretion that are induced experimentally by urinary tract obstruction and
when sodium transport in the cortical collecting tubule is blocked by amiloride.
Q 2018 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Renal tubular acidosis, Hyperkalemia, Metabolic acidosis, Distal RTA, Pseudohypoaldosteronism

INTRODUCTION by hyperkalemia as opposed to the classic finding of

Distal renal tubular acidosis (DRTA) was initially consid-
ered a single entity characterized by several findings
including the inability to maximally acidify the urine dur-
ing systemic acidosis, hypokalemia, and nephrocalcino-
sis.1-5 The mechanism proposed for DRTA initially was an
inability of the distal nephron to generate and maintain a
steep hydrogen ion gradient.6 A certain degree of associ-
ated sodium wastage would cause volume contraction
which then would activate the renin-angiotensin system
and aldosterone. This secondary hyperaldosteronism then
would promote increased potassium excretion and hypo-
kalemia.7 Indeed, many patients with DRTA may first pre-
sent with muscle weakness and even paralysis due to
hypokalemia.7,8 The other consequences of DRTA (i.e.,
stunted growth in children, osteomalacia, rickets, and
nephrocalcinosis) are also thought to result from the
persistent metabolic acidosis that results in increased
titration of the bone buffers and the consequent release of
bone calcium that is excreted in the urine leading to
hypercalciuria.9,10 The nephrocalcinosis is the result of
both hypercalciuria and decreased citrate excretion. The
decrease in citrate excretion has been attributed to the
decrease in intracellular pH in proximal tubular cells. The
fact that correction of the metabolic acidosis by the
administration of sodium bicarbonate results in the
resolution of most of the manifestations of DRTA lends
support to the suggestion that the main abnormality in
DRTA is the chronic metabolic acidosis that ensues from
failure to secrete hydrogen ions by intercalated cells of
the collecting tubule.
Over the last three decades, experimental, clinical, phys-
iologic, and genetic studies have shown that DRTA encom-
passes complex mechanisms that are now reasonably well
understood.11-34 Some of these disorders are accompanied
hypokalemia with distal or classic renal tubular acidosis
(RTA).35-52 Hyperkalemia with varying degrees of
metabolic acidosis develops with syndromes in which
the primary disturbance is either deficiency of
aldosterone, resistance to the action of aldosterone, or a
more diffuse tubular derangement of electrolyte
transport causing hyperkalemic RTA. These syndromes
span from rare genetic defects at the level of one
transporter (mutations in the epithelial renal sodium
channel, the mineralocorticoid receptor [MLR], or With
No lysine Kinase [WNK] mutations) to overlapping
syndromes associated with chronic kidney disease in
which “relative” aldosterone deficiency may coexist with
“relative” tubular resistance or with a distinct form of
hyperkalemic dRTA.41-44 Notwithstanding this overlap,
two pathogenic types of hyperkalemic metabolic acidosis
are frequently encountered in adults with underlying
chronic kidney disease. One type, which corresponds
to some extent to the animal model of selective
aldosterone deficiency (SAD) created experimentally by
adrenalectomy and glucocorticoid replacement, is
From the Division of Nephrology, Northwestern University Feinberg School of
Medicine, Chicago, IL; Division of Nephrology, University of Illinois at Chicago,
Chicago, IL.
Both authors contributed equally to this article.
Conflict of interest: Dr Batlle has received consulting fees from Relypsa and
Otsuka.
Support: Grant support to D.B. from R01DK104785.
Address correspondence to Daniel Batlle, MD, Northwestern University
Feinberg School of Medicine, Chicago, IL. E-mail: d-batlle@northwestern.edu
Ó 2018 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2018.05.004

Adv Chronic Kidney Dis. 2018;25(4):321-333 321

322 Batlle and Arruda

manifested in humans by low plasma and urinary tubular lumen has a negative voltage relative to the cell
aldosterone levels, reduced ammonium excretion, and interior, H1 ions will be secreted with less effort, and
preserved ability to lower urine pH below 5.5. This excretion of acid in the urine will increase accordingly in
clinical entity also referred to as type IV RTA or SAD is a buffer form (as NH41 or titratable acid). Such a
usually associated with low levels of plasma renin negative lumen voltage is generated by the principal cells
activity.37-59 In the other type of hyperkalemic metabolic during Na1 transport via apical Na1 channels (ENaC). In
acidosis, ammonium excretion is also reduced, and there addition, the cytosol of the principal cell (all kidney cells
is a tubular defect in distal hydrogen ion (H1) secretion, in fact) has a low concentration of Na1 relative to that in
as evidenced by the finding that urine pH cannot be the tubule fluid of the collecting duct. In combination,
lowered below 5.5 not only during acidemia but also these factors influence Na1 to move readily down its
after stimulation of sodium-dependent distal H1 secretion concentration gradient into the cell. Because there is no
by the administration of either sodium sulfate or loop di- directly coupled anion transport, in the principal cells,
uretics such as furosemide or bumetanide.41-43 The term these Na1 channels produce an increasingly negative
hyperkalemic dRTA is used to designate the latter lumen voltage as the positively charged Na1 ions move
syndrome, regardless of whether plasma aldosterone into the cell (the favorable concentration gradient
levels are normal, low, or elevated. In this review article, overpowers the induced negative voltage).
these hyperkalemic forms of RTA will be discussed. A number of factors may in this way enhance or diminish
this negative voltage and therefore enhancing or diminishing
DISTAL ACIDIFICATION: CELL TYPES AND acid excretion. Aldosterone increases the voltage by stimu-
TRANSEPITHELIAL lating Na1 reabsorption by
POTENTIAL DIFFERENCE the principal cells. Similarly,
CLINICAL SUMMARY
(VOLTAGE) infusion of salts containing
The a-intercalated cell consti- readily absorbable cations
 The acquired forms of hyperkalemic RTA develop in the
tutes 40% of the cells in the setting of CKD.
associated with poorly
distal nephron and has the absorbable anions, for
apical H1-adenosinetriphos-  Two major types of acquired hyperkalemic RTA have been example, sodium sulfate,
phatase (ATPase) pumps described: 1) selective aldosterone deficiency (also referred causes the voltage of the
which are responsible for to as type 4 RTA), where deficiency of aldosterone is the lumen to become increasingly
most H1 secretion and acidifi- main cause of impaired potassium and acid excretion,
negative after absorption of
and 2) hyperkalemic DRTA, where aldosterone can be
cation in this segment.60-64 normal and there is a tubular defect for the secretion of
sodium. Both of these factors
The other 60% of cells in the hydrogen ions and potassium. would then tend to enhance
distal tubule are the principal acid excretion. Conversely, a
cells that contain epithelial  Pseudohypoaldosteronism (PHA) is characterized by decrease in the negativity of
sodium channel (ENaC) and features of hyperkalemic hyperchloremic metabolic the lumen and therefore acid
acidosis with normal or high aldosterone levels in the
renal outer medullary small- excretion can result from fac-
presence of normal GFR.
conductance K channel tors that diminish Na1 reab-
(ROMK), the apical trans-  Two general types of genetic PHA have been described: type sorption from the tubule.
porters involved in reabsorp- I, caused by mutations in either the mineralocorticoid Such a diminution would be
tion of sodium and secretion receptor or ENaC; and type II (also known as Gordon seen when the delivery of
of potassium, respectively.65- syndrome), caused by mutations in WNKs that regulate Na1 to the distal tubule is
67 NCCT in the distal tubule.
Indirectly, however, the decreased, as would occur
principal cells contribute to with volume contraction. In a
H1 secretion as a result of similar fashion, the direct
sodium transport via ENaC. This generates a trans- Na1 channel inhibitor amiloride or a decrease in mineralo-
1
epithelial electrical (voltage) gradient that affects H corticoid activity, as occurs with aldosterone deficiency or
secretion by the intercalated cells (Fig 1). A decrease in the aldosterone receptor antagonist spironolactone, would
transepithelial voltage might impair H1 secretion and also diminish the negative lumen voltage and thereby uri-
also K1 secretion. The decreased voltage could be sec- nary acid excretion.
ondary to a process that decreases sodium transport The foregoing discussion has focused on the ability of the
through the apical channels, for instance, when blocked transepithelial voltage to influence active H1 secretion. It is
by drugs such as amiloride, triamterene, lithium, and important, however, to note that in isolated epithelium and
trimethoprim. Although inhibition of sodium reabsorp- perfused tubule segments, H1 secretion in the distal
tion can only occur at the level of the principal cells nephron can take place in the absence of Na1 reabsorption
that have the ENaC, the decreased transtubular voltage or when the voltage gradient created by Na1 absorption is
secondarily reduces hydrogen secretion by the neigh- nullified, albeit at a diminished pace. This independence is
boring a-intercalated cells that have the acid-base trans- not surprising because active H1 secretion by H1-ATPase
porters (Fig 1). and Na1 reabsorption through the Na1 channel, (ENaC)
1
The H -ATPase in the a-intercalated cell is an electro- although electrically coupled, are biochemically distinct
genic pump that transports positively charged protons events that occur in distinct cell populations. New experi-
out of the cell into the tubule lumen.68-70 Clearly, if the mental data on the role of the mammalian target of

Adv Chronic Kidney Dis. 2018;25(4):321-333

 Hyperkalemic RTA 323

Tubule Lumen Principal Cell Interstitial Space

Na+ ENaC

3Na+
Na+/K+ ATPase
ROMK 2K+
K+

Alpha-Intercalated Cell
CO2 + H2O
K+
H+/K+ HCO3-
ATPase H+ AE1 Cl-
CA II

Cl-
H+ KCC4
H+ K+
ATPase
Collecting Duct

Figure 1. Scheme of a principal cell next to an a-intercalated cell in the cortical collecting tubule. Principal cell: This cell has a
luminal membrane epithelial sodium channel, ENaC, and the ROMK. A transtubular electrical gradient, lumen negative, is
generated by sodium transport via ENaC that favors not only K secretion via ROMK by principal cells but also H1 secretion
by neighboring a-intercalated cell mainly via the V-type H1-ATPases, the voltage-dependent effect [see text section “Distal
Acidfication: Cell Types and Transepithelial Potential Difference (Voltage)”]. Alpha intercalated cell: Bicarbonate and proton
generation is catalyzed by cytosolic CA II providing protons for luminal V-type H1-ATPases and bicarbonate for basolateral
chloride/bicarbonate exchangers including AE1. Alpha intercalated cells also express basolateral KCC4 KCl-cotransporters
that maintain low levels of intracellular chloride. Alpha intercalated cells express also H1/K1-ATPases on their apical mem-
brane which serve mostly for preservation of potassium during potassium deficiency with a limited role of H1 secretion under
normal conditions. Abbreviations: ENaC, epithelial sodium channel; ROMK, renal outer medullary small-conductance K.

rapamycin (mTOR) pathway in the regulation of ENaC and
ROMK that may be relevant to altered potassium excretion
in patients with hyperkalemic RTA are discussed later.
ALDOSTERONE
Aldosterone has long been known to significantly influ-
ence sodium transport and urinary acidification in several
important ways.51,71-78 By increasing the activity of the
basolateral Na1/K1-ATPase of the principal cell,
aldosterone reduces the intracellular concentration of
Na1, thereby promoting the influx of Na1 through its
apical channel. Aldosterone also influences the
transepithelial voltage by increasing the number of Na1
channels in the principal cell. Aldosterone has an
additional direct effect on the intercalated cell, such as
that of redistributing vacuolar H1-ATPase to the apical
membrane, thereby increasing the quantity of H1-
ATPase in the cortical collecting duct (CCD).
Other effects of aldosterone on urinary acidification are
mediated by its effect on K1. An increase in urinary K1
and subsequent K1 depletion are well-known consequences
of hyperaldosteronism.78 Potassium depletion, in turn,
causes a marked increase in renal ammonia production.79-81
The increased ammonia production facilitates urinary acid
excretion by increasing the buffering capacity of the urine.
Deficiency of aldosterone by decreasing Na1 reabsorption
results in a diminished transepithelial voltage in the cortical
collecting tubule (CCT) and thereby decreases K1 and acid
excretion. The resulting increase in serum K1 decreases
ammoniagenesis further impairing acid excretion. In
addition, aldosterone stimulates ammonia formation, and
its deficiency further contributes to the decrease
attributable to the associated hyperkalemia.78
Deficiency of aldosterone also causes some degree of
Na1 wastage with volume contraction and consequently
a decrease in distal Na1 delivery, which would further
inhibit acid and potassium secretion. Of interest is the
observation that even when the effects on K1 and volume
homeostasis are prevented, aldosterone deficiency still de-
creases net acid excretion and has a small but demon-
strable effect on plasma HCO32 in adrenalectomized
humans.40 The effect on plasma bicarbonate is so small
in people with normal glomerular filtration rate (GFR)
that it emphasizes the importance of reduced GFR for
the development of acidosis and hyperkalemia with
SAD, a situation that usually occurs in the setting of CKD.
CLINICAL AND PATHOPHYSIOLOGIC FINDINGS
ATTRIBUTABLE TO ALDOSTERONE DEFICIENCY
In contrast to patients with hypokalemic DRTA who present
with a rich clinical phenotype that includes hypokalemia
and alterations in calcium metabolism, those with hyperka-
lemic RTA primarily attributable to aldosterone deficiency
are commonly asymptomatic and identified only during lab-
oratory studies. Occasionally, muscle weakness or cardiac ar-
rhythmias may be present. Early observations were made by
Lathem in a group of patients in which the renal disease was
attributed to “chronic pyelonephritis.”35 These patients had

Adv Chronic Kidney Dis. 2018;25(4):321-333

324 Batlle and Arruda
hyperchloremic acidosis, CKD, and hyperkalemia out of
proportion to the degree of renal insufficiency; subsequent
investigations disclosed several other groups of patients
with similar metabolic abnormalities and deficiency of aldo-
sterone which was later documented as a key finding.36-47
Diabetes accounts for approximately half of those patients;
the remainder have a variety of chronic interstitial
nephritides, but not all patients have aldosterone
deficiency as the main cause of the hyperkalemic RTA (see
below). These clinically diverse causes of CKD associated
with hyperkalemic RTA related to aldosterone deficiency
suggest a common pathophysiologic mechanism that
hampers the formation of aldosterone, a hormone that is
critically needed to prevent the development of
hyperkalemia and metabolic acidosis in CKD. The simplest
explanation is deficiency of renin in juxtaglomerular cells
which may be suppressed by the chronic interstitial
fibrosis commonly seen with CKD, particularly in the
setting of diabetic kidney disease.78 Low aldosterone pro-
duction in patients with SAD is indeed often associated
with low plasma renin activity, but it can also be associated
with normal or even high levels of plasma renin activity.56-59
For instance, heparin causes a decrease in aldosterone
synthesis and is thus associated with a reactive increase in
plasma renin activity.82 In critically ill patients, plasma renin
levels are very high, yet aldosterone deficiency is present (re-
viewed by Mitra and Batlle78).
The clinical features associated with SAD are typified by
the syndrome of hyporeninemic hypoaldosteronism, which
accounts for the majority of cases of SAD.36-56 The
syndrome has been the subject of extensive investigation.
Patients present with moderate hyperkalemia, which is
usually not associated with electrocardiographic
abnormalities. In some cases, hyperkalemia may be
intermittent. Most patients are of middle age or elderly,
have cardiovascular disease, and have moderate CKD,
usually stages 3 and 4. The existence of these comorbid
conditions may explain the lack of renal salt wasting,
which would otherwise be expected in someone with
aldosterone deficiency. Salt wasting may occur if the
levels of aldosterone are vanishingly low and when the
GFR is normal or near normal. The development of
hyperkalemic hyperchloremic metabolic acidosis in
patients with SAD is common and present in about 75%
of cases.39-44 The term type IV RTA was coined to
designate this entity by Sebastian and colleagues37 and is
still often used. Although most patients with adrenal insuf-
ficiency are hypotensive or exhibit postural hypotension,
patients with SAD have normal or elevated arterial blood
pressure owing to their underlying CKD. Postural hypoten-
sion, however, can be seen in patients with SAD, usually in
diabetic subjects, who have severe autonomic dysfunction.
Although initially considered a rare entity, SAD is
observed frequently. Failure to recognize it in the past
was probably due to the fact that most patients with
SAD have asymptomatic hyperkalemia. Classically, these
patients are admitted for other problems, and serum po-
tassium levels are usually in the range of 5 to 6 mEq/L
but at times may be much higher. Also common in 50%
to 60% of these patients is the presence of a mild hyper-
Table 1. Iatrogenic Causes of Renal Hyperkalemia
Aldosterone Deficiency Aldosterone Resistance
Nonsteroidal anti-inflammatory Cyclosporine A
drugs
Angiotensin-converting enzyme FK506 (tacrolimus)
inhibitors
Angiotensin II blockers Amiloride
Heparin Triamterene
Cyclosporine A Trimethoprim
FK506 (tacrolimus) Pentamidine
Drug-induced hyperkalemia separated on causes of aldosterone
deficiency and resistance. Cyclosporine A and tacrolimus are listed
under both the categories, see text.
Data from Mitra and Batlle.78
chloremic metabolic acidosis. The diagnosis of SAD is
easily made by excluding other causes of hyperkalemia
namely of iatrogenic origin (potassium chloride adminis-
tration, potassium sparing diuretics, renin-angiotensin
system (RAS) blockers, heparin, and so forth Table 1).
Demonstration of a relatively low aldosterone level rela-
tive to the level of plasma potassium is essential to the
diagnosis of SAD. The diagnosis of SAD is suggested
with the finding of hyperkalemia with a plasma aldoste-
rone to plasma potassium ratio of less than 3.0.44,46 The
levels of plasma cortisol, by definition, need to be normal.
STUDIES ON PATIENTS WITH SAD
Schambelan and colleagues39 prospectively studied pa-
tients with hyperkalemia and varying degrees of CKD.
Increased serum potassium levels could not be attributed
to any common factors capable of causing hyperkalemia.
The authors showed that urinary aldosterone secretion
was low when corrected for serum potassium in most of
their patients.39 Plasma renin activity was low and failed
to rise during volume contraction, and plasma cortisol
levels were normal.39 Therefore, these patients were classi-
fied as having hyporeninemic hypoaldosteronism. A
study by Arruda and colleagues44 confirmed these obser-
vations by showing that hyperkalemia due to aldosterone
deficiency was found in 80% of patients with CKD. A small
group of patients studied by Schambelan and colleagues
had increased levels of plasma potassium, and the urinary
aldosterone levels corrected by plasma potassium were
within the normal range.39 Despite these findings, the au-
thors classified this group of patients as having SAD. One
could argue that it is difficult to accept the diagnosis of se-
lective SAD in the presence of normal urinary aldosterone
levels. One could take the position, however, that the levels
of aldosterone, while in the normal range, can still be
considered inappropriately low in the face of hyperkale-
mia. To support this contention, it would be necessary to
measure urinary aldosterone in patients with CKD and
normal serum potassium levels. Potassium chloride
should then be given, and the measurement of aldosterone
be repeated. This would permit the determination of the
normal level of urinary aldosterone in a patient with
CKD and hyperkalemia. In other words, how much aldo-
sterone is necessary in renal insufficiency to allow normal
potassium excretion? Arruda and colleagues44 also noted
Adv Chronic Kidney Dis. 2018;25(4):321-333
 Hyperkalemic RTA
that 20% of patients studied with CKD had a normal
plasma aldosterone to plasma potassium ratio and classi-
fied these patients as having tubular unresponsiveness to
aldosterone. This study suffers from the same criticism
faced by Schambelan and colleagues’ study that aldoste-
rone levels were measured only when plasma potassium
was in the normal range.39 In both the studies, however,
a renal defect for potassium excretion was evident and
that potassium excretion, corrected for GFR and serum po-
tassium, was lower than that of controls with comparable
GFR. It will seem logical to anticipate that with chronic re-
ductions in GFR, an increased amount of aldosterone
would be required to maintain potassium homeostasis.
Indeed, there are data showing that aldosterone increases
with progressive loss of GFR.83 Such an increase in aldoste-
rone would help facilitate the adaptive increase in potas-
sium secretion and acid excretion per remaining
nephron, which is a characteristic of CKD.78
The mechanism of metabolic acidosis in SAD is not
completely understood. The metabolic acidosis has been
attributed to several factors. These include a direct effect of
aldosterone on the hydrogen ion pump. This contention is
supported by the experimental studies showing that aldo-
sterone increases urinary acidification in isolated bladders
of epithelial analogs of the mammalian collecting tubule75
and in perfused collecting tubules.51 In bladder membranes,
aldosterone increases the rate at which the pump operates
without affecting the force of the pump.75 This explains in
part why patients with selective, aldosterone deficiency
are capable of lowering the urine pH maximally in response
to acidosis. This ability to lower the urine pH maximally
would be the in vivo functional equivalent of the force of
the hydrogen ion pump but, of course, the lack of urinary
ammonia buffer associated with CKD and aldosterone defi-
ciency, in vivo, also explains the low pH.84 Aldosterone defi-
ciency can also lead to sodium wastage, volume contraction,
and decreased distal sodium delivery. This decreased distal
delivery can impair acid excretion. The role of decreased
distal sodium delivery in mediating the suppressed acid
secretion and potassium in SAD is controversial and has
not been adequately studied. It should be noted that the
experimental model of SAD (bilateral adrenalectomy with
replacement of glucocorticoids) may not replicate the clinical
counterpart of SAD. In the experimental model, the adrenal
medulla is removed, and this may contribute to the alter-
ation in GFR seen in these animals. Also, patients with
SAD have a decreased GFR, not because of volume contrac-
tion but rather because of renal disease. Animals with SAD
are volume contracted, whereas, most patients with selective
aldosteronism are volume expanded. Thus, any extrapola-
tion from the experimental model to the clinical counterpart
must be made with caution.
The administration of fludrocortisone into patients with
selective hypoaldosteronism increases net acid excretion.37
This finding has been used to support the theory that
aldosterone deficiency plays a major role in the decrease
in net acid excretion. It should be emphasized, however,
that fludrocortisone administration into these patients
also corrects serum potassium, and an inverse correlation
between potassium and ammonium excretion has been
Adv Chronic Kidney Dis. 2018;25(4):321-333
325
observed.37 Because hyperkalemia is well known to
decrease ammonium production, it is possible that fludro-
cortisone administration increases net acid excretion at
least in part by normalizing serum potassium and thus
increasing ammonium production.53
To further investigate the role of mineralocorticoid
replacement on acid-base homeostasis, Sebastian and col-
leagues40 studied adrenalectomized patients with normal
GFR. Patients who had undergone bilateral adrenalec-
tomy usually for breast cancer (cancer of the breast, Cush-
ing’s disease, and primary hyperaldosteronism) were
given glucocorticoid replacement and studied during
discontinuation of mineralocorticoid replacement or dur-
ing the initiation of mineralocorticoid replacement. All pa-
tients had normal GFRs, thus eliminating the presence of
CKD as a variable capable of influencing net acid excre-
tion. The authors observed that net acid excretion and
plasma bicarbonate concentration levels decreased in pa-
tients in whom mineralocorticoid replacement was discon-
tinued.40 Conversely, they observed that net acid excretion
and plasma bicarbonate concentration increased in pa-
tients in whom mineralocorticoid therapy was instituted.
There was a significant correlation between the change in
net acid excretion and the change in plasma bicarbonate
concentration. Absence of mineralocorticoids decreased
plasma bicarbonate concentration by only 1.1 mEq/L,
and maximum mineralocorticoid replacement increased
plasma bicarbonate concentration from 0.7 to 2.6 mEq/L.
It was concluded that in the presence of a normal GFR,
plasma aldosterone plays only a permissive role on net
acid excretion.40 It should be emphasized that the small
decrease in plasma bicarbonate concentration observed
during mineralocorticoid deficiency parallels the increase
in plasma bicarbonate concentration observed during the
administration of supraphysiological amounts of mineral-
ocorticoids. Therefore, the lower level of plasma bicarbon-
ate concentration in patients with SAD in the setting of
CKD must be attributed to factors other than aldosterone
alone. CKD in itself results in a marked reduction in
ammonium excretion.85,86
As renal function declines, aldosterone levels are ex-
pected to increase despite volume expansion. There are
data, albeit limited, that support this concept.83 This
increase in aldosterone plays a pivotal role in the adaptive
increase of potassium excretion seen with CKD. The levels
of ammonium in the urine in CKD fall as GFR declines.85,86
Accordingly, any associated deficiencies in aldosterone
would aggravate the metabolic acidosis by further
decreasing ammonium excretion. In aldosterone
deficiency, failure of the adaptive increase leads to
hyperkalemic hyperchloremic acidosis at relatively high
levels of the glomerular filtration rate. In the diseased
kidney, aldosterone deficiency further contributes to the
defect in renal sodium conservation. Yet, patients with
SAD seldom present with sodium wastage, indeed,
because associated CKD, CHF, and normal or excessive
salt intake edema may be present. Sodium wastage may
manifest itself clinically only when intercurrent illness
results in decreased dietary salt intake to a level below
the capacity of the diseased kidney to conserve sodium.
326 Batlle and Arruda
The diagnosis of SAD is easily made by excluding other
causes of hyperkalemia (e.g., potassium chloride adminis-
tration, potassium-sparing diuretics, transcellular shifts,
and RAS blockers [Table 1]). In the absence of these medi-
cations, a finding of a low aldosterone level after correcting
for the serum potassium suggests aldosterone deficiency.
Plasma renin activity is reduced in the majority of cases.
A urinary potassium level of less than 40 mEq/L or a
fractional potassium excretion of less than 20% in a
patient with overt hyperkalemia suggests a defect in renal
potassium excretion. Metabolic acidosis and elevated
serum potassium suggest either the presence of SAD or
defects in hydrogen ion and potassium secretion not pri-
marily caused by aldosterone deficiency as occurs in
obstructive uropathy or sickle cell nephropathy (discussed
below).
STUDIES IN PATIENTS WITH HYPERKALEMIC dRTA
Patients with hyperkalemic dRTA present with clinical
findings that are often indistinguishable from those of pa-
tients with hyperkalemic RTA due to SAD. In both entities,
the main finding is hyperkalemic hyperchloremic meta-
bolic acidosis, usually in the setting of preexisting chronic
renal disease of mild-to-moderate severity (GFR 25 to
90 mL/min). Aldosterone levels are usually normal or
high in patients with hyperkalemic dRTA, whereas
they are, by definition, low in SAD. In addition to the
aldosterone level, the distinguishing feature of this entity
is that urine pH cannot be lowered below 5.5 despite acid-
emia and other provocative tests that stimulate distal
urinary acidification.41-44 This is in contrast to patients
with SAD, whose urine pH is typically below 5.5.37,40-46
Patients with hyperkalemic dRTA and normal plasma
aldosterone levels have a rate of ammonium excretion
higher than that of patients with pure SAD which
supports the concept of an effect of aldosterone,
independent of potassium, in suppressing urinary
ammonium excretion.41 Hyperkalemic dRTA was best
characterized in some patients with obstructive uropathy
as discussed in the following.
HYPERKALEMIC DISTAL RTA ASSOCIATED WITH
OBSTRUCTIVE UROPATHY
In adults with chronic obstructive uropathy, a syndrome of
hyperkalemic RTA may be associated with high or low
levels of aldosterone, suggesting a mechanism distinctive
from SAD.41 We studied a group of 13 patients with
obstructive uropathy and hyperkalemic hyperchloremic
metabolic acidosis and divided into two main groups based
on their urine during acidemia.41 One group lowered the
urine pH below 5.5 and had reduced ammonium excretion.
These patients were found to have reduced plasma aldoste-
rone levels and therefore fulfilled the criteria for the syn-
drome of SAD as described previously. The other group
was of interest because patients were not able to lower their
urine pH below 5.5, and plasma aldosterone levels were not
reduced and, in fact, were increased in some cases, which is
appropriate for the concurrent presence of hyperkalemia.
Therefore rather than SAD, these patients had a distinctive
tubular defect that involves both acid and potassium excre-
tion. To investigate the mechanism of such defect, the pa-
tients were given 1 mg of fludrocortisone 24 hours before
the intravenous administration of sodium sulfate.41 Nor-
mally, in a mineralocorticoid-replete state, the infusion of
sodium sulfate allows for an amplification of the voltage
gradient usually found in the cortical collecting tubule.
This occurs because mineralocorticoid activity increases
the reabsorption of sodium via ENaC, leaving an increased
amount of poorly reabsorbable anion (sulfate, in this case)
in the lumen of the distal tubule/CCT. As noted previously,
this increase in lumen negativity in the CCT enhances the
secretion of hydrogen by a-intercalated cells and potassium
by principal cells (Fig 1). In patients who did not acidify
their urine or increase potassium excretion with the infu-
sion of sodium sulfate ammonium, titratable acidity and
net acid excretion also did not increase significantly. The
abnormal response of patients with obstructive uropathy
to sodium sulfate infusion in the face of mineralocorticoid
administration was attributed to a defect in sodium trans-
port in the CCD, that is, a voltage-dependent type of
DRTA.41 This would prevent the generation of the negative
potential difference in lumen and secondarily impair both
hydrogen and potassium secretion. Alternatively, there
could be a generalized defect in hydrogen ion and potas-
sium ion secretion due to the direct effect of obstructive
damage to the cells of the distal nephron. Finally, obstruc-
tive uropathy could damage the deep nephrons more
severely than the superficial nephrons, and nephron het-
erogeneity could be responsible in part for the defect in po-
tassium and hydrogen ion secretion.
In the cortical collecting tubule, potassium is secreted
mainly by a passive process. Sodium reabsorption occurs
in this segment as an active process leaving the lumen
negatively charged because the permeability to chloride
ion is much less than that for sodium reabsorption via
ENaC. Chloride movement therefore lags behind the
movement of sodium and the negative voltage results.
Because the concentration of potassium is high in the
tubular cells in comparison to the concentration in the
tubular fluid, potassium moves down from the principal
cell interior into the tubular lumen, down both an electrical
and at a concentration gradient. It can be readily seen that
factors that affect sodium reabsorption also clearly affect
potassium secretion via this mechanism in the same way
they affect hydrogen ion secretion. Furthermore, if reab-
sorption of sodium is decreased, sodium wastage results
and leads to intravascular volume contraction and
decreased distal delivery of sodium. If sodium is not deliv-
ered distally to be reabsorbed and to generate lumen nega-
tivity, hydrogen ion and potassium ion secretion could be
hampered as well. It should be emphasized, however, that
in this study, a defect of sodium reabsorption was not
examined by performing balance studies while on a low-
salt diet. The concept of a defect in sodium reabsorption
was based on animal studies in which the postobstructed
kidney displays a mineralocorticoid-resistant defect in so-
dium reabsorption.87 Hyperkalemic hyperchloremic
metabolic acidosis has also been described in children
with obstructive uropathy.88 These children had salt
Adv Chronic Kidney Dis. 2018;25(4):321-333
 Hyperkalemic RTA
wastage and high levels of plasma renin activity and
plasma aldosterone. Fractional K excretion was not
different from controls, but considering the serum K levels,
it is reasonable to attribute the hyperkalemia to a defect in
K excretion. After correction of obstructive uropathy,
the hyperkalemic hyperchloremic acidosis and other
biochemical abnormalities resolved, except for a mild
decrease in the urine Na/K ratio, thus indicating the persis-
tence of some defect in K and Na transport.88 These au-
thors concluded appropriately that hyperkalemia and
salt wastage due to obstructive uropathy in children
must be ruled out before the diagnosis of primary pseudo-
hypoaldosteronism (PHA) can be established.
Of potential interest to the mechanism of decreased K1
secretion as a cause of hyperkalemic DRTA is recent
work showing that the mTOR pathway has been implied
in the regulation of renal potassium excretion.89-91
mTOR has 2 distinct functional complexes termed
mTOR complex 1 (mTORC1) and mTORC2. Chen and
colleagues89 showed that mice with collecting duct–
specific ablation of TSC1 (tuberous sclerosis complex
protein) (CDTsc1KO) had greater mTORC1 activation in
the collecting duct. This model had features of PHA,
including hyperkalemia, hyperaldosteronism, and meta-
bolic acidosis. Interestingly, mTORC1 activation also
reduced the expression of serum and glucocorticoid-
inducible kinase 1, a crucial regulator of potassium homeo-
stasis in the kidney, and decreased the expression and/or
activity of ENaC and ROMK and Na1/K1-ATPase in the
CD.89 In this regard, mTORC1 activation could be another
mechanism that could explain the diffuse defect in collect-
ing tubule function with hyperkalemic metabolic acidosis
that we reported in patients with obstructive uropathy and
normal aldosterone levels.41
Recent work also has shown that pharmacologic inhibi-
tion of mTORC2 regulates tubular sodium uptake by pro-
moting ENaC activity. 90 Grahammer and colleagues91
generated a mouse model lacking mTORC2 in the distal
tubule (Rictor fl/fl Ksp-Cre mice). Interestingly, while on
a high-potassium diet, they developed hyperkalemia
despite an increase in serum aldosterone levels. They
attributed the hyperkalemia to reduced potassium excre-
tion owing to diminished secretion because of failure to
activate ROMK channels. Patch clamp experiments on
split-open tubular segments from the transition zone of
the late connecting tubule and early cortical collecting
duct demonstrated that Ba-sensitive apical K currents
were barely detectable in the majority of Rictor fl/fl Ksp-
Cre mice. Conversely, ENaC activity was largely preserved
suggesting that the reduced ability to maintain K homeo-
stasis is the result of impaired apical K conductance and
not a reduced electrical driving force for K secretion. These
findings show that upregulation of mTORC2 is an impor-
tant regulator of potassium excretion when the levels of
potassium increase. mTORC2 phosphorylates PKC alpha
and SGK1, thereby regulating ROMK abundance and
current at the plasma membrane. These mice also had an
increase in aldosterone levels, and when challenged with
a low-sodium diet, they were able to reduce sodium excre-
tion, suggesting appropriate collecting tubule sodium re-
Adv Chronic Kidney Dis. 2018;25(4):321-333
327
absorption.91 This mice model shows that hyperkalemia
can develop without an associated decrease in sodium
transport via ENaC, but no data were provided on the
renal handling of acid or the presence or absence of meta-
bolic acidosis. Therefore, we think that mTORC2 is an
important pathway for collecting tubule potassium secre-
tion, but alterations in this pathway are not likely to
account for the development of hyperkalemic DRTA.
STUDIES OF URINARY OBSTRUCTION IN THE
POSTOBSTRUCTED KIDNEY
A detailed analysis of potassium handling in experimental
models of obstructive uropathy has only been partially
completed.87 After the release of unilateral ureteral
obstruction, the postobstructed kidney had significantly
lower potassium excretion (corrected for GFR) than the
contralateral kidney during maneuvers that increase po-
tassium excretion, such as bicarbonate loading or volume
expansion. These results suggested a defect in the ability of
the postobstructed kidney to increase potassium excretion
in response to kaliuretic stimuli. The defect in potassium
excretion in the postobstructed kidney was further investi-
gated by giving dogs pharmacological doses of mineralo-
corticoid and Na2SO4. Infusion of Na2SO4 into animals or
patients treated with mineralocorticoids usually results in
increased potassium excretion as explained previously. In
the postobstructive kidney, Na2SO4 infusion not only
failed to increase potassium excretion but also failed to
decrease urine pH normally.87 This response is similar to
that observed in patients with obstructive uropathy as
described previously.
Under baseline conditions, the postobstructed kidney
had a higher urine pH than did the control kidney. The
postobstructed kidney also failed to increase the U–B
PCO2 gradient in response to HCO3 loading, further indi-
cating a defect in hydrogen ion secretion.87 The postob-
structed kidney failed not only to lower urine pH with
sodium sulfate but also to increase urine PCO2 in response
to phosphate infusion.87 These results were interpreted as
indicating a defect in hydrogen ion secretion by distal
nephron. By analogy to studies using amiloride, a hypoth-
esis explaining the nature of the acidification defect in the
postobstructed kidney was proposed by Arruda and
Kurtzman.12,14 Amiloride, a diuretic that blocks sodium
channels in the distal nephron, decreases sodium
transport and thus decreases or abolishes the negative
lumen potential difference. The latter phenomenon
results in a decrease in hydrogen and sodium ion
secretion due to the removal of the favorable electric
gradient (voltage dependent) for secretion of these ions.
In the turtle bladder, amiloride (in small concentrations)
caused a significant decrease in sodium transport and in
the negative lumen potential difference, but it failed to
decrease hydrogen ion secretion under short-circuit condi-
tions (the potential difference was clamped at 0 mV).14 Un-
der open circuit conditions, amiloride decreased hydrogen
ion secretion and the potential difference. Return of the po-
tential difference to baseline values (with an external
source of current) brought back hydrogen ion secretion
to control values despite the presence of amiloride.14
328 Batlle and Arruda
Thus, the effect of amiloride on hydrogen ion secretion was
interpreted as being solely the result of the removal of the
favorable electric gradient (voltage dependent). The post-
obstructed kidney also had a defect in sodium transport
unresponsive to mineralocorticoid administration and de-
fects in potassium ion and hydrogen ion secretion.87 It was
hypothesized that if the defect in sodium transport
occurred at the level of the collecting duct, the failure to
reabsorb sodium would prevent the generation of a favor-
able electrical gradient for the secretion of potassium and
hydrogen ions; this would result in a defect in potassium
ion and hydrogen ion secretion much like the effect of ami-
loride. Experiments with monoclonal antibodies to H1-
ATPase later showed a striking decrease in a-intercalated
cell H1-ATPase staining in the collecting duct of animals
with obstructive uropathy.92 A reduction in numbers of
vacuolar hydrogen pumps also plays a role in the acidifica-
tion defect of obstructive uropathy, whereas diminished
sodium transport by the principal cells may contribute
by causing a voltage defect.50
It could be interesting to study the mTOR pathway in the
postobstructed kidney, looking for alterations that may
also account for the defect in potassium secretion observed
in this model.
SICKLE CELL TRAIT AND SICKLE CELL DISEASE
Patients with sickle cell anemia may have an incomplete
form of distal acidification defect. De Jong and col-
leagues93 evaluated urinary acidification before and after
indomethacin administration in control subjects and in
patients with sickle cell anemia. Urinary acidification
was tested with the short NH4Cl-loading test. Urine pH
after NH4Cl loading was higher in sickle cell anemia pa-
tients than in controls, indicating the presence of a distal
acidification defect. Administration of indomethacin
failed to change urine pH in both the groups. However,
it increased titratable acid level in both the groups;
ammonia excretion was unchanged in controls and
decreased in SCA patients. Net acid excretion was un-
changed in sickle cell anemia patients and increased in
the controls. The authors concluded that the inability of
patients with SCA to lower urine pH is not corrected by
indomethacin, indirectly suggesting that prostaglandins
are not involved in the acidification defect.
DeFronzo and colleagues94 studied patients with sickle
cell disease. These patients had impaired potassium excre-
tion when challenged with an acute potassium load. This
defect could not be reversed by the administration of min-
eralocorticoids and sodium sulfate. Despite the defect of
potassium excretion, none of the patients studied by De-
Fronzo were hyperkalemic. It should be noted, however,
that the failure to disclose hyperkalemia in these patients
could be due to the fact that they had normal GFR. We
studied 6 patients with hemoglobinopathy (3 with sickle
cell anemia, 2 with sickle cell trait, and 1 with sickle cell
disease).43 Of note, these patients had developed a hyper-
kalemic hyperchloremic metabolic acidosis in the face of
only mild-to-moderate CKD. The decreased GFR was
attributed to the underlying disease process in the SS he-
moglobin patients. The cause of decreased GFR in the pa-
tients with SA hemoglobin was unclear. As in the study of
obstructive uropathy patients, some of these patients had
normal aldosterone levels, whereas others had subnormal
levels of aldosterone for the degree of hyperkalemia. It was
found that fractional potassium excretion in these patients
was lower than that of controls with comparable GFR and
normal serum potassium.43 The finding of a low baseline
fractional excretion of potassium in the presence of hyper-
kalemia that persisted after sodium sulfate infusion and
mineralocorticoid administration indicates the presence
of a defect in potassium excretion.
We attributed the presence of hyperkalemia in our pa-
tients with sickle cell disease and trait to a defect in collect-
ing tubule potassium excretion which was unmasked by
the presence of CKD. In CKD, there is an adaptive increase
in potassium excretion which prevents the occurrence of
hyperkalemia until the GFR is below 20 to 25 mL/min.
The mechanism of this adaptive increase includes overper-
fusion of the nephrons with poorly reabsorbable anions,
hypertrophy of the remaining nephrons with amplifica-
tion of the surface area of cells in the collecting tubule,
increased aldosterone, increased sodium potassium
ATPase activity, and possibly increased capacity of the jux-
tamedullary nephrons to secrete potassium. In sickle cell
nephropathy, the presence of a defect of potassium excre-
tion already present with a normal GFR would hamper
the normal adaptive increase in potassium excretion as
CKD supervenes. All 6 patients who were studied by us
had metabolic acidosis.43 Despite the presence of meta-
bolic acidosis, 4 patients were unable to lower the urine
pH below 5.5, indicating a distal acidification defect
similar to that described previously for patients with
obstructive uropathy.
HYPERKALEMIC RTA ASSOCIATED WITH OTHER
CONDITIONS
Hyperkalemic RTA is a common disorder in adult pa-
tients, particularly in the elderly. Cyclosporine A (Cy A)
and tacrolimus administrations are a well-recognized
cause of hyperkalemic RTA. The early study of Adu and
colleagues95 suggested that the mechanism responsible
for RTA in patients treated with Cy A is hyporeninemic hy-
poaldosteronism. Other mechanisms, however, are likely
involved because some patients have normal aldosterone
levels. Stahl and colleagues96 described 4 (out of 23) renal
transplant patients treated with Cy A who had hyperkale-
mic hyperchloremic metabolic acidosis and normal aldo-
sterone levels. Although one could argue that the
aldosterone levels may still be relatively low in the face
of hyperkalemia, it is reasonable to assume that these pa-
tients had sufficient mineralocorticoid activity to acidify
their urine and excrete potassium. A direct role of Cy A
is suggested by showing that reduction of the dose of Cy
A improved both the acidosis and the hyperkalemia.96
Experimental studies showed that high-dose Cy A
administration for 8 days to rats results in mild acidifica-
tion defect as well as a defect in potassium excretion.97
The mechanism responsible for these abnormalities was
attributed to a voltage defect.97 Consistent with this mech-
anism, a transplant patient studied by Kamel and
Adv Chronic Kidney Dis. 2018;25(4):321-333
 Hyperkalemic RTA
colleagues98 had increased potassium excretion when
distal sodium delivery was increased by bicarbonate
administration but not after mineralocorticoid administra-
tion; to date, the mechanism of calcineurin-induced hyper-
kalemic RTA is not completely understood.
Kushner and Sitrin described two patients treated with
triamterene (200 mg twice a day) or amiloride (10 mg/d)
who developed hyperchloremic metabolic acidosis while
on hyperalimentation.99 The occurrence of hyperchloremic
acidosis during the concomitant diuretic administration
and hyperalimentation would be explained by the acid
load provided by hyperalimentation in the presence of
impaired acid excretion by diuretics that are sodium-
channel antagonists. In essence, these human studies
reproduce animal studies in which high doses of amiloride
alone failed to induce acidosis, but when an acid load is
given, a significant acidification defect was disclosed.
The occurrence of RTA with hyperkalemia in patients
with systemic lupus erythematosus (SLE) has been well
recognized. The prevalence of this disorder in SLE is un-
known, and also, the possible correlation between tubular
defects and histologic abnormalities is unclear. Kozny and
colleagues100 reported 30 patients with SLE studied for the
presence of an acidification defect. Eighteen patients
showed some form of defect for H1, K, or Na transport.
Of the patients with tubular defect, 16 had systemic
acidosis. In some patients, the tubular defect disappeared
during remission of the disease. Kozny and colleagues
used several tests of acidification, including urine pH dur-
ing acidosis, urine pH during administration of Na2SO4,
and urine-blood pCO2 gradient during NaHCO3 infusion
to characterize the acidification defect.100 In addition, they
measured serum potassium, fractional potassium, and Na
excretions. Five patients had an acidification defect associ-
ated with hyperkalemia. Of these, one patient clearly ful-
filled the criteria for hyporeninemic hypoaldosteronism,
whereas the remaining 4 patients had a “voltage-depen-
dent defect.” The remaining 13 patients were normokale-
mic, and 8 of these patients could not lower the urine pH
maximally in response to acidosis or to Na2SO4 infusion.
In summary, 1 group of patients with SLE had an acidifica-
tion defect and hyperkalemia, whereas the other group
had only an acidification defect. The patients with tubular
defect appeared to have more severe interstitial disease as
inferred by the finding that 75% of the patients appeared to
have more severe histologic abnormalities. This study in-
dicates that tubular defects are common in patients with
SLE, who have tubule interstitial involvement. The failure
to find a significant correlation between the tubular defect
and histologic changes may be due to the relatively small
number of patients studied.
Table 2. Causes of Pseudohypoaldosteronism
Type Mode of Inheritance
Pseudohypoaldosteronism type IA Dominant
Pseudohypoaldosteronism type IB Recessive
Pseudohypoaldosteronis type IIA Dominant
Data from.78
Adv Chronic Kidney Dis. 2018;25(4):321-333
329
In addition to PHA discussed below, the clinician should
suspect other adrenal disorders and tubular defects in
young patients with hyperkalemic RTA. In this context, it
should be remembered that moderate hyperkalemia with
appropriately higher levels of aldosterone may be present
in children who have undergone successful correction of
congenital hydronephrosis. Rodriguez-Soriano and col-
leagues101 described hyperkalemic RTA in 2 infants with
salt-losing congenital adrenal hyperplasia (CAH). The
diagnosis was established by the finding of elevated levels
of 17-hydroxyprogesterone; normal aldosterone levels;
high plasma renin activity; and the presence of hyponatre-
mia, hyperkalemia, and metabolic acidosis. The acidifica-
tion defect was corrected by chronic administration of
hydrocortisone or by acute administration of fludrocorti-
sone. This finding strongly suggests that resistance to adre-
nal steroids was responsible for the acidification defect and
that replacement in pharmacologic doses corrected the
defect. Even though aldosterone levels were normal, the
acidification defect seems related to mineralocorticoids
because pharmacologic doses of fludrocortisone corrected
the acidification defect. This apparent paradox can be ex-
plained by the fact that in CAH, there are adrenal steroids
that are mineralocorticoid antagonists and compete for the
MLR. These antagonists would displace aldosterone from
the receptor and thus prevent the action of aldosterone.
The acute administration of fludrocortisone would
displace these antagonists for the receptor and result in
normal acidification. In addition, chronic administration
of hydrocortisone corrected the acidification defect, pre-
sumably by suppressing the production of adrenal ste-
roids that were antagonizing the action of aldosterone.
GENETIC CAUSES OF PHA
The syndromes of PHA are characterized by features of
hyperkalemia hyperchloremic metabolic acidosis with
normal or high aldosterone levels in the presence of
normal GFR.102-113 These syndromes can be subdivided
into two categories (Table 2): type I PHA or PHA of infancy
which was described by Cheek and Perry in 1958 and is
manifested by salt wasting and failure to thrive.102 The
spectrum of clinical manifestations varies from severely
affected patients who die in infancy to asymptomatic car-
riers. Typically, infants present with weight loss, dehydra-
tion, hypotension, failure to thrive, high urinary sodium
despite volume depletion and hypotension, a non-anion
gap metabolic acidosis, and hyperkalemia. Plasma and
urine aldosterone levels are elevated, and plasma renin ac-
tivity is increased. More recently, this syndrome has been
designated as primary PHA I. Many but not all of the pa-
tients have MLR mutations transmitted in an autosomal
Gene Mutations Clinical Features
Mineralocorticoid receptor Milder
Epithelial sodium Channel Severe phenotype
WNK 1, WNK4, KLHL3, CUL 3 Hypertension, short stature,
responsive to thiazides
330 Batlle and Arruda
dominant fashion (PHA type IA). Mutations of ENaC
(PHA type IB) have also been identified and associated
with PHA IB. In general, the phenotype is less severe in
the one caused by the MLR mutations (reviewed by Mitra
and Batlle78).
Gordon syndrome, also known as PHA II, is a familial
disorder characterized by hypertension, hyperkalemia,
and normal renal function. The syndrome is associated
with hyperchloremic metabolic acidosis and suppressed
renin activity. As reviewed by Gordon,108 a patient with
hypertension, normal GFR, persistent hyperkalemia, and
normal aldosterone levels had been previously described
by Paver and Pauline. This patient had low urinary potas-
sium excretion and persistently positive potassium bal-
ance, indicating that the hyperkalemia was due to a
defect in renal potassium excretion. Studies of acid excre-
tion during ammonium chloride administration showed
a blunted increase in ammonium and titratable acid excre-
tion. The plasma renin response to upright posture or to a
low-sodium diet was blunted. Aldosterone levels varied
from low to high, depending on the level of hyperkalemia.
Other associated features included intellectual impair-
ment, short stature, and unusual facial appearance. Later
Gordon and colleagues107 described a similar patient,
but with low aldosterone levels. The disease is also charac-
terized by a marked sensitivity to thiazide diuretics, with
improvement in excretion of potassium and correction of
the hyperkalemia. Gordon syndrome may be a familial
disease as 17 of 28 patients described by Gordon origi-
nated from 4 families.108 Actually, hypertension is not uni-
formly present; a review of all reported cases showed a
prevalence of only 68%. Other features, which may or
may not be present, include short stature, intellectual
impairment, and unusual facial appearance. Virtually
every patient has a normal glomerular filtration rate and
hyperchloremic metabolic acidosis.
Gordon proposed that the primary abnormality was a
natriuretic factor deficiency, which, coupled with high
Na1 intake, would increase sodium reabsorption proximal
to the site of Na1 reabsorption regulated by aldosterone.107
Such increased Na1 retention would cause volume-
dependent hypertension and chronic inhibition of the
renin-angiotensin system, resulting in levels of aldosterone
too low to maintain potassium homeostasis, despite the
presence of hyperkalemia. The suppressed K1 and H1
secretion, which is dependent on distal Na1 delivery and
aldosterone levels, would then result in hypertension, hy-
perkalemia, and hyperchloremic acidosis. This view was
supported by the finding that a low-salt diet resulted in
increased plasma renin levels and controlled the hyperten-
sion and hyperkalemia. A possible mechanism was later
suggested by Schambelan and colleagues112 who proposed
an abnormal increase in renal tubular chloride reabsorption
(“chloride shunting”). Renal clearance of potassium was
low, despite normal/high levels of serum and urinary aldo-
sterone (after normal dietary intake of NaCl). Potassium
clearance remained low, despite administration of supra-
physiologic levels of mineralocorticoids or the concomitant
administration of mineralocorticoids with NaCl infusion,
suggesting mineralocorticoid resistance. Renal clearance
of potassium increased only with the administration of
mineralocorticoid and sodium coupled with a poorly reab-
sorbable anion such as sulfate. It was therefore postulated
that there was an abnormally increased rate of reabsorption
of chloride in the distal tubule (chloride shunt), resulting in
a decrease in the negative transtubular electric gradient and
decreased K1 secretion.112
Recently, it has been shown that mutations in WNK ki-
nases have resulted in a clinical scenario similar to Gordon
syndrome. WNK stands for “With No lysine Kinase” at a
key catalytic kinase residue. Wilson and colleagues114
identified 2 human genes associated with PHA II. New
kindred with typical features of PHA II were studied,
and it was found that inheritance of the trait was consistent
with autosomal dominant transmission with high pene-
trance. Both genes encoded members of the WNK family
and were found to be homologous to the rat WNKl and
WNK4. WNK4 was localized almost exclusively in the kid-
ney, whereas WNKl was found in other tissues as well.
Both WNKl and WNK4 localize to the distal collecting tu-
bule and cortical collecting tubule, adjacent to segments of
the distal nephron which play key roles in salt, water, K1,
and pH homeostasis. The putative relationship of WNK1
and WNK4 can be described as follows. Normally,
WNK4 inhibits Na(1)-Cl(2) cotransporter (NCCT)
expression in the distal collecting tubule membrane. Loss
of WNK4 activity would relieve this inhibition and there-
fore result in increased NCCT expression. WNK1 was
found to inhibit WNK4. Mutations of WNK1 that result
in increased WNK1 activity would cause further suppres-
sion of WNK4 activity and therefore result in an increase in
NCCT membrane expression. WNK4 also decreases para-
cellular Cl permeability and inhibits the renal K1 channel,
ROMK. The inhibition of ROMK is independent of WNK4
kinase activity and mediated by a mechanism distinct from
NCCT inhibition. WNK4 mutations that cause loss of inhi-
bition of NCCT expression resulted in increased inhibition
of ROMK. Mutant WNK4 found in Gordon Syndrome re-
sults in increased NCCT membrane expression, decreased
ROMK function via inhibition, and increased paracellular
chloride permeability, all of which explains the hyperten-
sion, hyperkalemia, and hyperchloremic acidosis seen in
Gordon syndrome.
To add to the extreme complexity of this syndrome,
involvement of two other genes such as kelch-like 3 and
cullin 3 has been described recently.115 It has been reported
that these two genes form a RING-type E3-ubiquitin ligase
complex that modulates WNK1 and WNK4 abundance.
WNKs regulate the activity of the NCCT, via the phos-
phorylation of other serine-threonine kinases known as
SPAK-OSR1. The ubiquitous isoform of WNK1 known as
L-WNK1 activates the kinase SPAK, which, in turn, phos-
phorylates and activates NCCT.116
TREATMENT
Although mineralocorticoid replacement should be
considered in patients with SAD, the reality is that most
patients with this syndrome have CKD with hypertension
and often congestive heart failure. This greatly limits this
form of therapy. In the absence of heart failure or
Adv Chronic Kidney Dis. 2018;25(4):321-333
 Hyperkalemic RTA
uncontrolled hypertension, a low dose of 0.1 gm of fludro-
cortisone can be considered. When this approach is not
tolerated, the administration of a loop diuretic helps to
control the hyperkalemia by increasing sodium delivery
to the cortical collecting tubule. Education on avoiding
potassium-rich foods, of course, is part of the treatment
strategy as well as avoiding drugs that can precipitate hy-
perkalemia (Table 1).
The amount of alkali therapy is usually about 30 mEq per
day as these patients are only moderately acidotic. Another
approach that is already feasible is the use of potassium
binders such as patiromer for the treatment of chronic hy-
perkalemia in CKD.117-121 Potassium binders suitable for
chronic use such as patiromer, by lowering plasma
potassium, may increase ammonium excretion and help
correct the metabolic acidosis. However, studies
demonstrating this expected beneficial effect of lowering
plasma potassium on increasing ammonium and
increasing plasma bicarbonate are not currently available.
With the expected introduction of novel therapies for
the treatment of metabolic acidosis in CKD, such as
TRC101,120 the treatment of SAD and hyperkalemic distal
RTA may be further facilitated.
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