in
Brief
Renal Tubular Acidosis
Jonathan Pelletier, MD,* Rasheed Gbadegesin, MD, MBBS,† Betty Staples, MD*
*Department of Pediatrics and †Department of Pediatric Nephrology, Duke Children’s Hospital
and Health Center, Durham, NC
AUTHOR DISCLOSURE Drs Pelletier,
Gbadegesin, and Staples have disclosed no
financial relationships relevant to this article.
This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.
Clinical Approach to Renal Tubular Acidosis
in Adult Patients. Reddy P. Int J Clin Pract.
2011;65(3):350–360
Genetic Causes and Mechanisms of Distal
Renal Tubular Acidosis. Batlle D, Haque SK.
Nephrol Dial Transplant. 2012;27
(10):3691–3704
Mechanisms in Hyperkalemic Renal Tubular
Acidosis. Karet FE. J Am Soc Nephrol. 2009;20
(2):251–254
Proximal Renal Tubular Acidosis: A Not So
Rare Disorder of Multiple Etiologies. Haque
SK, Ariceta G, Batlle D. Nephrol Dial Transplant.
2012;27(12):4273–4287
Renal Tubular Acidosis. Gbadegesin R,
Foreman W. In: Chand DH, Valentini RP, eds.
Clinician’s Manual of Pediatric Nephrology. 1st
ed. Singapore: World Scientific Publishing Co;
2011
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The body temporarily buffers hydrogen ions (Hþ) with plasma proteins, hemo-
globin, and bicarbonate (HCO" 3 ), but H must be excreted to prevent acidosis.
þ
The major functions of the kidneys in acid-base homeostasis are to excrete Hþ and
reabsorb HCO" 3 . Failure to perform these functions results in HCO3 wasting,
"
leading to renal tubular acidosis (RTA), which is categorized into 3 major groups:
distal (type I), proximal (type II), and hyperkalemic (type IV) RTA.
DISTAL RTA (TYPE I)
Excretion of Hþ to balance acid production is primarily the function of the distal
convoluted tubule and collecting duct (DCT/CD), where a-intercalated cells
actively transport Hþ into the tubule. Secreted Hþ combines with ammonia to
form ammonium in the DCT/CD lumen. Because of its positive charge,
ammonium cannot diffuse out of the tubular lumen, and it is passed in the
urine.
In distal RTA, a-intercalated cells cannot secrete sufficient Hþ into the tubular
lumen, resulting in decreased urinary ammonium excretion. Patients present
with normal anion gap metabolic acidosis and inappropriately alkaline urine pH.
The urine anion gap (UAG) is a surrogate marker for ammonium production:
UAG ¼ ½urine  Naþ % þ ½urine  Kþ % " ½urine  Cl" %
Under acidic conditions, healthy patients will have large amounts of urine
ammonium chloride production and a negative UAG. Patients with distal RTA
will have an inappropriately positive UAG because of decreased ammonium
chloride excretion. In addition, these patients have low urine (citrate) and high
urine (calcium), leading to nephrocalcinosis.
Causes of distal RTA include medications, infections, and congenital
malformations. Typical drugs include amphotericin, ifosfamide, lithium,
and toluene. The approach to evaluation for distal RTA is shown in the
Figure. Bicarbonate therapy, typically with combination NaHCO3 and
KHCO 3 salts, in doses of 1 to 3 mEq/kg per day of HCO" 3 , is the mainstay
of treatment.
PROXIMAL RTA (TYPE II)
Bicarbonate is filtered by the glomerulus and reabsorbed in the proximal
convoluted tubule (PCT) through a series of reactions catalyzed by carbonic
anhydrase.
Patients with proximal RTA have a reduced HCO" 3 threshold, or a maximum
amount of HCO" 3 that can be reabsorbed by the PCT. When the plasma HCO3
"
Vol. 38 No. 11 NOVEMBER 2017 537
 Figure. Algorithm for the clinical evaluation of non–anion gap metabolic acidosis.
RTA¼renal tubular acidosis. (Modified with permission from Gbadegesin R, Foreman W. Renal tubular acidosis. In: Chand DH, Valentini RP, eds. Clinician’s
Manual of Pediatric Nephrology. 1st ed. Singapore: World Scientific Publishing Co; 2011.)

level exceeds the threshold, the excess HCO" 3 is ex-
creted in the urine until the plasma level falls to the point
that reabsorption equals filtration. At that point, bicarbonaturia
ceases. Thus, these patients present with non–anion gap
metabolic acidosis from inappropriate HCO " 3 wasting.
However, because distal tubular function and urinary
acidification remains intact, they have appropriately
acidic urine. When challenged with HCO" 3 supplemen-
tation, the filtered HCO " 3 threshold value is exceeded,
causing alkaline urine and elevated fractional excretion
of HCO " 3.
Patients most commonly present with other signs of PCT
dysfunction, termed Fanconi syndrome. Common causes
include carbonic anhydrase inhibitor therapy, ifosfamide,
platinum-based chemotherapies, topiramate, and amino-
glycoside therapy. Genetic mutations in carbonic anhy-
drase are a rare cause. Cystinosis is an important genetic
cause of Fanconi syndrome. The clinical approach to a
patient with suspected proximal RTA is shown in the
Figure. Bicarbonate supplementation is the principal com-
ponent of therapy; typical doses are 10 to 30 mEq/kg per
day of HCO" 3.
HYPERKALEMIC RTA (TYPE IV)
Aldosterone has several effects on renal acid-base handling.
Aldosterone acts on the principal cells of the DCT/CD to
increase Naþ reabsorption with reciprocal Hþ and potassium

538 Pediatrics in Review

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ion inflow into the tubule and passage into the urine.
Aldosterone also has direct stimulatory effects on
a-intercalated cells, causing them to increase Hþ secretion.
Patients with hyperkalemic RTA have a primary defect in
aldosterone production or aldosterone receptor sensitivity.
Clinically, they present with normal anion gap metabolic
acidosis and hyperkalemia. Common etiologies include
therapy with angiotensin-converting enzyme inhibitors,
potassium-sparing diuretics, trimethoprim-sulfamethoxazole
therapy, and immunosuppressive medications. Other
causes include adrenal insufficiency, sickle cell nephrop-
athy, and obstructive uropathy. Pseudohypoaldosteronism
type I and Gordon syndrome are rare genetic causes.
Evaluation for hyperkalemic RTA is shown in the
Figure.
Therapy for hyperkalemic RTA depends on the under-
lying etiology. Cessation of the offending drug may be
COMMENTS: This In Brief provides a clear overview of the
pathophysiology and differential causes of RTA. I have
encountered this as an important diagnosis when evaluating
infants with failure to thrive. Genetic testing has revealed
more gene mutations, but understanding the different types
may lead to a better understanding of genetic versus acquired
types of RTA and facilitate treatment.
–Janet R. Serwint, MD
Associate Editor, In Brief
Summary
Renal tubular acidosis arises from the failure of the kidney to reabsorb
filtered HCO" 3 (proximal RTA), from the inability to excrete sufficient H
þ
to balance net endogenous acid production (distal RTA), or from
disruption of the renin-angiotensin-aldosterone axis (hyperkalemic RTA).
Normal anion gap metabolic acidosis is the hallmark clinical
characteristic, with adjunct tests such as the fractional excretion of HCO"
3

sufficient. Relief of obstruction and adequate hydration
with normal saline is the cornerstone of treatment in
obstructive uropathy. Patients with primary hypoaldostero-
nism are given mineralocorticoid replacement. In some
cases, loop diuretics or cation exchange resins may be
used.
and UAG clarifying the etiology. Correction of acidosis is accomplished
with HCO" 3 supplementation in proximal and distal RTA. Therapy for
hyperkalemic RTA depends on etiology. The prognosis is good, as
normalization of pH typically prevents the development of sequelae
such as growth failure, nephrocalcinosis, and chronic kidney disease.

ANSWER KEY FOR NOVEMBER 2017 PEDIATRICS IN REVIEW:

Jaundice: Newborn to Age 2 Months: 1. C; 2. B; 3. A; 4. C; 5. A.
Hand and Foot Color Change: Diagnosis and Management: 1. A; 2. E; 3. C; 4. C; 5. E.
Recognition of Impending Systemic Failure: 1. C; 2. B; 3. D; 4. A; 5. E.

Vol. 38 No. 11 NOVEMBER 2017 539

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 Renal Tubular Acidosis
Jonathan Pelletier, Rasheed Gbadegesin and Betty Staples
Pediatrics in Review 2017;38;537
DOI: 10.1542/pir.2016-0231

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 Renal Tubular Acidosis
Jonathan Pelletier, Rasheed Gbadegesin and Betty Staples
Pediatrics in Review 2017;38;537
DOI: 10.1542/pir.2016-0231

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/38/11/537

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