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Acidosis Renal Tubular
Acidosis Renal Tubular
Acidosis Renal Tubular
CAII
H2O + CO2 CO2 + H2O
C H2CO3
CAIV
V
H2CO3 Na+
ATP
TP
NBCE
NBCE1
E1
E
H+-ATPase
HCO3- + H+ H+ 3HCO3-
3
3H
ADP
P + Pi
2K+
H+
NHE3
NHE3
3 Na+/K+-ATPase
Na+ 3Na+
Figure 1. A schematic of the roles of acid-base transporters and carbonic anhydrases in acid (hydrogen ion [H1]) secretion and
bicarbonate (HCO3-) reabsorption in the kidney proximal tubule. Sodium ion (Na1)/H1 exchanger isoform 3 (NHE3) and H1-transport-
ing adenosine triphosphatase (H1-ATPase) are expressed on the apical membrane, whereas the sodium bicarbonate cotransporter
(NBCE1) is located on the basolateral membrane of the proximal tubule. Carbonic anhydrase IV (CAIV) and CAII are detected on
the apical membrane and in the cytoplasm, respectively. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate;
CCD, cortical collecting duct; DCT, distal convoluted tubule; IMCD, inner medulla collecting duct; K1, potassium ion; OMCD, outer
medulla collecting duct; PCT, proximal convoluted tubule; Pi, inorganic phosphate; TAL, thick ascending limb.
and H1-ATPase, basolateral NBCE1, and membrane luminal Cl-, primarily by the apical Cl-/HCO3-
and cytoplasmic carbonic anhydrases in acid (H1) exchanger pendrin. The intracellular acid generated
secretion and HCO3- reabsorption in the kidney subsequent to HCO3- secretion in B-intercalated cells
proximal tubule. is transported into blood membrane by the basolateral
H1-ATPase.
Acid-Base Regulation in the Distal Nephron
Secreted H1 by A-intercalated cells is buffered by
(Collecting Duct)
titratable acids (mainly phosphate) and ammonia
The collecting duct has a main role in systemic (NH3; to generate NH41), matching daily acid pro-
acid-base homeostasis by ne-tuning acid and base duction. Although the amount of urinary phosphate is
excretion. The cortical collecting duct expresses 3 xed, urinary NH41 level varies because it is stimu-
distinct cell types: A-intercalated cells, which secrete lated by systemic acidemia (and hypokalemia). H1
H1 (acid); B-intercalated cells, which secrete HCO3- secretion by H1-ATPase is modulated by the activity
(base); and principal cells, which reabsorb Na1 and of the epithelial sodium channel (ENaC) in principal
water and secrete potassium ion (K1). A-intercalated cells and by angiotensin II, aldosterone, and the
cells secrete acid (H1) primarily by apical calcium sensing receptor. Aldosterone plays a key
H1-ATPases (and H1/K1-ATPases), generating new role in H1 secretion by stimulating ENaC and
HCO3- under the control of cytosolic CAII. The H1-ATPase. Aldosterone deciency is characterized
generated HCO3- is transported to the blood in ex- by sodium wasting, hyperkalemia, and RTA (see
change for chloride ions (Cl-) by the basolateral Cl-/ Hyperkalemic RTA section). The schematic in Fig 2
HCO3- exchangers, including the kidney anion shows the localization of acid-base transporters and
exchanger 1 (AE1). Contrary to A-intercalated cells, CAII in the cortical collecting duct and their role in
which are detected along the length of the cortical and acid-base transport.
medullary collecting ducts, B-intercalated cells are
predominantly detected in the cortical collecting duct Physiology of Ammoniagenesis and HCO3-
and are almost absent in the medullary collecting Regeneration
duct. B-intercalated cells secrete HCO3- into the NH3 generates in the proximal tubule from metabolism
cortical collecting duct lumen in exchange for the of glutamine through the process of ammoniagenesis.
Lumen Blood
H2CO3
Cl- CAII ATP
Pendrin H+
Figure 2. A schematic depict-
ADP + Pi ing localization of acid-base trans-
HCO3- B- porters and carbonic anhydrase II
intercalated (CAII) in the cortical collecting
cell duct (CCD) and their role in acid-
base transport. Hydrogen ion
(H1)-transporting adenosine tri-
phosphatase (H1-ATPase) and
ATP
A
AT P H2CO3 H1/K1-ATPase are expressed
H+ CAII Cl- on the apical membrane of A-
H+-ATPase intercalated cells and mediate H1
ADP + Pi AE1 secretion into the lumen, whereas
the Cl-/HCO3- exchanger AE1 is
H+ A- located on the basolateral mem-
HCO3-
H
H /K -ATPase
+ +
intercalated brane of A-intercalated cells and
K+ cell facilitates the transport of bicar-
bonate (HCO3-) to the blood. The
apical Cl-/HCO3- exchanger pen-
+
Na+ MR Aldosterone
drin is located on the apical
membrane of nonA-intercalated
ENaC cells and facilitates HCO3- secre-
tion into the lumen of the CCD in
3Na+
exchange for Cl- absorption.
K+ Sodium ion (Na1) and water are
Na+/K+-ATPase absorbed by the epithelial sodium
channel (ENaC) and aquaporin 2
AQP2 2K+ (AQP2), respectively, in principal
H2O Principal cells. Abbreviations: Pi, inorganic
cell phosphate; MR, mineralcorticoid
receptor.
The NH3 thus generated is secreted into the proximal of the collecting duct. The schematic in Fig 3 shows
tubule lumen, where it combines with H1 (secreted by NH41 generation and excretion in kidney tubules
H1-ATPase) or is transported by the NHE3, which and their impact on HCO3- generation and acid
can function as an Na1/NH41 exchanger. Ammonia- elimination.
genesis is regulated by intracellular pH (and indirectly
by intracellular K1). NH41 is transported along the Additional Readings
length of the proximal tubule to the medullary thick Adrogue HJ, Madias NE. Tools for clinical assessment. In:
ascending limb, where it is absorbed into the Gennari FJ, Adrogue HJ, Galla JH, Madias NE, eds. Acid-
Base Disorders and Their Treatment. Boca Baton, FL: Taylor
medullary interstitium primarily by the apical Na1/ and Francis Group; 2005:801-816.
K1/2Cl- cotransporter. Then the NH3 is secreted into Brown AC, Hallouane D, Mawby WJ, et al. RhCG is the
the collecting duct lumen, where it is trapped as major putative ammonia transporter expressed in the hu-
NH41 by H1 secreted through intercalated cells by man kidney, and RhBG is not expressed at detectable
H1-ATPase (and H1/K1-ATPase). Collecting duct levels. Am J Physiol Renal Physiol. 2009;296(6):F1279-
F1290.
NH41 excretion requires the presence of Rhesus Capasso G, Unwin R, Rizzo M, et al. Bicarbonate transport
protein, RhCG, which is detected on both the apical along the loop of Henle: molecular mechanisms and regula-
and basolateral membrane of most cells of the distal tion. J Nephrol. 2002;15(suppl 5):S88-S96.
convoluted tubule and intercalated cells of the con- Hamm LL, Nakhoul N, Hering-Smith KS. Acid-base ho-
necting tubule and collecting duct. It is believed that meostasis. Clin J Am Soc Nephrol. 2015;10:2232-2242.
Hamm LL, Simon EE. Roles and mechanisms of urinary
under normal circumstances, RhCG is the key puta- buffer excretion. Am J Physiol. 1987;253:F595-F605.
tive NH3 transporter expressed in the human kidney Kim GH, Han JS, Kim YS, Joo KW, Kim S, Lee JS. Eval-
and RhBG is expressed at below detectable levels. uation of urine acidication by urine anion gap and urine
NH41 excretion by the kidney results in elimination osmolal gap in chronic metabolic acidosis. Am J Kidney Dis.
of acid in the collecting duct and generation of new 1996;27(1):42-47.
Li HC, Du Z, Barone S, et al. Proximal tubule specic
HCO3- in the proximal tubule. Aldosterone plays a knockout of the Na/H exchanger NHE3: effects on bicar-
major role in NH3 generation both through regulation bonate absorption and ammonium excretion. J Mol Med
of K1 homeostasis and H1 secretion into the lumen (Berl). 2013;91:951-963.
Lumen Blood
NH4+
Gln
G
NH3
NH
H3
A
ATP Glu
u
+
+
H+-ATPase Proximal
H H+
ketogluta
-ketoglutarate tubule cell
ADP + Pi
NH4+ NH4+
(H+) Na+
NHE3 N E1
NBC
NBCE1
HCO3-
Na+ 3HCO3-
3H
PCT
A-intercalated cell
TAL NH3
OMCD
NH4+
IMCD
Figure 3. Generation and excretion of ammonium ion (NH41) in kidney tubules and their impact on bicarbonate (HCO3-) generation
and acid elimination. NH41 is primarily generated in the proximal tubule consequent to the metabolism of glutamine. NH41 transport
along the length of the nephron, its absorption in the thick ascending limb, and its secretion into the collecting duct are shown. Abbre-
viations: CCD, cortical collecting duct; DCT, distal convoluted tubule; G, glomerulus; Gln, glutamine; Glu, glutamate; IMCD, inner me-
dulla collecting duct; NBCE1, sodium bicarbonate cotransporter; OMCD, outer medulla collecting duct; TAL, thick ascending limb.
Purkerson JM, Schwartz GJ. The role of carbonic anhydrases carbonic anhydrase, or defects in the exit of HCO3- by
in renal physiology. Kidney Int. 2007;71:103-115. the Na1/3HCO3- cotransporter NBCE1. pRTA could
Sastrasinh S, Tannen RL. Effect of potassium on renal NH3
production. Am J Physiol. 1983;244:F383-F391.
also present as a component of Fanconi syndrome due
Tannen RL. Relationship of renal ammonia production and to generalized impairment of solute reabsorption in
potassium homeostasis. Kidney Int. 1977;11:453-465. the proximal tubule, manifesting as renal loss of
Wagner CA, Devuyst O, Bourgeois S, Mohebbi N. Regulated glucose, amino acids, phosphate, uric acid, and other
acid-base transport in the collecting duct. Pugers Arch. organic anions.
2009;458:137-156.
Weiner ID, Hamm LL. Molecular mechanisms of renal Classication of pRTA
ammonia transport. Annu Rev Physiol. 2007;69:317-340.
Weiner ID, Verlander JW. Renal acidication mechanisms. pRTA can present in hereditary or acquired forms.
In: Brenner B, ed. Brenner and Rectors The Kidney. 9th ed. Hereditary pRTA. Hereditary pRTA may manifest
Philadelphia, PA: W.B. Saunders; 2011:293-325. as autosomal recessive, autosomal dominant, or spo-
radic forms. Patients with autosomal recessive pRTA
RENAL TUBULAR ACIDOSIS present with short stature, cataracts, and central ner-
Based on clinical presentation and pathophysiologic vous system calcication, and the condition is linked
mechanism, RTA is classied into proximal (pRTA to mutations in the Na1/3HCO3- cotransporter
or type II), distal (dRTA or type I), and hyperkalemic NBCE1 (Fig 1). In severe forms of pRTA, serum
(or type IV) RTA (RTA type III [ie, combined pRTA HCO3- concentrations , 10 mEq/L and blood
and dRTA] is not detailed in this Curriculum because pH , 7.1 have been reported. Although inactivation
of its rarity). of NHE3 could result in HCO3- wasting and pRTA in
animal models, mutations in NHE3 causing pRTA in
Proximal RTA humans have not been reported. Mutations in CAII
pRTA is caused by defective HCO3- reabsorption lead to recessive mixed pRTA and dRTA, or type III
in the proximal tubule (Figs 1 and 3). This could RTA, with a predominance of distal acidication
be due to defects in H1 secretion by NHE3 defect. Patients with CAII mutations present with
or H1-ATPase, impairment of luminal or cytosolic HCO3- wasting, inability to lower urine pH to ,5.5,
and decreased NH41 excretion. The gene(s) involved these patients. However, this test has unacceptable rates
in autosomal dominant pRTA has (have) not yet of false-positive and -negative results. Another
been identied. The most common forms of familial approach is to treat patients with HCO3- at 1 to 2
Fanconi syndrome are due to cystinosis and Wilson mEq/kg/d and check serum HCO3- concentration after
disease. Other inherited causes of pRTA include: 2 to 3 weeks. In dRTA, serum HCO3- concentration
Lowe syndrome (oculocerebrorenal syndrome approaches the reference range, whereas it will remain
[OCRL]), an X-linked disorder characterized signicantly below normal in pRTA and urine will be
by cataract, mental retardation, and Fanconi-like (or become) markedly alkaline due to HCO3- wasting.
pRTA, results from mutations in the OCRL gene, Treatment of pRTA
encoding a-phosphatidylinositol (4,5)-biphosphate
The goal is to increase serum HCO3- concentration
phosphatase (PIP2P);
as close to normal as possible. However, this is often
Fanconi-Bickel syndrome, an autosomal recessive
very difcult due to the decrease in HCO3- tubular
disorder characterized by pRTA and impaired uti-
maximum. Oral HCO3- at doses of 10 to 15 mEq/kg/d
lization of glucose and galactose, is due to defects
with potassium supplementation is often used. Hy-
in monosaccharide transport across the tubular
drochlorothiazide may be helpful by increasing the
membranes; and
HCO3- tubular maximum; however, hypokalemia
Dent disease, an X-linked recessive disorder char-
must be prevented with supplemental potassium and/
acterized by low-molecular-weight proteinuria,
or treated. In patients with Fanconi syndrome, phos-
hypercalciuria, nephrocalcinosis, and neph-
phate supplementation is often required.
rolithiasis, results from mutations in either the
chloride channel gene CLCN5 or the OCRL gene. Distal RTA
dRTA reects a failure to reabsorb HCO3- by
Acquired pRTA. Most common causes include intercalated cells in the collecting duct, resulting in
tubular injury by light chains, amyloidosis, multiple persistent alkaline urine. It is characterized by
myeloma, autoimmune disorders, toxins such as impaired acid excretion and the inability to reduce
cadmium or lead, and drugs, including ifosfamide, urinary pH to ,5.3 when confronted with sponta-
valproic acid, carbonic anhydrase inhibitors, and neous acidemia or acid loading. The defect in H1
various antiretrovirals such as tenofovir (especially secretion in the collecting duct leads to reduced NAE
when administered to patients with human immuno- subsequent to decreased NH41, titratable acid excre-
deciency virus [HIV] infection who are concomi- tion, and HCO3- wasting. This results in a decrease in
tantly receiving protease inhibitors such as ritonavir serum HCO3- concentration and generation of
or reverse transcriptase inhibitors such as didanosine). hyperchloremic metabolic acidosis. The abnormalities
Acquired pRTA may present as Fanconi syndrome, in H1 secretion in the collecting duct are secondary to
characterized by glycosuria, aminoaciduria, phos- defects in H1-ATPase, cytosolic CAII, or kidney
phaturia, and uricosuria. AE1. NH41 excretion is reduced in dRTA due to
Clinical Presentation and Diagnosis of pRTA. impaired trapping of luminal NH3 in the collecting
Patients with pRTA can be asymptomatic or could duct subsequent to defects in H1 secretion. One
present with weakness/paralysis due to severe hypo- unique feature of dRTA is very low urinary citrate
kalemia and, in rare cases, with bone pain/fracture due levels. This is due to the increase in reabsorption of
to osteomalacia. Hyperchloremic metabolic acidosis in citrate by the proximal tubule in response to intra-
pRTA tends to be milder because distal HCO3- recla- cellular acidosis.
mation is intact and bicarbonaturia disappears when
HCO3- load falls below the HCO3- tubular maximum Classication of dRTA
(often at serum HCO3- level of 14-18 mEq/L). dRTA can be hereditary (primary) or acquired
The key laboratory nding is the presence of (secondary).
hyperchloremic metabolic acidosis with hypokalemia Hereditary dRTA. The vast majority of inherited
and variable urinary pH, with alkaline urine pH if serum forms of dRTA are due to defects in AE1 or
HCO3- concentration is above the tubular maximum H1-ATPase. In addition, cytosolic CAII gene muta-
and pH , 5.3 when it is below the tubular maximum. If tions are associated with a mixed picture of pRTA and
the diagnosis of pRTA is not clear, urinary pH should dRTA. Mutations in the basolateral Cl-/HCO3-
be measured after an acid load with ammonium chlo- exchanger AE1 lead to the impairment of HCO3- ab-
ride (0.1 g per kilogram of body weight). In patients sorption in A-intercalated cells in the collecting duct.
with pRTA, but not dRTA, urine pH decreases to ,5.3. Both autosomal recessive and autosomal dominant
Because furosemide also decreases urine pH and is mutations have been reported. Mutations in apical
easier to use than ammonium chloride, measuring urine H1-ATPase in A-intercalated cells impair H1 sec-
pH after the use of furosemide has been suggested in retion into the lumen of the collecting duct. Some
patients with H1-ATPase mutations present with (hyperchloremic metabolic acidosis) with respect to
sensorineural deafness. The mutations in H1-ATPase the source of HCO3- loss (gastrointestinal vs kidney)
are predominantly of the autosomal recessive form. and the delineating features of serum K1 concentra-
Mutations in CAII impair HCO3- reabsorption in the tion, urinary NH41 excretion, and urine pH in dis-
proximal tubule and collecting duct (mixed dRTA and tinguishing various types of hyperchloremic
pRTA). It also affects bone osteoclasts resulting in metabolic acidosis. The pathophysiology of hyper-
osteopetrosis. kalemic RTA (type IV) is discussed in more detail in
Acquired dRTA. The most common causes are the following sections.
autoimmune diseases such as Sjgren syndrome, sys-
Treatment of dRTA
temic lupus erythematosus, rheumatoid arthritis, and
hypergammaglobulinemia; kidney transplantation; dRTA, in contrast to pRTA, has a relatively small
sickle cell disease; and drugs including ifosfamide daily loss of HCO3-, often in the range of 1 to 2 mEq/
(more commonly causing pRTA than dRTA), kg/d. The amount of supplemental sodium or potas-
amphotericin B, lithium carbonate, and intravenously sium bicarbonate is therefore 1 to 2 mEq/kg/d. In
administered bisphosphonates such as zoledronate. In children, normal growth is dependent on an adequate
Sjgren syndrome, 3% to 6.5% of patients have supply of HCO3- and maintenance of normal serum
complete dRTA, whereas up to 33% have incomplete HCO3- concentration. This often requires an HCO3-
dRTA. A small number have combined dRTA and dose of 4 to 8 mEq/kg/d.
pRTA, including Fanconi syndrome. A variety of an- Incomplete dRTA
tibodies against H1-ATPase, kidney AE1 transporter,
Incomplete dRTA is dened as having normal
and CAII have been reported in these patients. Box 1
serum HCO3- concentration while lacking the ability
summarizes the causes of classical dRTA (type 1).
to acidify urine when challenged with an acid-loading
test. This should be considered in patients with idio-
Clinical Presentation and Diagnosis pathic renal calculi with alkaline urine, as well
Patients with dRTA often present with signs and as patients with Sjgren syndrome, children with
symptoms related to severe hypokalemia, including posterior urethral valve disease, and patients
proximal muscle weakness, polydipsia, and polyuria. with amphotericin toxicity. Kidney stones are due
In milder cases, symptoms related to renal calculi may
be the rst sign of an abnormality in acid secretion.
Box 2. Measuring Urinary Ammonium Excretion
Laboratory studies show hyperchloremic metabolic
acidosis with persistent urine pH . 5.3 often associ- Because urinary ammonia is not directly measured by the
ated with hypokalemia. Patients with dRTA and clinical laboratory, it is estimated by measuring UAG or
hyperkalemic RTAs have low urinary NH41 (positive urine osmolar gap
Both calculations only give a qualitative and not a
urinary anion gap and low urine osmolal gap), quantitative measure of urinary ammonia
whereas patients with hyperchloremic metabolic UAG
acidosis due to gastrointestinal HCO3- loss (diarrhea) Urinary cations [Na1 1 K1] urinary anions [Cl-]
usually have elevated urinary anions (negative urinary In patients with hyperchloremic metabolic acidosis
and normal kidneys, UAG would be , 0
anion gap and high urine osmolal gap of more than A positive UAG indicates low urinary NH41
300-400 mEq/L). Box 2 shows a summary of urinary UAG cannot be used if:
NH41 estimation by measuring urinary anion gap and - Urine pH . 7, as this would indicate the presence
Hyperchloremic acidosis
UNH4+ UNH4+
primarily to low urinary citrate levels combined with understood and involves an increase in aldosterone
a high urine pH (Fig 5). levels due to sodium wasting, as well as metabolic
acidosis. In amphotericin Binduced dRTA, both the
Kidney Stones and Nephrocalcinosis in RTA impairment in H1 secretion and K1 loss are due to a
Kidney stones and nephrocalcinosis are primarily defect in membrane permeability. However, this
seen in dRTA. The pathogenesis includes low uri- defect is unique to amphotericin B toxicity and has
nary citrate, high urinary calcium, and high urinary not been shown in other forms of dRTA. In pRTA,
pH favoring calcium phosphate precipitation. The treatment with HCO3- supplement will result in
use of carbonic anhydrase inhibitors (eg, acetazol- marked bicarbonaturia. An increase in urinary HCO3-
amide, topiramate, and zoniramate) results in a excretion may obligate an increase in K1 secretion,
similar scenario and is associated with an increased thereby worsening the hypokalemia. Please refer to
incidence of kidney stones. Patients with pRTA have Fig 4 for a summary of features of various types
normal urinary citrate levels and their urinary pH is of hyperchloremic metabolic acidosis with regard
commonly in an acidic range, protecting against to serum K1 level, urine pH, and urine NH41
stone formation. excretion.
Potassium-sparing diuretics: these drugs cause and renin inhibitors can cause hyperkalemia by
hyperkalemic RTA by either blocking the action of reducing aldosterone synthesis
aldosterone on the collecting tubule cells through Heparin and low-molecular-weight heparin:
competing for the aldosterone receptor (spi- can cause hyperkalemia by inhibiting adrenal
ronolactone or eplerenone) or inhibiting the ENaC gland release of aldosterone from the zona
(amiloride) glomerulosa
Antibiotics: 2 antibiotics, trimethoprim and pent-
amidine, can cause hyperkalemia by inhibiting Diagnosis of Hyperkalemic RTA
ENaC Diagnosis of hyperkalemic RTA is usually
Nonsteroidal anti-inammatory drugs: nonsteroidal straightforward and based on the initial clinical and
anti-inammatory drugs interfere with the secretion laboratory presentation. However, in patients with
of renin and also impair angiotensin IIinduced more complex cases, further studies are done to
release of aldosterone document low NH41 and K1 excretion. This includes
Calcineurin inhibitors: both cyclosporine and estimating urinary NH41 excretion by measuring uri-
tacrolimus can cause hyperkalemia by inducing nary anion and/or urinary osmolal gaps (Box 2). Urine
aldosterone resistance. The effect of tacrolimus is pH should be appropriately acidic (pH , 5.5),
through activation of the thiazide-sensitive Na1/Cl- although pH . 5.5 is seen in obstructive uropathy.
cotransporter and inhibition of the renal outer Low urinary K1 excretion can be assessed by a
medullary K1 channel (ROMK) in the distal transtubular K1 gradient or urinary potassium-
nephron creatinine ratio. To establish the cause of hyper-
Angiotensin inhibitors: angiotensin-converting kalemic RTA, specic causes including drugs should
enzyme inhibitors, angiotensin II receptor blockers, be sought. When indicated, random serum renin and
Figure 6. Pathogenesis of hyperkalemia. Medications, diseases, and the renin-angiotensin II-aldosterone axis and their role in
potassium ion (K1) homeostasis. Abbreviations: Na1, sodium ion; NSAID, nonsteroidal anti-inflammatory drug. Reproduced from
Palmer (A Physiologic-Based Approach to the Evaluation of a Patient With Hyperkalemia AJKD 2010;56:387-393) with permission
of the National Kidney Foundation.
Figure 7. Pathogenesis, classification, and clinical presentation of renal tubular acidosis (RTA). The pathogenesis and contrasting
features of proximal RTA (type II), distal RTA (type I), and hyperkalemic RTA (type IV) are depicted.
aldosterone levels are helpful in establishing the Batlle DC, Arruda JA, Kurtzman NA. Hyperkalemic distal
diagnosis of hypoaldosteronism, with or without renal tubular acidosis associated with obstructive uropathy. N
Engl J Med. 1981;304:373-380.
hyporeninism. Urinary obstruction should always be Batlle DC, Itsarayoungyen K, Arruda JA. Hyperkalemic
considered when other more common causes have hyperchloremic metabolic acidosis in sickle cell hemoglo-
been ruled out. Figure 7 summarizes the distinctive binopathies. Am J Med. 1982;72:188-192.
features of pRTA (type II), dRTA (type I), and DuBose TD Jr. Molecular and pathophysiologic mechanisms
hyperkalemic RTA (type IV) with respect to their of hyperkalemic metabolic acidosis. Trans Am Clin Climatol
Assoc. 2000;111:122-133, discussion 133-124.
pathogenesis and emphasis on the contrasting pres- Furgeson SB, Linas S. Mechanisms of type I and type II
ence of nephrocalcinosis and generation of kidney pseudohypoaldosteronism. J Am Soc Nephrol. 2010;21:
stones, urine citrate, and NH41 excretion. 1842-1845.
Karet FE. Mechanisms in hyperkalemic renal tubular
acidosis. J Am Soc Nephrol. 2009;20:251-254.
Treatment of Hyperkalemic RTA Kutyrina IM, Nikishova TA, Tareyeva IE. Effects of heparin-
The goal of the treatment initially is to normalize induced aldosterone deciency on renal function in patients
serum K1 concentration because this may improve with chronic glomerulonephritis. Nephrol Dial Transplant.
1087;2:219-223.
metabolic acidosis by increasing urinary NH3 Perazella MA, Rastegar A. Disorders of potassium and
responsible for buffering secreted H1, as well as by acid-base metabolism in association with renal disease.
enhancing HCO3- generation in the proximal tubule In: Schrier RW, Coffman TM, Falk RJ, Molitoris BA, Niel-
by enhanced glutamine metabolism (Fig 3). If this is son EJ, eds. Schrier Diseases of the Kidney.
Philadelphia, PA: Lippincott Williams & Wilkens &
inadequate, attempts should be made to improve
Wolters Kluwer; 2013:2082-2116.
metabolic acidosis. Box 3 discusses long-term Sastrasinh S, Tannen RL. Effect of potassium on renal NH3
treatment of hyperkalemia in patients with hyper- production. Am J Physiol. 1983;244:F383-F391.
kalemic RTA.
Box 3. Long-term Treatment of Hyperkalemia in Patients With
Additional Readings Hyperkalemic Renal Tubular Acidosis
Arruda JA, Batlle DC, Sehy JT, Roseman MK, 1. Discontinue all drugs affecting potassium
Baronowski RL, Kurtzman NA. Hyperkalemia and renal 2. Restrict dietary potassium
insufciency: role of selective aldosterone deciency and 3. Control hyperglycemia
tubular unresponsiveness to aldosterone. Am J Nephrol. 4. Treat metabolic acidosis
1981;1:160-167. 5. Treat volume depletion
Batlle DC. Hyperkalemic hyperchloremic metabolic 6. Use loop diuretics
acidosis associated with selective aldosterone deciency 7. Mineralocorticoids
and distal renal tubular acidosis. Semin Nephrol. 1981;1: 8. Kayexalate
260-273.
Schambelan M, Sebastian A, Biglieri EG. Prevalence, path- Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal
ogenesis, and functional signicance of aldosterone de- mechanism of trimethoprim induced hyperkalemia. Ann
ciency in hyperkalemic patients with chronic renal Intern Med. 1993;119:296-301.
insufciency. Kidney Int. 1980;17:89-101.
Sebastian A, Schambelan M, Lindenfeld S. Amelioration of
metabolic acidosis with udrocortisone therapy in hypo-
ACKNOWLEDGEMENTS
reninemic hypoaldosteronism. N Engl J Med. 1977;197: Support: None.
576-583. Financial Disclosure: The authors declare that they have no
Tannen RL. Relationship of renal ammonia production relevant nancial interests.
and potassium homeostasis. Kidney Int. 1977;11:453- Peer Review: Evaluated by 3 external reviewers, the Education
465. Editor, and the Editor-in-Chief.