REVIEW ARTICLE

Clinical approach to renal tubular acidosis in adult

patients
P. Reddy

Department of Medicine,
University of Florida College of
Medicine, Jacksonville, FL, USA
Correspondence to:
Pramod Reddy, MD,
Department of Medicine,
University of Florida, 653-1
West Eighth Street, Jacksonville,
FL 32209, USA
Tel.: + 1 904 244 3530
Fax: + 1 904 244 3087
Email:
pramod.reddy@jax.ufl.edu
Disclosures
None.
SUMMARY
Renal tubular acidosis (RTA) is a group of disorders observed in patients with nor-
mal anion gap metabolic acidosis. There are three major forms of RTA: A proximal
(type II) RTA and two types of distal RTAs (type I and type IV). Proximal (type II)
RTA originates from the inability to reabsorb bicarbonate normally in the proximal
tubule. Type I RTA is associated with inability to excrete the daily acid load and
may present with hyperkalaemia or hypokalaemia. The most prominent abnormality
in type IV RTA is hyperkalaemia caused by hypoaldosteronism. This article exten-
sively reviews the mechanism of hydrogen ion generation from metabolism of nor-
mal diet and various forms of RTA leading to disruptions of normal acid-base
handling by the kidneys.
Review Criteria
I gathered the information in this review article
from various text books and journals as listed in
the references.
Message for the Clinic
Renal tubular acidosis appears extremely complex
when briefly heard in the conferences, but once
you spend more time understanding the
pathophysiology it becomes unforgettable and easy
to teach students and residents. Clinicians are
encouraged to study this topic in depth rather than
just before the examinations.

as seen with gastrointestinal and proximal renal bicar-

Introduction
Normal urinary acidification involves bicarbonate
reabsorption in the proximal tubules and hydrogen
ion excretion in the distal tubules. Impairment of
any of these critical functions leads to renal tubular
acidosis (RTA). All forms of RTA are characterised
by a normal anion gap (hyperchloraemic) metabolic
acidosis (see Table 1).
The first step in the evaluation of a patient with
suspected RTA is to confirm the presence of a nor-
mal anion gap metabolic acidosis (1).
The serum anion gap is: is:
½Naþ  þ ½Cl  HCO
3 :
bonate wasting. A positive urine anion gap suggests
the possibility of distal RTAs resulting in lower
amounts of NH4+ and chloride in the urine (3).
Gastro-intestinal losses of bicarbonate (diarrhoea,
urinary diversion procedures and fistulas) should be
ruled out by detailed history and physical examina-
tion.
Although alkaline urine pH is variably seen in all
three types of RTAs, only patients with complete
type I distal RTA have a urine pH > 5.3 even during
periods of severe metabolic acidosis. By contrast,
urine pH transiently becomes acidic in both type II
and type IV RTAs till the extra acid load is excreted
into the urine (see Figure 1 and Table 1).

Pseudo normalisation of the elevated anion gap

secondary to severe hypoalbuminaemia must be care-
fully ruled out (in general, each 1 g ⁄ dl decline in
serum albumin from the normal value of 4.5 g ⁄ dl,
decreases the serum anion gap by 2.5 mEq ⁄ l). Once
normal anion gap metabolic acidosis is confirmed,
the urine anion gap is calculated to indirectly esti-
mate the urine NH4+ levels (2).
The urine anion gap is:
½urine Naþ þ urine Kþ   urine Cl :
High urine chloride levels leading to a negative gap
are typically accompanied by high amounts of NH4+,
Basic principles of acid–base balance
The kidneys have a major role in regulating the H+
ion concentration or pH of the body fluids. In a
healthy individual, the arterial pH of the extra cellu-
lar fluid (ECF) has a range of 7.38–7.42 and this
corresponds to the H+ ion concentration of
42–38 nmol ⁄ l (0.00004 mmol ⁄ l).
The major threats to the pH of the body fluids are
from the acids formed in the metabolism of carbohy-
drates, fats and proteins consumed in a daily diet
(4,5). These metabolic acids can be divided into
three categories.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
350 doi: 10.1111/j.1742-1241.2009.02311.x
 Renal tubular acidosis 351

Table 1 Differential diagnosis of RTA

Distal renal tubular acidoses

Type I classic
Proximal RTA Type IV Acidosis of chronic
Characteristic features Type II All other causes Back diffusion hyperkalaemic renal insufficiency

Basic defect Diminished Decreased distal Back diffusion Aldosterone deficiency Inability to produce
proximal HCO3) acidification of H+ ions or resistance or to excrete NH4+ ion
reabsorption
UAG = urine NH4+ Negative or positive Positive Positive Positive Positive
Minimal urine pH when < 5.3 > 5.3, usually > 6 > 5.3 < 5.3 < 5.3
HCO3) < 13 (after NH4+Cl) load)
Urine pH after alkali (NaHCO3) load > 5.3 > 5.3 > 5.3 > 5.3 > 5.3
U–B pCO2 gradient after Normal > 20 mmHg Diminished Normal (> 25) Normal Normal
HCO3) loading with urine pH > 7.6 (close to zero)
FeHCO3) (%) > 15 <5 <5 <5 <5
Urine pH after furosemide < 5.3 > 5.3 < 5.3 or > 5.3 < 5.3 < 5.3
GFR N N N fl flfl
Plasma HCO3) 12–18 Variable 8–15 Variable 8–15 > 17 > 17
Plasma K+ Low Low or high Low High High
(SLE, SCD)
Plasma Cl) › › › › ›
24-h urinary citrate Normal Low Low Normal Normal
Nephrocalcinosis ) + + ) )
Osteomalacia ++ + + ) )
Diagnosis Response Response to Plus U-B pCO2 Plasma aldosterone Creatinine clearance
to NaHCO3 NH4+Cl) or difference concentration
NaHCO3
HCO3) replacement doses Large Modest Modest Modest Modest
Mineralocaorticoid replacement ) ) ) ++ )

RTA, renal tubular acidosis; GFR, glomerular filterate rate; UAG, urine anion gap; U–B, urine–blood; SLE, systemic lupus erythematosis; SCD, sickle cell disease;
flfl, severely decreased; fl, decrease; ›, increase; N, normal.

Volatile acids Fixed acids

When there is adequate tissue perfusion in the pres- Fixed acids are typically produced from protein
ence of insulin, oxidation of carbohydrates and fats metabolism;
yield carbon dioxide (CO2), as the major end prod-
• Sulphuric acid from sulphur containing amino
uct. CO2 reacts with water to form carbonic acid
acids methionine and cysteine.
(H2CO3), which in turn, can dissociate to form H+
• Phosphoric acid from the metabolism of phospho-
and HCO3):
lipids, nucleic acids, phospholipoproteins and phos-
CO2 þ H2 O ¼ H2 CO3 ¼ Hþ þ HCO
3:
phoglycerides.
• Amino acids glutamate and aspartate have both
Carbon dioxide is called a volatile acid, as it can COO) and NH3+ groups at physiological pH and
be excreted via the lungs. All acids other than oxidation of these groups will result in production of
H2CO3 are non-volatile acids, hence they are not equal amounts of bicarbonate and ammonium.
excreted by the lungs.
The liver is the major net producer of fixed acids
from protein metabolism. It also removes excess
Organic acids
NH4+ by urea synthesis and also transports ammonia
These acids are formed from incomplete metabolism
to kidneys via glutamine. For each ammonium con-
of carbohydrates (e.g. lactate) and fats (e.g. ketones)
verted to urea in the liver, a single molecule of bicar-
when there is poor tissue perfusion and insulin defi-
bonate is consumed:
ciency. Organic acids are considered non-volatile
acids and they consume bicarbonate for conversion 2NHþ 
4 þ 2HCO3 ¼ >Urea þ CO2 þ 3H2 O:
into CO2.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
352 Renal tubular acidosis

Hyperchloremic Normal Anion Gap Metabolic Acidosis

Proximal (type II)

RTA with Urine AG –ve Urine AG +ve Urine AG +ve Urine AG +ve
serum HCO3 Urine pH <5.3 Urine pH >5.3 Urine pH <5.3
above threshold

Proximal (type II)

RTA with serum Distal RTA’s Acidosis of glomerular
HCO3 below Insufficiency
threshold

Fe HCO3 > 15%

Urine pH >5.3 IV Sodium Bicarbonate load NH4Cl– load

Urine pH Urine pH
Proximal (type II) Type I RTA persistently >5.3 transiently <5.3 Type IV RTA
RTA Confirmed Confirmed
Confirmed E.g.; Diabetes
Check U-B pCO2
& Urine K before
and after diuretics
Voltage defect Gradient defect
Confirmed Hyperkalemia and unchanged K Urine-Blood pCO2 difference > 25 mm Confirmed
E.g.; Sickle excretion after diuretics E.g.; Amphotericin B
cell disease

Hypokalemia and
increased K excretion
after diuretics

H-ATPase pump
defect confirmed
E.g.; Sjogren’s
syndrome

Figure 1 Algorithm for diagnosing RTA. RTA, renal tubular acidosis; NH4+Cl), ammonium chloride; AG, anion gap

A typical protein rich western diet would yield
approximately 100 mmol (1–1.5 mmol ⁄ kg) H+ every
day. It represents a 25,000-fold increase in basal H+
concentration and could be disastrous unless
excreted by the kidneys.
As the non-volatile acids are buffered for the most
part by the bicarbonate buffer system, the body is left
with an overall deficit of HCO3). To maintain acid-
base balance, the kidneys must not only reclaim all
the filtered HCO3), but also generate new HCO3).
Most of the filtered HCO3) is reabsorbed in the
proximal tubules and generation of new HCO3)
occurs in the distal and collecting tubules during the
excretion of H+.
Normally, 80–85% of the filtered bicarbonate is
reabsorbed in the proximal tubule with the help of
the enzyme carbonic anhydrase (CA; 6). Epithelial
cells of the proximal tubule synthesise H2CO3 via CA.
H2CO3 then ionizes into H+ and HCO3). The process
of Na+-H+ exchange recreates H2CO3 in the lumen
and NaHCO3 in the cell, which is absorbed into the
peritubular venous blood. The net effect is the reab-
sorption of one molecule of HCO3) and one molecule
of Na+ from the tubular lumen into the blood stream
for each molecule of H+ secreted (7). This mechanism
does not lead to the net excretion of any H+ from the
body as the H+ is consumed in the reaction with the
filtered bicarbonate in the tubular lumen.
Proximal tubule is also the major site of ammonia
synthesis from amino acid glutamine (8). Most of
the proximally secreted ammonia is removed from
the tubular fluid by the thick ascending loop of Henle
into the medullary interstitium and is later secreted
into the collecting tubules.
Around 10% of the filtered bicarbonate is reab-
sorbed in the loop of Henle and the remaining
5–10% is reabsorbed in the collecting tubules. The
process of bicarbonate reabsorption in the distal
tubule involves an HCO3Cl) exchanger. Principal
cells reabsorb Na+ via the epithelial Na+ channels
causing an electronegative tubular lumen, which
favours the secretion of both K+ (principal cells) and
H+ (intercalated cells) into the lumen.
Hydrogen ion secretion from the intercalated cells
in the distal convoluted tubule involves the H+-
ATPase pump. Although this proton secretory pump
is under direct influence of aldosterone, acid excre-
tion can occur indirectly by the negative charge cre-
ated by Na+ reabsorption in the cortical collecting
tubules. In comparison, the process of hydrogen ion
excretion in the medullary collecting tubules is
sodium independent (9).

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360

Distal tubules secrete the daily acid load as H+ ions
generated within the cells from the dissociation of
H2O (H2O = H+ and OH) ions). These OH) ions
combine with CO2 to form HCO3) ions by intracellu-
lar CA. Thus, secretion of each H+ ion into the lumen
is associated with generation of one HCO3) ion within
the tubular cell, which is returned to the plasma.
Distal nephrons are capable of actively secreting
hydrogen ions against large concentration gradients
(Final urine pH may reach 4.4 while blood pH is
7.4) and the distal luminal membrane is normally
resistant to passive back diffusion of secreted H+ ions
(certain drugs can compromise this barrier, resulting
in reduced net secretion of acid).
The filtered bicarbonate in the distal tubular
lumen combines with the secreted H+ ions to form
H2CO3. As CA is not readily accessible to the collect-
ing tubular lumen, the formed H2CO3 slowly dehy-
drates to CO2 and H2O, which are passively
reabsorbed and converted into HCO3) ions inside
the cells. This delayed dehydration of H2CO3
increases urinary pCO2 values (> 65 mm) well in
excess of that in the blood samples (40 mm). As this
increment in urinary pCO2 is ultimately derived
from distally secreted protons, the urine–blood
(U–B) pCO2 difference (> 25 mm) becomes a semi
quantitative index of distal nephron acid secretion
during bicarbonate loading.
It is important to emphasise that the daily acid
load cannot be excreted till all of the filtered HCO3)
has been reabsorbed. H+ ions secreted in excess of
those required to reabsorb filtered HCO3) bind with
non-bicarbonate buffers in the tubular fluid, most
important of which are ammonia and phosphate.
A low pH in the collecting tubule caused by active
H+ secretion and low bicarbonate concentration
greatly augments transfer of ammonia from the med-
ullary interstitium into the luminal fluid. Ammonia
buffers the luminal H+ ions in the collecting duct
and becomes NH4+ in the tubule lumen and is elimi-
nated in the urine. For every molecule of NH4+
excreted, a molecule of HCO3) is returned to the
systemic circulation from the proximal tubule. In the
absence of an acidic pH in the collecting tubule,
ammonia in the medullary interstitium will be
returned to the liver by the systemic circulation
where it will be converted to urea, while consuming
HCO3) during the process. Thus, the overall process
of HCO3) regeneration is not complete unless the
NH4+ is excreted (10).
The amount of ammonia produced by the proxi-
mal tubules can increase markedly in acidosis. This
involves synthesis of new enzymes and requires sev-
eral days for complete adaptation (11). Plasma K+
concentration alters ammonia production, which is
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
Renal tubular acidosis 353
inhibited by hyperkalaemia and stimulated by hypo-
kalaemia.
Titratable acidity (TA) represents the H+ ion, which
is buffered by the limited amounts of filtered phosphate
in the urine (HPO4) + H+ = H2PO4)). In comparison
with ammonia, production of phosphate cannot
increase significantly in the presence of acidosis. The
TA can be measured in the urine from the amount of
sodium hydroxide needed to titrate the urine pH back
to 7.4, hence the name ‘titratable acidity’ (12). Ammo-
nium is not measured as part of the TA because the
high pK value of ammonium prevents H+ from being
removed from NH4+ during titration to a pH of 7.4.
The net effect of the excretion of one H+ is the
return of one HCO3) and one Na+ to the blood
stream. RTAs result from various forms of congenital
and acquired tubular dysfunction resulting in
impaired urinary acidification (13). Their differenti-
ating clinical features are described below (see
Table 1).
Proximal renal tubular acidosis (type II
RTA)
Type II RTA occurs in two phases (14).
The period of transient HCO3) wasting
When the reabsorption capacity of the proximal
tubule is impaired (rather than complete inhibition),
less of the filtered HCO3) is reabsorbed in this seg-
ment. The increased distal HCO3) delivery over-
whelms the limited capacity of the distal nephron,
leading to bicarbonaturia. This period of transient
bicarbonate wasting results in ECF volume contrac-
tion and secondary hyperaldosteronism with result-
ing hypokalaemia. Chloride reabsorption is enhanced
secondary to ECF volume contraction. The alkaline
collecting tubule lumen reduces net acid excretion
causing a hyperchloremic metabolic acidosis as an
end result. During this period, FeHCO3 is high with
an alkaline urine pH (> 6) and urine anion gap may
be negative.
The steady state
Urinary bicarbonate wasting continues until the
plasma HCO3) level reaches a new low level
(12–18 meq ⁄ l), at which point most of the filtered
bicarbonate is reabsorbed as a result of enhanced
distal tubular reabsorption, resulting in acidic urine
pH (< 5.3). Thus, type II RTA is a self-limiting dis-
order and the systemic acidosis is not progressive
despite total absence of proximal HCO3) reabsorp-
tion (15).
With oral bicarbonate therapy or when challenged
with IV sodium bicarbonate infusion, the amount of
354 Renal tubular acidosis
bicarbonate in the urine increases (FeHCO3 > 15%)
and the urine pH becomes alkaline. Impaired pro-
duction of NH3 in the proximal tubule may result
from diffuse tubular dysfunction, which may lower
the rate of NH4+ excretion into the urine with a
positive urine anion gap.
Aetiology and clinical features of
proximal (type II) RTA
Proximal (type II) RTA in children results from
inherited defects in the genes for the transmembrane
transporters responsible for proximal acidification
(16–18).
Inactivating mutations of the Na+HCO3) symport-
er can cause permanent isolated proximal RTA. As
the Na+HCO3) symporter is expressed in multiple
ocular tissues and pancreas, patients may present
with various ocular abnormalities (glaucoma, cata-
racts) and pancreatitis (19,20). Inactivating muta-
tions of the CA II gene leading to proximal (type II)
RTA is typically accompanied by osteopetrosis and
mental retardation (21). In children, proximal (type
II) RTA is also commonly associated with cystinosis
and with the chemotherapeutic agent Ifosfamide,
which is used in the treatment of several solid
tumours.
The two most common causes of proximal (type
II) RTA in adults are multiple myeloma and the
use of CA inhibitors (22,23). The light chains are
resistant to degradation by proteases in lysosomes
in the proximal tubular cells and their accumulation
is presumably responsible for the tubular impair-
ment (24).
The proximal defect in bicarbonate reabsorption
may appear as an isolated defect or as a more gen-
eralised impairment of all the substances reabsorbed
by the proximal tubule (varying degrees of phos-
phate, glucose, amino acids, calcium, citrate and
uric acid wasting often accompanies the bicarbonate
wasting). The latter form is called Fanconi syn-
drome and the majority of cases of proximal (type
II) RTA are manifested by this abnormality (25)
(Table 2).
Type II RTA causes osteomalacia, rickets in chil-
dren and osteopenia, pseudofractures in adults in
about 20% of the patients (26).
Despite high calcium excretion in patients with
proximal (type II) RTA, nephrocalcinosis is rare,
because the following factors limit the amount of
free calcium available to precipitate with phosphate
or oxalate: (i) concomitant excretion of citrate,
which can form soluble complexes with calcium, and
(ii) acidic distal tubular urine pH in steady state
increases the solubility of calcium phosphate.
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
Table 2 Common causes of proximal (type II) RTA
Isolated defect
Autosomal dominant proximal RTA from unknown gene
mutation
Autosomal recessive sodium-bicarbonate symporter (NBC1)
protein mutation in SLC4A4 gene
Inherited carbonic anhydrase II deficiency caused by mutations
in CA2 gene – associated with mental retardation, cerebral
calcifications and osteopetrosis (Sly syndrome)
Drugs (acetazolamide)
Generalised defect (Fanconi syndrome)
Primary (genetic)
Inborn errors of metabolism (cystinosis, Wilson’s disease,
galactosemia, hereditary fructose intolerance, methylmalonic
academia, glycogen storage diseases)
Dysproteinemic states (myeloma, monoclonal gammopathy)
Secondary hyperparathyroidism with chronic hypocalcaemia,
vitamin D deficiency
Tubulointerstitial diseases (Sjogren’s syndrome, medullary
cystic disease, renal transplantation)
Nephrotic syndrome
Amyloidosis
Paroxysmal nocturnal haemoglobinuria
Toxins (lead, mercury, copper, cadmium, glue sniffing)
Drugs (outdated tetracycline, ifosfamide, cisplatin, gentamycin,
valproic acid)
RTA, renal tubular acidosis.
Diagnosis and treatment of proximal
(type II) RTA
The presence of type II RTA should be suspected in
any patient with an unexplained normal anion gap
metabolic acidosis, even if the urine pH is below 5.3
and urine anion gap may be negative or positive (see
Figure 1).
When patients in the steady state are treated with
alkali therapy (IV sodium bicarbonate 0.5–
1.0 meq ⁄ kg ⁄ h), the plasma HCO3) increases above
the threshold and bicarbonaturia ensues resulting in
urine pH > 7.5 and FeHCO3 > 15–20% (27):
Urine HCO
3  Plasma Cr
FeHCO
3 ¼  100:
Plasma HCO3  Urine Cr
As distal renal tubules have substantial bicarbonate
reabsorptive capacity, the plasma bicarbonate concen-
tration usually does not fall below 12 meq ⁄ l in patients
with proximal (type II) RTA. As the exogenous alkali
is rapidly excreted in the urine, high doses
(10–30 mEq ⁄ kg ⁄ day) of citric acid ⁄ sodium citrate
(Bicitra; Ortho-Mcneil-Janssen pharmaceuticals, Inc.,
Titusville, NJ) are required to restore adequate serum
bicarbonate levels. Citrate is rapidly metabolised to
HCO3) and is better tolerated than HCO3) solutions.

Correcting the HCO3) to near-normal values (22–
24 mEq ⁄ l) is desirable in children to preserve normal
growth, but not required in adults. Patients with
proximal (type II) RTA tend to become hypokalemic
once alkali therapy is initiated. When the plasma
HCO3) concentration is normalised, the high distal
delivery of bicarbonate induces kaliuresis, requiring
large supplements of K+ (28).
When large doses of alkali are ineffective or poorly
tolerated, the addition of a distal diuretic may
increase the proximal reabsorption of sodium along
with bicarbonate secondary to volume depletion.
Amiloride is preferred over thiazides because of the
potassium sparing effect (29).
Classic distal renal tubule acidosis
(type I RTA)
The characteristic feature of classic RTAs is an inabil-
ity to acidify the urine maximally (to less than pH
5.3) in the face of systemic acidosis (13,30). In most
patients with classic RTA, the urine pH is around
6.5, reflecting the unabsorbed normal distal load of
bicarbonate.
The causes of type I RTA can be grouped as
hypokalaemic and hyperkalaemic forms (see Table 3):
Hypokalaemic type I RTA
• Impaired net secretion of H+ ions. As a result of the
defects in the basolateral membrane ATPase. This
Table 3 Common causes of type I RTA
Hypokalaemic classic renal tubular acidosis
Calcium induced Tubular damage
Idiopathic hypercalciuria
Primary hyperparathyroidism
Hypervitaminosis D
Medullary sponge kidney
Drugs and Toxins
Amphotericin B
Ifosfamide
Lithium
Analgesic abuse
Multiple myeloma
Toluene
Idiopathic causes
Marfan’s syndrome
Wilson’s disease
Ehlers-Danlos syndrome
Hyperkalaemic classic renal tubular acidosis
Decreased effective intravascular volume of any cause Sickle cell anaemia
Urinary tract obstruction
Renal transplant rejection
RTA, renal tubular acidosis; SLE, systemic lupus erythematosis.
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
Renal tubular acidosis 355
could be genetic or acquired because of diseases like
Sjogren’s syndrome. This results in reduced acid
excretion despite normal aldosterone effect on
H+-ATPase pump.
• Increased permeability of the luminal membranes to
secreted protons. This results in back diffusion of H+
ions despite the presence of an effective pump. This
gradient defect is classically seen in patients treated
with Amphotericin B (31). Before the back diffusion
occurs, the secreted H+ ions in the tubular lumen
bind with HCO3) to form H2CO3. As there is no
luminal CA, H2CO3 is slowly dehydrated to CO2 and
water and this results in transient high urine pCO2
levels in the urine. This is the only type of classic
RTA with high urine pCO2levels (> 65 mmHg) and
corresponding high urine-blood pCO2 difference
(> 25 mmHg).
Patients with the above conditions tend to have
urinary potassium wasting and hypokalaemia prior
to therapy because sodium reabsorption in the
collecting tubules occurs more in exchange with
potassium, as the net distal hydrogen ion secretion is
diminished. Chronic metabolic acidosis results in less
bicarbonate reabsorption by the proximal tubule,
which in turn results in less proximal sodium reab-
sorption. Increased sodium wasting in the urine
results in secondary hyperaldosteronism leading to
hypokalaemia.
Concurrent decreased activity of the second pro-
ton pump (H+ K+ ATPase) in the intercalated cells is
Autoimmune Diseases
Sjogen’s syndrome
Rheumatoid arthritis
SLE
Polyarteritis nodosa
Thyroiditis
Primary biliary cirrhosis
Chronic active hepatitis
Cryoglobulinemia
Idiopathic and Hereditary causes
Mutations in the SLC4A1 gene encoding the chloride-bicarbonate exchanger AE1
H+ATPase subunit mutations in ATP6V1B1 and ATP6V0A4 genes
SLE
Amyloidosis
356 Renal tubular acidosis
sometimes seen along with defective primary proton
pump activity. As the main function of this pump is
to reabsorb potassium in states of depletion, its inhi-
bition may promote urinary K+ wasting.
Hyperkalaemic type I RTA (voltage-dependent
defect)
Normal gradient-driven proton secretion requires a
higher number of cations in the cell compared with
the lumen, creating a transepithelial negative voltage
gradient. This negative gradient can be altered by the
following conditions:
• Reduced distal sodium delivery as a result of
enhanced proximal tubule reabsorption. Seen in condi-
tions with decreased effective arterial volume (CHF,
nephrotic syndrome, cirrhosis) and also any cause of
marked volume depletion.
• Reduced distal sodium reabsorption. Seen when
sodium channels are blocked by use of drugs (Amilo-
ride, Triamterene, Lithium, Trimethoprim or Pent-
amidine) or by urinary tract obstruction. Patients
with sickle cell disease and lupus nephritis may pres-
ent with hyperkalaemic variant of classic RTA
(33,34).
As a consequence of increased intraluminal
sodium, the distal tubular lumen becomes relatively
less electronegative compared with the cell (voltage-
dependent defect) and transepithelial K+ secretion is
impaired leading to hyperkalaemia (32). The patho-
genesis of metabolic acidosis is the result of the unfa-
vourable voltage, which impairs H+ secretion by the
intercalated cells or the inhibition of ammonium
production and transport as a consequence of hyper-
kalaemia. These patients have normal aldosterone
levels and normal amounts of H+-ATPase in the
intercalated cells (34).
Aetiology and clinical features of
type I RTA
The most common causes in adults are autoimmune
disorders (Sjogren’s syndrome, rheumatoid arthritis),
hypercalciuria, recreational toluene sniffing and
drug-induced (amphotericin B) and -marked volume
depletion (see Table 3).
In children, type I RTA is most often a hereditary
condition. Genetic mutations in the chloride-bicar-
bonate cotransporter (SLC4A1 gene) and in the api-
cal H+-ATPase (ATP6V1B1 and ATP6V0A4 genes)
have been identified (35–38).
Patients with Sjögren’s syndrome may reveal com-
plete absence of H+-ATPase pumps in the interca-
lated cells in renal biopsy (39). They also show
presence of high titres of autoantibodies directed
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
against CA II enzyme. CA II inhibition further
impairs hydrogen ion generation within the cell for
secretion into the lumen (40).
Type I RTA is associated with abnormalities in
potassium balance, depending on the type of defect.
Occasionally, patients with severe hypokalaemia may
present with quadriplegia or respiratory arrest (41).
Nephrolithiasis is very frequently associated with
untreated classic RTA. Chronic persistent metabolic
acidosis increases calcium phosphate release from the
bone during buffering of excess hydrogen ions and
also reduces tubular reabsorption of these ions. The
resulting hypercalciuria and hyperphosphaturia lead
to the precipitation of calcium phosphate stones.
This process is also promoted by low urinary cit-
rate levels, as citrate normally binds to calcium and
is excreted in the urine as calcium citrate (42).
Hypocitraturia results from enhanced proximal
tubule reabsorption, which is facilitated by acidosis
in the proximal tubular cells (43,44).
Diagnosis and treatment of type I RTA
The presence of classic RTA should be suspected in
any patient with a normal anion gap metabolic aci-
dosis and a urine pH > 5.3. Urinary tract infection
with Proteus and other urea-splitting organisms
should be excluded, as NH3 is generated from hydro-
lysis of urea and can alkalinise the normally formed
urine in the urinary bladder.
The characteristic feature of type I RTA is persis-
tent urine pH of > 5.3 even in the presence of a
metabolic acidosis induced by NH4+Cl) loading (see
Table 1). As oral ammonium chloride administration
(100 mg ⁄ kg) often induces nausea and vomiting, an
alternative test of urinary acidification, which is actu-
ally faster and more reliable is the simultaneous oral
administration of Furosemide (40 mg) and Fludro-
cortisone (1 mg) (47). Urinary acidification response
to simultaneous furosemide and fludrocortisone is
typically seen within 3–4 h.
Response to loop diuretics and
mineralocorticoid
Loop diuretics increase distal sodium delivery and
increased sodium reabsorption in the cortical collect-
ing tubule enhances the luminal electronegativity
resulting in more H+ and K+ ion secretion. Fludro-
cortisone may be administered along with loop
diuretics to further enhance intercalated cell proton
secretion (47).
In normal subjects with metabolic acidosis, the
expected acidic urine pH (< 5.3) is further lowered by
loop diuretics. By contrast, patients with diffuse impair-
ment of the H+-ATPase pump will have a persistently
 Renal tubular acidosis 357

alkaline urine pH, but will show a rise in K+ excretion, equal to 1–3 mEq ⁄ kg ⁄ day. Citric acid, potassium
reflecting the intact principal cell function (48). citrate, sodium citrate (Polycitra; Ortho-Mcneil-Jans-
In contrast to hypokalaemic classic distal RTA, sen pharmaceuticals, Inc.) are especially useful in this
patients with hyperkalaemic classic RTA (voltage- setting (52). Maintenance of normal serum bicarbon-
dependent defect) do not increase H+ or K+ excretion ate with alkali therapy also raises urinary citrate, low-
in response to furosemide (49). Hyperkalaemic type I ers the frequency of nephrolithiasis and tends to
RTA may appear similar to type IV RTA. However, in restore normal growth in children (53).
type I RTA aldosterone levels are normal and the
acidifying defect is more severe, leading to a urine pH
Hyperkalaemic type IV renal tubule
that is above 5.3 and a plasma bicarbonate concentra-
acidosis
tion below 15 meq ⁄ l. These patients are unable to
increase acid or K+ excretion in response to furose- Aldosterone directly stimulates H+ ion secretion by
mide or fludorcortisone (see Table 4). the H+-ATPase pump in the intercalated cells and
also K+ ion secretion by the principal cells. By
Urine–blood pCO2 difference after bicarbonate increasing sodium reabsorption, aldosterone increases
loading luminal electronegativity and indirectly increases H+
When the distal tubule becomes markedly alkaline ion secretion (54).
after bicarbonate loading, secretion of H+ ions leads
to the formation of H2CO3, which dehydrates into
Aetiology and clinical features of type
CO2 and H2O (45,46). In patients with defective H+
IV RTA
ion secretion, the U–B pCO2 difference is close to
that of blood. Higher U–B pCO2 difference (higher Aldosterone deficiency, resistance or inhibition
pCO2 levels in urine than blood) is seen only in (Table 5) may result in hyperkalaemic, hyperchlorae-
patients with intact H+ ion secretion and with H+
ion back diffusion. Amphotericin B-induced distal Table 5 Common causes of type IV RTA
RTA is the most common example of such a ‘gradi-
ent’ defect (31). Aldosterone deficiency Aldosterone resistance
Addison’s disease Obstructive uropathy
Incomplete type I RTA 21-hydroxylase deficiency Sickle cell nephropathy
Hyporeninemia Amyloidosis
Some patients may have an incomplete variant of the
Diabetic nephropathy Diabetic nephropathy
disease and retain normal serum bicarbonate levels
AIDS Lupus nephritis
despite alkaline urine pH. Nephrolithiasis may still
Tubulointerstitial disease Pseudohypoaldosteronism
occur in them because of hypocitraturia (50). As IgM monoclonal gammopathy
opposed to complete type I RTA, they retain normal NSAIDS
rates of ammonium excretion from possible enhanced Aldosterone inhibition Drugs that interfere
production of ammonia by the proximal tubules with tubular Na+
(51). These patients still fail to excrete the acid load channel function
when challenged with ammonium chloride and retain Spironolactone Amiloride
urine pH > 5.3. Recognition of incomplete type I Analgesics Triamterene
RTA is important in these patients, as the administra- Cyclooxygenase inhibitors Trimethoprim
Heparin Pentamidine
tion of potassium citrate can reduce stone formation.
Lovenox
Correction of acidosis is required to allow normal
Drugs that interfere with basolateral Na+K+ATPase
growth in children, to prevent osteopenia and to
Cyclosporine and tacrolimus
minimise nephrolithiasis. Alkali requirements may be

Table 4 Response to diuretics in different types of type I RTA

Urine studies before diuretics Urine studies after diuretics

Defect Urine pH Urine K Urine pH Urine K

Normal response < 5.0 Normal 20–70 meq ⁄ l Further decline in pH Increased
H+ ion excretion defect > 5.3 Increased > 5.3 Further Increased
H+ Ion back diffusion > 5.3 Increased < 5.3 or > 5.3 (variable) Further Increased
Sodium reabsorptive ⁄ voltage defect > 5.3 Decreased > 5.3 No response

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
358 Renal tubular acidosis
mic acidosis (55–60). In addition, the resulting
hyperkalaemia impairs renal ammonia synthesis (61).
This effect may result from:
• Decrease in ammonium production by the proxi-
mal tubule.
• Competitive inhibition of binding of NH4+ to K+
site on the Na+-K+-2Cl) carrier in the loop of Henle.
• Decreased NH4+ concentration in the medullary
interstitium.
• Decrease in NH3 ⁄ NH4+ secretion into outer and
inner medullary conducting duct.
As gradient driven H+ ion secretion continues
despite the absence of aldosterone, the resulting met-
abolic acidosis is not as severe as seen in classic
RTA. Urine pH becomes acidic during periods of
acute metabolic acidosis or NH4+Cl) loading (see
Figure 1).
Limitation of basolateral Na+ K+-ATPase activity
by cyclosporine and tacrolimus decreases intracellular
K+ and the transepithelial potential, which together
decrease the driving force for K+ secretion (62).
Hyporeninemic hypoaldosteronism is the most
common cause of type IV RTA. Patients with this
disorder are usually older diabetics and exhibit mild
renal insufficiency.
Diagnosis and treatment of type IV
RTA
Both the metabolic acidosis and the hyperkalaemia
are usually out of proportion to the level of reduc-
tion in glomerular filtration rate (GFR). The meta-
bolic acidosis seen with type IV RTA is generally
mild and correcting the hyperkalaemia often leads to
increased NH4+ excretion and correction of acidosis.
Although mineralocorticoid replacement is effective,
as most patients with type IV RTA have underlying
renal insufficiency, this can exacerbate oedema or
hypertension. Loop diuretics often effectively induce
renal potassium and salt excretion (63).
Acidosis of glomerular insufficiency
The metabolic acidosis seen from reduction in func-
tional renal mass is initially hyperchloraemic in nat-
ure (GFR, 20–30 ml ⁄ min), but converts to the
normochloraemic, high-AG variety as renal insuffi-
ciency progresses and the GFR falls below 15 ml ⁄ min
(64). The principal defect in net acid excretion in
these patients is not an inability to secrete H+ in the
distal nephron, but rather an inability to produce or
to excrete NH4+ ion. There is impaired net acid
excretion when the plasma HCO3) concentration is
in the normal range, with preserved ability to lower
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 350–360
the urine pH during acidosis. The U–B pCO2 gradi-
ent is normal, reflecting the intact distal H+ secretory
capacity.
When the net acid excretion is impaired, alkaline
salts from bone buffer the positive acid load and this
results in progressive dissolution of bone and muscle
wasting. Alkali replacement (1–2 mEq ⁄ kg ⁄ day) to
maintain the plasma bicarbonate concentration above
22 meq ⁄ l usually restores acid-base equilibrium and
prevents acid retention.
Conclusions
The presence of RTA should be considered in any
patient with an otherwise unexplained normal anion
gap metabolic acidosis. The diagnosis of proximal
(type II) RTA is made by measurement of the urine
pH and fractional bicarbonate excretion during a
bicarbonate infusion. The hallmark is urine pH
above 7.5 and the appearance of more than 15 per
cent of the filtered bicarbonate in the urine when the
serum bicarbonate concentration is raised to a nor-
mal level. Classic type I distal RTA presents with an
inappropriately high urine pH (greater than 5.3) in
the presence of acidosis and is often associated with
nephrolithiasis. Type IV RTA is because of either
aldosterone deficiency or resistance and hyperkala-
emia is the primary electrolyte abnormality in these
patients.
Serum electrolytes such as blood urea nitrogen, cal-
cium, phosphorus and creatinine should be obtained.
A urinalysis is performed for the evaluation of glycos-
uria and proteinuria. Renal ultrasonography can be
performed to identify obstructive uropathies. When
nephrolithiasis is present, a 24 h urinary calcium mea-
surement may identify hypercalciuria. The mainstay of
therapy in all forms of RTA is bicarbonate replace-
ment with varying dose requirements in each condi-
tion. As the prognosis is dependent on the nature of
the underlying disease, a thorough diagnostic work up
should be carried out for any new onset RTA.
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Paper received September 2009, accepted November 2009