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Mechanisms in Hyperkalemic Renal Tubular Acidosis

Fiona E. Karet
Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom

ABSTRACT
The form of renal tubular acidosis associated with hyperkalemia is usually attrib- dosterone synthesis by heparin.6,7
utable to real or apparent hypoaldosteronism. It is therefore a common feature in Hyporeninemic hypoaldosteronism is
diabetes and a number of other conditions associated with underproduction of also predictable with ␤ blockade.8
renin or aldosterone. In addition, the close relationship between potassium levels
and ammonia production dictates that hyperkalemia per se can lead to acidosis.
Here I describe the modern relationship between molecular function of the distal APPARENT OR FUNCTIONAL
portion of the nephron, pathways of ammoniagenesis, and hyperkalemia. HYPOALDOSTERONISM
J Am Soc Nephrol 20: 251–254, 2009. doi: 10.1681/ASN.2008020166
Functional hypoaldosteronism occurs in
the context either of various inherited
disorders (see next section) or of a num-
To begin, we need a definition and dif- of apical proton pumps on intercalated ber of drugs that affect aldosterone activ-
ferential diagnosis for hyperkalemic cells, in rodents at least.2,3 ity, either directly by interference with its
(type IV) renal tubular acidosis (RTA). receptor or by affecting its target path-
Inability of the kidney either to excrete way.9 For example, mineralocorticoid
sufficient net acid or to retain sufficient TRUE HYPOALDOSTERONISM receptors on the basolateral surface of
bicarbonate results in a group of disor- distal nephron epithelia (Figure 1A) are
ders known as RTAs.1 These all are nor- Low levels of aldosterone or tubular un- antagonized by spironolactone and
mal anion gap hyperchloremic acido- responsiveness to this hormone are eplerenone, whereas the ENaC itself is
ses; in their traditional classification, present in the majority of patients with blocked not only by amiloride and triam-
type IV refers to the only variant asso- hyperkalemia and impaired renal func- terene but also by trimethoprim and
ciated with hyperkalemia. Unlike other tion before end stage.4,5 The most com- pentamidine.10,11 Cyclosporine therapy
distal RTAs, the collecting duct here mon medical conditions associated with interferes with the sodium gradient in
fails to excrete both protons and potas- hyporeninemic hypoaldosteronism in- the collecting duct by interference with
sium. Such a situation arises when al- clude diabetes and various forms of in- the basolateral Na/K-ATPase and possi-
dosterone is insufficient in either terstitial disease, including amyloid, bly NKCC2 and/or distal K⫹ channels.12
quantity or activity and/or because of monoclonal gammopathies, and partic-
some intrinsic (genetic) or acquired ularly the interstitial nephritis associated
molecular defect in relevant transport- with nonsteroidal anti-inflammatory WHAT CAN WE LEARN FROM
ers. Sufficiency of aldosterone is both agents. In the last case, renin levels may MENDELIAN DISORDERS?
quantitatively and functionally neces- be normal, and some patients with dia-
sary for adequate sodium reabsorption betes fail to respond with aldosterone Single-gene disorders that affect the re-
by the epithelial sodium channel synthesis or release despite hyperkale- nal transporters mentioned in the previ-
(ENaC) located on the luminal surface mia. Other situations in which hypoal-
of principal cells in the terminal por- dosteronism is present but not matched Published online ahead of print. Publication date
tions of the nephron, which under nor- by hyporeninism include adrenal de- available at www.jasn.org.

mal conditions leads to the lumen-neg- struction (whether surgical, malignant, Correspondence: Prof. Fiona E. Karet, Cambridge
ative potential essential for potassium or hemorrhagic), Addison disease, an- Institute for Medical Research (Room 4.3), Adden-
brooke’s Hospital Box 139, Hills Road, Cambridge,
and proton secretion (Figure 1A). In giotensin-converting enzyme inhibitor CB2 0XY, UK. Phone: ⫹44-1223-762617; Fax: ⫹44-
addition, aldosterone has a direct, Na- therapy or angiotensin receptor block- 1223-331206; E-mail: [email protected]
independent, nongenomic effect on ade, critical illness (because of direct ad- Copyright 䊚 2009 by the American Society of
proton secretion through upregulation renal suppression), and inhibition of al- Nephrology

J Am Soc Nephrol 20: 251–254, 2009 ISSN : 1046-6673/2002-251 251

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preted as being due to decreased renal

A Principal cell ammonia production.20,21 In the pres-
LUMEN ENaC BLOOD
Na+
NH4+ ence of normal aldosterone production,
however, a high intake of K⫹ does not
MR NH3

K+ commonly lead to metabolic acidosis per

ROMK2
se in humans compared with rodents, in
N
LUMEN BLOOD
BLOOD
α-intercalated cell which dietary manipulation results in a
H+ NH3 C Gln much bigger K⫹ load. Reduction in am-
NH3
monia production in humans is offset by
Glu
an increase in distal sodium delivery and
B NH3
NH3 αKG aldosterone upregulation, which pro-
K + pH mote K⫹ and H⫹ excretion as discussed
NH3
NH3 already.
H+ Na+
+ +
The roles of aldosterone and hyperka-
LUMEN BLOOD NH4 H
lemia in the physiology of human hy-
perkalemic acidosis were considered in a
case report in the New England Journal of
Medicine.22 The case concerned a patient
Figure 1. Factors involved in hyperkalemic acidosis. (A) Proper function of the ENaC at with hyperkalemic hypoaldosteronism
the apical surface of principal cells is necessary for K⫹ secretion by ROMK in these same but only moderate renal impairment.
cells and H⫹ secretion by adjacent intercalated cells. Inherited or acquired loss of ENaC The authors demonstrated reduced uri-
function or its regulation by aldosterone via the mineralocorticoid receptor (MR) gives rise
nary ammonium excretion that resolved
to hyperkalemic acidosis. (B) Hyperkalemia raises intracellular pH by exchange with
protons, impairing enzymes involved in ammoniagenesis. (C) Ammoniagenesis in the
with the use of ion exchange resins to
proximal tubule is chiefly by deamidation of filtered or secreted glutamine (Gln). Ammo- correct the hyperkalemia, whereas re-
nia (NH3) diffusing into the nascent urine assists in buffering H⫹; both NH3 and NH4⫹ placing the mineralocorticoid only partly
undergo further reabsorption in the medullary loop followed by distal nephron move- corrected the biochemical and acid-base
ment into the final urine. Glu, glutamate; aKG, ␣-ketoglutarate. disturbance. This finding implicated hy-
perkalemia itself in the pathophysiology.
ous section also contribute to knowledge brane is impaired because of mutation in The mechanism of this observation
of the complex interplay between salt one of their regulators, the WNK (with was not addressed in the article, and the
handling and acid-base balance. A good no lysine [K] kinases.18 Both of these de- vast majority both of in vivo and in vitro
example is pseudohypoaldosteronism fects have the effect of impairing distal studies from which conventional wis-
type 1 (OMIM 264350, 177735). Here, K⫹ secretion—the former because distal dom is extracted concern the kidneys of
despite activation of the renin-aldoste- sodium delivery falls and the latter be- experimental animals. Experiments in
rone axis, renal salt wasting is accompa- cause K⫹ secretion fails.19 In either case, dogs were probably the first to reveal that
nied by hyperkalemia and hyperchlor- the renin-aldosterone axis fails to com- mineralocorticoid deficiency led not
emic metabolic acidosis, all of which are pensate. Whether WNK kinases also reg- only to hyperkalemia but also to dimin-
due either to loss of function of ENaC ulate proton pumps in the collecting ished ammonia production and proton
because of mutations in one of the three duct is unknown. secretion23,24 and revealed a species dif-
genes encoding its subunits in the severe, Rare nonrenal conditions that impair ference in that dogs are unable to lower
recessive form of the disease13,14 or to ab- mineralocorticoid synthesis include inher- urine pH in this context, whereas hu-
normalities in the mineralocorticoid re- ited enzyme defects such as 21-hydroxy- mans do. Kamm reported to the Ameri-
ceptor in the milder, dominant form.15 lase, 3␤-hydroxysteroid dehydrogenase, can Society of Nephrology in a 1971 ab-
These phenotypes are recapitulated in and corticosterone methyloxidase defi- stract that chronic K⫹ loading in rats
mouse models.16,17 ciency (OMIM 201910, 201810, 203400, reduced ammonium excretion.25 A vari-
Pseudohypoaldosteronism type 2 610600). ety of studies thereafter agreed, albeit
(OMIM 145260), also known as Gordon with differing percentage falls, DuBose
syndrome, represents a different prob- and Good26 reporting a 40% drop in uri-
lem: that of dominantly inherited hy- HOW DOES HYPERKALEMIA nary ammonium excretion with 50% fall
perkalemic hypertension with an associ- CAUSE ACIDOSIS? in whole-kidney ammonium produc-
ated (usually mild) acidosis, in which tion; however, the fine details of how this
either removal of the distal NaCl co- Thirty-five years ago, normal men who happens mechanistically are still to some
transporter from the distal convoluted were fed a high-K⫹ diet were observed to extent unclear, in part because of meth-
tubule apical surface or insertion of decrease their urine pH, ammonium, odologic as well as species differences be-
ROMK into the collecting duct mem- and net acid excretion. This was inter- tween studies. For example, rats fed a

252 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 251–254, 2009
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high-K⫹ diet for 1 wk showed dimin- olism was not greatly affected by high po- cated in the acidosis of hyperkalemia.39
ished distal nephron ammonium secre- tassium.36 These differing observations In the loop, ammonium reabsorption is
tion in the isolated perfused kidney, al- are in contrast to increased mitochon- furosemide sensitive, suggesting a role
though this was not significantly drial activity repeatedly observed in K⫹ for the apical Na/K/2Cl co-transporter.40
different from control animals, whereas depletion. The differences may be ac- Hyperkalemia diminishes this transcel-
perfusing individual kidney tubules with countable by in vitro experimental varia- lular transport, probably by direct com-
K⫹ led to a 30% fall in ammoniagen- tions and/or effects of build-up of inter- petition between elevated luminal K⫹
esis.27 The finding was amiloride inde- mediate metabolites,37 and it is notable and ammonium for the K⫹ binding site
pendent,28 but the role of aldosterone that assessments of changes in systemic on the co-transporter.41,42 Similarly, in
was not addressed at that point. and/or intracellular pH have not in gen- the inner medulla, failure of normal,
Looking at the role of the proximal eral been reported in dietary K⫹ studies. transcellular ammonium secretion into
tubule at the level of the single nephron, In addition, the reported effects of di- urine in the context of hyperkalemia has
both acute and chronic K⫹ loading in rect pH change on isolated mitochondria been linked to impaired capacity of the
rats diminishes proximal ammonia gen- do not necessarily mirror those on intact collecting duct’s basolateral sodium
eration but does not affect the rate of its cells, as exemplified by Tannen and pump to carry the NH4⫹ ion.43 In addi-
transport in easily accessible cortical Kunin’s36 finding that lowering medium tion, reduced availability in the collect-
nephrons,26,29 leading to the suggestion pH seems to inhibit isolated mitochon- ing duct lumen of ammonia will pre-
that deeper nephrons contribute a drial ammonia production in rats, clude buffering of directly secreted
greater net effect on ammonia physiol- whereas, contrary to expectation, it was protons (Figure 1A).
ogy. Isolated perfused mouse nephrons alkalosis that had this effect in a dog Thus, interplay between renal potas-
yielded similar findings: a significant fall study.38 Again, most studies are con- sium and acid-base homeostatic func-
in proximal tubular ammonia production cerned with metabolic acidosis as the pri- tion is complex,44 involving direct effects
without affecting the rate of secretion.30 mary insult rather than hyperkalemia. of one on the other through modulation
Despite agreement that proximal pro- Overall, however, there is agreement that of ion transport by aldosterone, lowering
duction is affected, how this is achieved is ammonia production in the proximal tu- of ammonia formation, and defective
unclear. It probably involves potassium bule is indeed decreased by hyperkale- medullary ammonium handling. In the
entry into cells, displacing protons and mia, with the caveat that many studies clinical context, hypoaldosteronism is
thereby raising intracellular pH,31,32 have focused more on states of K⫹ deple- the dominant factor in human hy-
which by extrapolation from the oppo- tion. perkalemic RTA, and rodent studies of
site effects of acidosis likely leads to re- Further down the nephron, intersti- hyperkalemic metabolic alterations must
duced enzyme function (Figure 1B); tial accumulation of both ammonia and be extrapolated with caution.
however, a number of unresolved issues ammonium by their movement out of
remain. First, it is not clear whether this the loop of Henle and their subsequent
would be an acute or a chronic adapta- reappearance in the final urine play im- ACKNOWLEDGMENTS
tion: In an early study, long-term K⫹ portant roles in normal acid-base and
loading of rats led to drops in ammonia fluid balance that may be disturbed in F.E.K. is a Senior Clinical Research Fellow of
levels in kidney slices of 5% in cortex and hyperkalemia and therefore contribute the Wellcome Trust. With thanks to Tom
36% in medulla, whereas acutely treating to the acidosis. Because a proportion of DuBose and Kevin O’Shaughnessy for helpful
kidney slices with K⫹ solution ex vivo did proximally produced ammonia is pro- discussion and Andy Fry for editorial assis-
not have the same effect33 Conversely, tonated by the extruded H⫹ ions ex- tance.
another study showed rat cortical slices changed for Na⫹ by NHE3 (Figure 1C),
acutely exposed to K⫹ up to 10 mmol/L both nonionic diffusion of ammonia and
inhibited ammonia formation.34 ionic transport of ammonium are re- DISCLOSURES
None.
Second, there has been controversy as quired for transport from lumen to in-
to the actual mechanism modulating terstitium and back again. These have
ammonia production, a large proportion been the subject of large bodies of work
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J Am Soc Nephrol 20: 251–254, 2009 Hyperkalemic Acidosis 253

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254 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 251–254, 2009