Acidosis Tubular Renal

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Etiología y diagnóstico de la acidosis tubular renal

distal (tipo 1) y proximal (tipo 2)
Autores: Dr. Michael Emmett, Biff F. Palmer, MD
Redactor de sección: Dr. Richard H. Sterns
Redactor adjunto: John P. Forman, MD, MSc
Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de
revisión por pares .
Revisión de la literatura actual hasta: agosto de 2022. | Última actualización de este tema: 08 de
septiembre de 2021.
INTRODUCCIÓN
La acidosis tubular renal (ATR) distal (tipo 1) y proximal (tipo 2) son trastornos poco comunes,
particularmente en adultos. La RTA proximal se caracteriza por una reducción en la
capacidad de reabsorción de bicarbonato proximal que conduce a la pérdida de bicarbonato
en la orina hasta que la concentración sérica de bicarbonato ha caído a un nivel lo
suficientemente bajo como para permitir que se reabsorba todo el bicarbonato filtrado. En
comparación, el defecto principal en la RTA distal es la acidificación distal alterada. Estos
diferentes mecanismos patogénicos dan como resultado diferentes manifestaciones clínicas,
pero un cierto grado de hipopotasemia está comúnmente presente con la mayoría de las
formas de ATR distal y proximal ( tabla 1 ).
La etiología y el diagnóstico de la RTA distal y proximal se revisarán aquí. La patogenia de las

diferentes formas de RTA, el tratamiento de estos trastornos, el impacto que tienen en el
equilibrio de potasio y una descripción general de la RTA se analizan por separado:
● (Consulte "Resumen y fisiopatología de la acidosis tubular renal y el efecto sobre el

equilibrio de potasio" .)
● (Consulte "Tratamiento de la acidosis tubular renal distal (tipo 1) y proximal (tipo 2)" .)
Las formas hiperpotasémicas de RTA incluyen la RTA tipo 4, que es otra forma de RTA en la
que el problema principal es la disminución de la secreción de aldosterona, la resistencia a la
aldosterona o un defecto de voltaje. Estos pacientes suelen tener una acidosis metabólica
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leve (concentración de bicarbonato sérico superior a 17 mEq/L) y la principal manifestación

es la hiperpotasemia. (Consulte "Etiología, diagnóstico y tratamiento del hipoaldosteronismo
(ATR tipo 4)" .)
Aunque inicialmente se usó para describir una forma transitoriamente grave de ATR distal
en lactantes, el término "ATR mixta (tipo 3)" se aplica con mayor frecuencia a un síndrome
autosómico recesivo raro (resultado de la deficiencia de anhidrasa carbónica II) con
características de afección tanto proximal como distal. RTA [ 1,2 ]. Además de RTA, los
pacientes afectados sufren de osteopetrosis, calcificación cerebral y discapacidad intelectual.
(Consulte "Etiología y manifestaciones clínicas de la acidosis tubular renal en bebés y niños",
sección "ATR mixta (tipo 3)" .)
ETIOLOGÍA
Las diferentes formas de acidosis tubular renal (ATR), que conducen a una acidosis
metabólica hiperclorémica (desequilibrio aniónico normal), pueden ser causadas por una
amplia variedad de trastornos, la mayoría de los cuales son raros [ 3 ]. Las causas más
frecuentes varían según el tipo de RTA.
RTA distal (tipo 1) : las principales causas de RTA distal de nueva aparición en adultos son
enfermedades autoinmunes (p. ej., síndrome de Sjögren y artritis reumatoide) e
hipercalciuria (que es el defecto principal en algunas familias) ( tabla 2 ) [ 1,3 -8 ]. La RTA
distal puede ser la manifestación de presentación de enfermedades autoinmunes como el
síndrome de Sjögren. Por lo tanto, los adultos con RTA distal aparentemente idiopática
deben ser evaluados para el síndrome de Sjögren. (Consulte "Enfermedad renal en el
síndrome de Sjögren primario" y "Diagnóstico y clasificación del síndrome de Sjögren" .)
En comparación, la RTA distal hereditaria es más común en niños. Las mutaciones genéticas
en el intercambiador de cloruro-bicarbonato basolateral ( gen SLC4A1 ) y en la hidrógeno-
ATPasa apical ( genes ATP6V0A4 y ATP6V1B1 ) se han identificado como causas principales de
RTA distal hereditaria. Las mutaciones en otros genes, incluidos ATP6V1C2 y el factor de
transcripción forkhead FOXI1 , pueden ser responsables de otros casos [ 9,10 ]. Las
mutaciones en los genes ATP6V0A4 y ATP6V1B1 conducen a la RTA distal autosómica recesiva
y, a menudo, se acompañan de deficiencia auditiva neurosensorial [ 11 ]. Mutaciones en el
SLC4A1 (AE1)El gen puede causar RTA distal y se hereda más comúnmente de forma
autosómica dominante. Estos pacientes no presentan defectos auditivos. También se ha
descrito una mutación autosómica recesiva en AE1 , que se acompaña de anemia hemolítica.
Los mecanismos por los cuales las mutaciones en estos genes producen RTA distal se
analizan por separado. (Consulte "Resumen y fisiopatología de la acidosis tubular renal y el
efecto sobre el equilibrio de potasio" .)

Ifosfamide, a chemotherapeutic agent that is an analog of cyclophosphamide, is a cause of

both distal and proximal RTA in children and adults. Other drugs have also been implicated,
and there are multiple case reports of distal, and less commonly proximal, RTA as a
complication of ibuprofen alone or in combination with codeine [12-14]. (See "Ifosfamide
nephrotoxicity", section on 'Clinical manifestations'.)
Toluene inhalation due to glue sniffing had been considered a relatively common cause of
distal RTA in recreational drug abusers. However, metabolism of toluene to benzoic and
hippuric acid is a more important cause of the acidosis than RTA in this disorder. Affected
patients usually present with a normal anion gap because the hippurate is both filtered and
secreted into the tubular lumen and then rapidly excreted in the urine with sodium,
potassium, or ammonium [15]. (See "The delta anion gap/delta HCO3 ratio in patients with a
high anion gap metabolic acidosis", section on 'D-lactic acidosis and toluene inhalation' and
"Urine anion and osmolal gaps in metabolic acidosis".)
Proximal (type 2) RTA — Proximal RTA occurs rarely as an isolated defect of proximal

bicarbonate reabsorption and more commonly in association with other defects in proximal
tubular function that impair reabsorption of other solutes such as phosphate, glucose, uric
acid, and amino acids. Such patients can present with hypophosphatemia, renal glucosuria
(glucosuria with a normal serum glucose concentration), hypouricemia, and/or
aminoaciduria. Generalized proximal tubule dysfunction is called the Fanconi syndrome
( table 3).
A major cause of proximal RTA in adults is proximal tubular toxicity related to increased
excretion of monoclonal immunoglobulin light chains due to monoclonal gammopathies
that are otherwise latent [16]. The light chains that produce renal tubule toxicity appear to
have unique biochemical characteristics such as a variable domain that is resistant to
degradation by lysosomal proteases in the proximal tubular cells [17,18]. Accumulation of
the variable domain fragments is presumably responsible for the impairment in tubular
function. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies:
Etiology and evaluation", section on 'Light chain proximal tubulopathy'.)
Proximal RTA in adults may also result from carbonic anhydrase inhibitors such as
acetazolamide and topiramate, which impair proximal bicarbonate reabsorption without
affecting the reabsorption of other proximal tubule solutes [19]. However, inhibition of
carbonic anhydrase usually also impairs distal tubule acidification. Nephrotoxic drugs, such
as tenofovir and ifosfamide, and inflammatory disorders, such as Sjögren's syndrome, can
produce a Fanconi syndrome ( table 3) [20-22]. (See "Ifosfamide nephrotoxicity", section
on 'Clinical manifestations'.)
In children, idiopathic RTA, ifosfamide therapy, and cystinosis are the most common causes
of proximal RTA [23-26]. Although most children present with Fanconi syndrome, some have
isolated proximal RTA. (See "Etiology and clinical manifestations of renal tubular acidosis in
infants and children" and "Ifosfamide nephrotoxicity" and "Cystinosis".)
Isolated proximal RTA can be due to inherited defects in the genes that direct synthesis of
the transmembrane transporters responsible for proximal acidification. Mutations in the
gene (SLC4A4) that directs the synthesis of NBCe1, the basolateral sodium bicarbonate
transporter, result in autosomal recessive proximal RTA with short stature and ocular
abnormalities [27-31].
In addition, some families have a pure proximal RTA transmitted as an autosomal dominant
trait. The molecular basis for this form of familial proximal RTA is unclear, and it is not due to
a defect in genes that are known to be involved in proximal bicarbonate reabsorption [32].
One possibility is a mutation in the basolateral, inwardly rectifying potassium subchannel
called Kir4.2, encoded by KCNJ15. Dysfunction of this potassium channel leads to
depolarization of the proximal tubular cell (ie, a decrease in electronegativity of the cell). This
change results in less bicarbonate exit coupled to sodium ions via NBCe1 since this co-
transporter caries a net negative charge and is driven by intracellular electronegativity. The
net effect is increased cell pH and downregulation of proteins involved in ammoniagenesis,
resulting in features of a proximal RTA in the absence of generalized tubular dysfunction
[33]. (See "Overview and pathophysiology of renal tubular acidosis and the effect on
potassium balance", section on 'Proximal (type 2) RTA'.)
DIAGNOSIS
The presence of distal or proximal renal tubular acidosis (RTA) should be considered in any
patient with an otherwise unexplained normal anion gap (hyperchloremic) metabolic
acidosis [3]. Metabolic compensation for respiratory alkalosis produces an electrolyte
pattern that is identical to that seen in a normal anion gap metabolic acidosis. Thus, the first
step in the diagnosis of a patient with a reduced serum bicarbonate and elevated chloride
concentration is to confirm that metabolic acidosis is present by measuring the blood pH.
(See "Approach to the adult with metabolic acidosis", section on 'Physiologic interpretation of
the serum anion gap'.)
When a normal anion gap acidosis is confirmed, a variety of disorders other than RTA must
be considered ( table 4). These include the loss of bicarbonate and/or "potential"
bicarbonate (eg, lactate, acetate or butyrate, which can be metabolized to bicarbonate) in
the stool due to diarrhea due to a malfunctioning urinary bladder reconstruction or
diversion, due to recovery from ketoacidosis, or due to toluene inhalation (usually from
spray paint or glue sniffing, which may be denied by the patient). (See "The delta anion
gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'D-
lactic acidosis and toluene inhalation'.)
Thus, the next steps in the diagnosis of possible RTA in patients who have a normal anion
gap metabolic acidosis are measurement of the urine pH and measurement or estimation of
urinary ammonium excretion. (See 'Urine pH' below and 'Urine ammonium excretion' below.)
Urine pH — Patients with normal kidney function and normal renal acidification
mechanisms who develop metabolic acidosis usually have a urine pH of 5.3 or less. An
exception to this general rule can occur in patients with chronic metabolic acidosis who also
have hypokalemia, as may be seen with diarrhea [34,35]. In such patients, potassium moves
out of the cells, and electroneutrality is maintained by the entry of hydrogen and sodium
into the cells. In the kidney, the resulting intracellular acidosis stimulates both hydrogen
secretion and ammonia production [36,37]. Ammonia (NH3) in the tubular lumen combines
with hydrogen ions to form ammonium (NH4+). The reduction in the free hydrogen ion
concentration elevates the urine pH. Depending upon the chronicity of the acidosis and the
degree of hypokalemia, the urine pH may be 5.5 or higher, incorrectly suggesting a
diagnosis of distal RTA. The urine pH is also generally higher than 5.5 in patients with a
normal anion gap due to toluene inhalation in whom urinary ammonium excretion is also
increased. (See "Hypokalemia-induced kidney dysfunction", section on 'Increased ammonia
production'.)
In most cases of distal RTA, the urine pH is persistently 5.5 or higher, reflecting the primary
defect in distal acidification, and a urine pH below 5.5 generally excludes distal (but not
proximal) RTA. However, the urine pH can be reduced below 5.5 in occasional patients (2 of
17 in one study) with distal RTA [38-41]. A possible mechanism is that the rate of hydrogen
ion secretion is impaired more than the ability to lower the urine pH. This disorder has been
called "rate-dependent" RTA [41] and may be more common in children [40]. The
pathogenesis of the different types of distal RTA is discussed separately. (See "Overview and
pathophysiology of renal tubular acidosis and the effect on potassium balance", section on
'Distal (type 1) RTA'.)
In contrast to the persistently elevated urine pH in distal RTA, the urine pH is variable in
proximal RTA, a disorder characterized by diminished proximal bicarbonate reabsorption.
The urine pH will be inappropriately elevated if patients with proximal RTA are treated with
alkali, increasing the serum bicarbonate concentration enough to produce a filtered
bicarbonate load that exceeds the reduced proximal reabsorptive capacity; this most
commonly occurs when alkali is given for the diagnosis or treatment of this disorder. By
contrast, once the serum bicarbonate concentration has fallen sufficiently so that all of the
filtered bicarbonate can be reabsorbed, the distal nephron functions normally and can
reduce the urine pH to 5.3 or less. Such untreated patients have metabolic acidosis but are
able to excrete the daily acid load and are in acid-base balance.

In patients presenting with a normal anion gap metabolic acidosis, several scenarios can
produce a misleading elevation in the urine pH that incorrectly suggests the presence of
RTA:
● Chronic metabolic acidosis, usually accompanied by hypokalemia, can markedly

increase renal ammonium excretion and thereby raise the urine pH above 5.5.
● Urinary tract infections with urea-splitting organisms may increase the urine pH
because urea is converted to ammonia and bicarbonate. Thus, assessment of the urine
pH should include a urinalysis and, if indicated, a urine culture.
● Severe volume depletion (which indirectly and reversibly limits hydrogen ion secretion
by reducing distal sodium delivery) can impair urine acidification [34,42]. Thus, reliable
interpretation of an inappropriately high urine pH requires that the urine sodium
concentration be greater than 25 mEq/L.
Urine ammonium excretion — A urine pH of 5.5 or higher in patients with a normal anion
gap acidosis is characteristic of distal RTA. However, as mentioned in the preceding section,
it can also occur in patients with intact distal acidification who have a normal anion gap
metabolic acidosis, hypokalemia, and increased urinary ammonium excretion as a result of
disorders such as diarrhea and toluene inhalation (glue sniffing). By contrast, urine
ammonium excretion is reduced in distal RTA (see 'Urine pH' above). Thus, either direct
measurement or indirect estimation of the urine ammonium concentration can be helpful in
establishing the correct diagnosis.
Urinary ammonium concentration cannot be directly measured in most clinical laboratories.

However, an indirect estimate of urine ammonium concentration can be obtained by
calculating the urine anion gap and/or the urine osmolal gap (calculator 1 and calculator 2
and calculator 3). These calculations are discussed in detail elsewhere. (See "Urine anion and
osmolal gaps in metabolic acidosis".)
Estimation of ammonium excretion is not useful in patients with proximal RTA. As

mentioned in the preceding section, untreated patients are in acid-base balance at a lower-
than-normal serum bicarbonate concentration since bicarbonate wasting has ceased. They
will excrete "normal" quantities of ammonium. Patients treated with alkali will have a urine
pH of 5.5 or higher due to bicarbonate wasting.
Distal versus proximal RTA — Once a diagnosis of RTA has been established, distal and
proximal RTA must be distinguished from one another:
● In distal RTA, there is an inability to excrete the daily acid load. In the absence of alkali
therapy, this results in progressive hydrogen ion retention. The serum bicarbonate
concentration usually stabilizes at a level greater than 10 mEq/L. To make a diagnosis
of distal RTA, the urine pH should be persistently 5.5 or higher, the urine sodium
concentration should be above 25 mEq/L (since lower levels can impair distal
acidification in the absence of RTA), and the urine ammonium excretion should be
reduced. The urine ammonium concentration can be estimated by calculating a urine
anion gap or urine osmolal gap. Because the urine anion gap may be misleading in
certain situations (hypovolemia, high urinary excretion of unmeasured anions such as
hippurate or ketoacid anions), the urine osmolal gap generally provides a better
estimate of urinary ammonium excretion. (See "Urine anion and osmolal gaps in
metabolic acidosis", section on 'Limitations of the UAG'.)
● Proximal RTA is caused by a reduced capacity to reclaim filtered bicarbonate in the

proximal tubule. Consequently, bicarbonate wasting occurs when the serum
bicarbonate concentration is raised above the diminished bicarbonate reabsorptive
threshold. The more distal renal tubule segments have substantial bicarbonate
reabsorptive capacity but cannot replace the function of the proximal tubule. The
serum bicarbonate concentration in untreated patients with proximal RTA is usually
between 12 and 20 mEq/L. When the serum bicarbonate is low, most of the filtered
bicarbonate can be reabsorbed and distal acidification then proceeds normally. The
urine pH will then be appropriate for the patient's diet. After an acid load, the urine pH
can be normally reduced to 5.3 or less. (See 'Proximal (type 2) RTA' above.)
Proximal RTA can occur as an isolated defect in bicarbonate reabsorption or in

association with other defects in proximal tubular function, such as impaired
reabsorption of phosphate, glucose, uric acid, and/or amino acids (called the Fanconi
syndrome). Such patients can present with hypophosphatemia, renal glucosuria
(glucosuria with a normal serum glucose concentration), hypouricemia, and/or
aminoaciduria. These features are not found in distal RTA. (See "Etiology and clinical
manifestations of renal tubular acidosis in infants and children", section on 'Fanconi
syndrome'.)
The diagnosis of proximal RTA can be established by raising the serum bicarbonate
concentration toward normal (18 to 20 mEq/L) with an intravenous infusion of sodium
bicarbonate at a rate of 0.5 to 1 mEq/kg per hour [3]. The urine pH, even if initially acid,
will rise rapidly once the reabsorptive threshold for bicarbonate (which is abnormally
diminished) is exceeded. As a result, the urine pH will increase above 7.5 and the
fractional excretion of bicarbonate (FEHCO3) will exceed 15 to 20 percent. The latter can
be determined from simultaneous urine and serum specimens using a formula similar
to that for the fractional excretion of sodium, where U and S refer to the urine and
serum concentrations of bicarbonate (HCO3) and creatinine (Cr) (calculator 4 and
calculator 5):

UHCO3 x SCr
FEHCO3 = ————————— x 100
SHCO3 x UCr
By contrast, raising the serum bicarbonate concentration to 18 to 20 mEq/L in patients with

distal RTA has little effect on bicarbonate excretion since there is no defect in proximal
reabsorptive capacity. As a result, the urine pH will remain stable (though elevated) and the
fractional excretion of bicarbonate will remain less than 3 percent.
Incomplete distal RTA — The term "incomplete distal RTA" refers to a disorder in which
impaired urinary acidification and an inability to reduce the urine pH to 5.3 or below with an
acid load exists, but net acid excretion is maintained at a rate equal to acid generation. This
is achieved by an increase in ammonium excretion that offsets the reduction in titratable
acid excretion caused by the high urine pH. Thus, patients with this disorder are able to
maintain a normal serum bicarbonate concentration [3,43]. Some patients with incomplete
distal RTA progress to overt distal RTA, and some have a family history of RTA. (See "Overview
and pathophysiology of renal tubular acidosis and the effect on potassium balance", section
on 'Incomplete distal RTA'.)
Patients with incomplete distal RTA have reduced urine citrate levels and may present with
or develop calcium stone disease, typically calcium phosphate stones [44,45]. Urine citrate
excretion is increased, and the frequency of stone formation is decreased, by correcting the
metabolic acidosis with exogenous bicarbonate or bicarbonate precursor salts such as
potassium citrate or potassium bicarbonate [46].
Patients with distal RTA are often hypercalciuric and may develop otherwise unexplained
osteoporosis [47,48], although not all studies support this conclusion [49]. (See
"Nephrolithiasis in renal tubular acidosis", section on 'Treatment' and "Kidney stones in
adults: Prevention of recurrent kidney stones", section on 'Low urine citrate'.)
Patients with recurrent calcium stones (particularly calcium phosphate stones), a normal
serum bicarbonate concentration, and a urine pH that is persistently 5.5 or higher should be
evaluated for incomplete distal RTA. The diagnosis should also be considered in patients with
a family history of distal RTA and perhaps in those with unexplained osteoporosis. This
evaluation typically includes measurement of urinary citrate excretion, which is reduced in
this condition [50]. However, a fasting morning urine pH <5.3 and a serum potassium >3.8
excludes nearly all patients with incomplete distal RTA (negative predictive value of 98
percent) [45].
The gold standard for the diagnosis of incomplete RTA is an ammonium chloride
acidification test, although this is not commonly performed. The ammonium chloride
acidification test is usually done with a single oral dose of ammonium chloride (0.1 g/kg)

[3,43,48]. Serum bicarbonate concentration and urine pH are measured several times over
the subsequent six hours, ideally at two, four, and six hours [48]. The urine pH must be
measured with a pH meter. Collection of the urine under mineral oil is not necessary [51,52].
The serum bicarbonate concentration should fall by more than 3 mEq/L. Failure of the urine
pH to fall to 5.3 or less is consistent with incomplete distal RTA.
Some patients with suspected incomplete RTA cannot tolerate the ammonium chloride
because of gastric irritation, nausea, and vomiting, which occur commonly. An alternative
acidification test employs the simultaneous oral administration of furosemide (40 mg) and
fludrocortisone (1 mg), followed by hourly urine collections for eight hours. Normal subjects
can reduce their urine pH below 5.3, and patients with distal RTA cannot [45,53].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Fluid and electrolyte
disorders in adults".)
SUMMARY AND RECOMMENDATIONS
● Distal (type 1) and proximal (type 2) renal tubular acidosis (RTA) are uncommon
disorders. Proximal RTA is characterized by a reduction in proximal bicarbonate
reabsorptive capacity that leads to bicarbonate wasting in the urine. Distal RTA is
characterized by impaired distal acidification. Hypokalemia is commonly present in
both. (See 'Introduction' above.)
● Causes of distal RTA in adults include autoimmune diseases (eg, Sjögren's syndrome
and rheumatoid arthritis) and hypercalciuria ( table 2). Hereditary distal RTA is more
commonly diagnosed in children. Drugs such as ifosfamide and amphotericin cause
distal RTA in adults and children. (See 'Distal (type 1) RTA' above.)
● Causes of proximal RTA in adults include light chain-induced proximal tubular toxicity in
multiple myeloma and other monoclonal gammopathies, and carbonic anhydrase
inhibitors such as acetazolamide or topiramate ( table 3). Causes of proximal RTA in
children include inherited mutations (eg, cystinosis) and ifosfamide therapy. (See
'Proximal (type 2) RTA' above.)
● The diagnosis of RTA requires measurement of the urine pH and estimation of urinary
ammonium excretion. The urine pH is persistently 5.5 or higher in patients with distal
RTA. The urine pH is variable in proximal RTA: it will be elevated if the filtered
bicarbonate load exceeds the reduced proximal reabsorptive capacity, which is most
often due to alkali therapy, and it will be appropriately 5.3 or less if the filtered
bicarbonate load is reduced and can be completely reabsorbed, which most often
occurs in untreated patients. (See 'Urine pH' above.)
● Urinary ammonium excretion may distinguish patients with distal RTA from those who
have a normal anion gap metabolic acidosis and hypokalemia resulting from other
causes (such as diarrhea or toluene inhalation). Although urinary ammonium excretion
cannot be directly measured in most clinical laboratories, an estimate can be obtained
by determination of the urine anion gap and/or urine osmolal gap. (See 'Urine
ammonium excretion' above.)
● Distal and proximal RTA may be distinguished from one another by demonstrating
changes in the urine pH in response to changes in the serum bicarbonate
concentration (see 'Distal versus proximal RTA' above):
• To make a diagnosis of distal RTA, the urine pH should be 5.5 or higher regardless of
the serum bicarbonate concentration, the urine sodium concentration should be
above 25 mEq/L (since lower levels can impair distal acidification in the absence of
RTA), and the urine anion gap and urine osmolal gap should be consistent with a
low urine ammonium concentration.
• In proximal RTA, the urine pH may be 5.3 or less if the filtered bicarbonate load
(which is directly related to the serum bicarbonate concentration) is below the
bicarbonate reabsorptive threshold, which most often occurs in untreated patients.
The diagnosis of proximal RTA can be established by raising the serum bicarbonate
concentration toward normal (18 to 20 mEq/L) with an intravenous infusion of
sodium bicarbonate at a rate of 0.5 to 1 mEq/kg per hour. The urine pH, even if
initially acid, will rise rapidly once the reabsorptive threshold for bicarbonate is
exceeded, resulting in a urine pH above 7.5 and a fractional excretion of bicarbonate
(FEHCO3) exceeding 15 to 20 percent.
● The term "incomplete distal RTA" refers to patients who have impaired urinary
acidification and an inability to reduce the urine pH to 5.3 or below but who are able to
maintain net acid excretion at a rate equal to acid generation and to maintain a normal
serum bicarbonate concentration via an increase in ammonium excretion. Such
patients may present with calcium stone disease or unexplained osteoporosis. (See
'Incomplete distal RTA' above.)
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cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal
tubular acidosis and bilateral glaucoma. J Am Soc Nephrol 2001; 12:713.
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unraveling the transporter's structure-functional properties. Front Physiol 2013; 4:350.

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Topic 2328 Version 28.0

GRAPHICS
Características de los diferentes tipos de acidosis tubular renal (ATR)
RTA hipopotasémica RTA hiperpota
ATR tipo 2
ATR tipo 1 (ATR RTA tipo 4
(ATR
distal) (hipoaldosteronismo
proximal)
Defecto primario Deterioro del Reabsorción Disminución de la

túbulo proximal de secreción de aldosterona
distal/acidificación HCO 3 o resistencia a la
del conducto reducida . aldosterona.
colector.
HCO 3 plasmático Variable. Usually 12 to Usually greater than 17

20 mEq/L. mEq/L.
May be below 10
mEq/L.
Urine pH Always >5.3. Variable. Variable.
Greater than Usually greater than 5.3.

5.3 during
periods of
bicarbonaturia
usually related
to therapeutic
increases in
serum
[HCO3].
Otherwise
<5.3.
Plasma potassium Usually reduced May be Increased.

and generally normal or
corrects with reduced;
alkali therapy. worsened by
bicarbonaturia
induced by
alkali therapy.
Urine anion gap (UAG)/urine UAG >20 mEq/L or Variable. UAG >20 mEq/L or UOG
osmolal gap (UOG) UOG <150 <150 mosm/kg.
mosm/kg. Consistent with low urine

Consistent with ammonium

low urine concentration.
ammonium
concentration.
Urine Ca/Cr ratio Increased Normal Normal
Nephrolithiasis/nephrocalcinosis Yes No No
HCO3: bicarbonate; Ca/Cr: calcium/creatinine.
Graphic 58428 Version 10.0

Major causes of type 1 (distal) renal tubular acidosis (RTA)
Primary
Idiopathic (sporadic)
Familial
Autosomal dominant (mainly due to mutations causing defects in the kidney anion exchanger
[kAE1] in distal tubule/collecting duct intercalated cells)
Autosomal recessive (due to a variety of mutations causing defects in one of the multiple
subunits of V-ATPase in distal tubule/collecting duct intercalated cells)
Secondary
Autoimmune disorders
Sjögren's syndrome
Autoimmune hepatitis/primary biliary cirrhosis
Systemic lupus erythematosus (also can generate hyperkalemic RTA)
Rheumatoid arthritis
Drugs
Ifosfamide (also can cause proximal RTA with Fanconi syndrome)
Amphotericin B
Lithium carbonate
Ibuprofen
Hypercalciuric conditions
Hyperparathyroidism
Vitamin D intoxication
Sarcoidosis
Idiopathic hypercalciuria
Other
Medullary sponge kidney
Obstructive uropathy
Kidney transplant rejection
Wilson disease

Major causes of type 2 (proximal) renal tubular acidosis with or without

the Fanconi syndrome
Primary
Idiopathic (sporadic)
Familial
Recessive
Proximal tubule cell sodium bicarbonate co-transporter (NBCe1) defect in SLC4A4
Carbonic anhydrase type 2 deficiency (usually causes mixed type 2 and type 1 or type
3)
Dominant, isolated HCO3 wasting
Cystinosis
Tyrosinemia
Hereditary fructose intolerance
Galactosemia
Glycogen storage disease (type I)
Wilson disease
Lowe syndrome
Acquired disorders
Drugs
Ifosfamide
Tenofovir and other antiretroviral drugs
Carbonic anhydrase inhibitors – Acetazolamide, topiramate
Aminoglycosides
Oxaliplatin/cisplatin
M-protein disorders
Amyloidosis
Multiple myeloma/light chain disease
Heavy metals
Lead
Cadmium
Mercury
Copper
Vitamin D deficiency or vitamin D resistance
Kidney transplantation

Paroxysmal nocturnal hemoglobinuria
Sjögren syndrome (more commonly causes distal RTA)
RTA: renal tubular acidosis; CNS: central nervous system; HCO3: bicarbonate.

Major causes of metabolic acidosis
Mechanism of acidosis Increased AG Normal AG
Increased acid production Lactic acidosis
Ketoacidosis
Diabetes mellitus
Starvation
Alcohol associated
Ingestions
Methanol
Ethylene glycol
Aspirin
Toluene (if early or if kidney Toluene ingestion (if late and if

function is impaired) kidney function is preserved;
due to excretion of sodium
and potassium hippurate in
the urine)
Diethylene glycol
Propylene glycol
D-lactic acidosis A component of non-AG

metabolic acidosis may coexist
due to urinary excretion of D-
lactate as Na and K salts
(which represents potential
HCO3)
Pyroglutamic acid (5-

oxoproline)
Pérdida de bicarbonato o Diarrea u otras pérdidas

precursores de bicarbonato intestinales (p. ej., drenaje por
sonda)
ATR tipo 2 (proximal)
Postratamiento de la
cetoacidosis
Inhibidores de la anhidrasa
carbónica
Derivación ureteral (p. ej., asa

ileal)
Disminución de la excreción Disfunción renal grave (TFGe Disfunción renal moderada

2
renal de ácido <15 a 20 ml/min/1,73 m ) (TFGe >15 a 20 ml/min/1,73 m
2
)
Tipo 1 (distal) RTA

(hipopotasémica)
RTA hiperpotasémica
RTA tipo 4
(hipoaldosteronismo)
defecto de voltaje
Infusión de gran volumen de Acidosis por difusión

solución salina normal
AG: brecha aniónica; RTA: acidosis tubular renal.
Gráfico 77464 Versión 14.0

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MD, MSc No relevant financial relationship(s) with ineligible companies to disclose.
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are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
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4/9/22, 18:48 Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis - UpToDate

Reimpresión oficial de UpToDate ®

Etiología y diagnóstico de la acidosis tubular renal

La etiología y el diagnóstico de la RTA distal y proximal se revisarán aquí. La patogenia de las

● (Consulte "Resumen y fisiopatología de la acidosis tubular renal y el efecto sobre el

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leve (concentración de bicarbonato sérico superior a 17 mEq/L) y la principal manifestación

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tub… 2/22

Ifosfamide, a chemotherapeutic agent that is an analog of cyclophosphamide, is a cause of

Proximal (type 2) RTA — Proximal RTA occurs rarely as an isolated defect of proximal

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tub… 5/22

● Chronic metabolic acidosis, usually accompanied by hypokalemia, can markedly

Urinary ammonium concentration cannot be directly measured in most clinical laboratories.

Estimation of ammonium excretion is not useful in patients with proximal RTA. As

● Proximal RTA is caused by a reduced capacity to reclaim filtered bicarbonate in the

Proximal RTA can occur as an isolated defect in bicarbonate reabsorption or in

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tub… 7/22

FEHCO3 = ————————— x 100

By contrast, raising the serum bicarbonate concentration to 18 to 20 mEq/L in patients with

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14. Chávez-Iñiguez JS, Espinosa-García F, Pacheco-Plascencia A, et al. The Case | Severe

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25. Stöhr W, Paulides M, Bielack S, et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma

26. Ho PT, Zimmerman K, Wexler LH, et al. A prospective evaluation of ifosfamide-related

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tu… 12/22

33. Bignon Y, Pinelli L, Frachon N, et al. Defective bicarbonate reabsorption in Kir4.2

36. Tizianello A, Garibotto G, Robaudo C, et al. Renal ammoniagenesis in humans with

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Características de los diferentes tipos de acidosis tubular renal (ATR)

RTA hipopotasémica RTA hiperpota

Defecto primario Deterioro del Reabsorción Disminución de la

HCO 3 plasmático Variable. Usually 12 to Usually greater than 17

Urine pH Always >5.3. Variable. Variable.

Greater than Usually greater than 5.3.

Plasma potassium Usually reduced May be Increased.

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tu… 15/22

Consistent with ammonium

Urine Ca/Cr ratio Increased Normal Normal

HCO3: bicarbonate; Ca/Cr: calcium/creatinine.

Graphic 58428 Version 10.0

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tu… 16/22

Major causes of type 1 (distal) renal tubular acidosis (RTA)

Autoimmune hepatitis/primary biliary cirrhosis

Systemic lupus erythematosus (also can generate hyperkalemic RTA)

Ifosfamide (also can cause proximal RTA with Fanconi syndrome)

Medullary sponge kidney

Kidney transplant rejection

Graphic 56437 Version 11.0

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Major causes of type 2 (proximal) renal tubular acidosis with or without

Dominant, isolated HCO3 wasting

Hereditary fructose intolerance

Glycogen storage disease (type I)

Tenofovir and other antiretroviral drugs

Carbonic anhydrase inhibitors – Acetazolamide, topiramate

Multiple myeloma/light chain disease

Vitamin D deficiency or vitamin D resistance

https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis/print?search=acidosis tu… 18/22

Paroxysmal nocturnal hemoglobinuria