REVIEW

CURRENT
OPINION Renal tubular acidosis
Fernando Santos a,b, Helena Gil-Peña a, and Silvia Alvarez-Alvarez a

Purpose of review
To facilitate the understanding and knowledge of renal tubular acidosis by providing a summarized
information on the known clinical and biochemical characteristics of this group of diseases, by updating
the genetic and molecular bases of the primary forms renal tubular acidosis and by examining some issues
regarding the diagnosis of distal renal tubular acidosis (RTA) in the daily clinical practice.
Recent findings
The manuscript presents recent findings on the potential of next-generation sequencing to disclose new
pathogenic variants in patients with a clinical diagnosis of primary RTA and negative Sanger sequencing
of known genes. The current review emphasizes the importance of measuring urinary ammonium for a
correct clinical approach to the patients with metabolic acidosis and discusses the diagnosis of incomplete
distal RTA.
Summary
We briefly update the current information on RTA, put forward the need of additional studies in children to
validate urinary indexes used in the diagnosis of RTA and offer a perspective on diagnostic genetic tests.
Keywords
ammonium, children, metabolic acidosis, renal tubular acidosis

INTRODUCTION It is of note that the majority of pediatric cases

Metabolic acidosis results from the net loss of with hyperchloremic metabolic acidosis seen in
HCO3 or from the net gain of acid. It is diagnosed clinical practice are transient and result from gastro-
by a low plasma bicarbonate concentration (<22– intestinal disorders, such as acute diarrhea.
24 mEq/l in children and <20–22 mEq/l in infants) It should also be kept in mind that, in adults,
and low blood pCO2 (<40 mmHg in children and many forms of RTA are secondary to systemic dis-
<35 mmHg in infants). Metabolic acidosis is usually eases, such as Sjögren syndrome, systemic lupus
classified according to the values of serum or plasma erythematosus, rheumatoid arthritis, hypergamma-
anion gap estimated by the difference between the globulinemia, kidney transplantation and sickle cell
sum of the sodium and potassium ion concen- disease, or exposure to drugs, such as amphotericin
trations minus the sum of the chloride and B, lithium carbonate and intravenous bisphospho-
bicarbonate anion concentrations. Several disorders nates [3] or toxins, whereas most pediatric cases
can give rise to metabolic acidosis in children, correspond to primary disorders resulting from
usually transient. specific genetic defects in a protein involved in
the processes of HCO3 reabsorption, HCO3 regen-
eration and Hþ secretion. Primary RTA usually
GENERAL DESCRIPTION presents early in infancy or early childhood with
The term renal tubular acidosis (RTA) refers to a hyperchloremic metabolic acidosis, persistent if it
group of diseases characterized by normal serum is not treated, associated with clinical episodes of
anion gap or hyperchloremic metabolic acidosis
caused by the inability of the renal tubule to retain a
Department of Pediatrics, Hospital Universitario Central de Asturias and
bicarbonate (HCO3) or to secrete hydrogen ions b
Área de Pediatrı́a, Dpto. de Medicina, Universidad de Oviedo, Oviedo,
(Hþ) in the presence of normal or moderately Spain
impaired glomerular filtration rate [1]. Correspodence to Fernando Santos, Facultad de Medicina, Universidad
There are four types of primary RTA whose main de Oviedo, C/Julián Claverı́a 6, 33006, Oviedo, Spain.
diagnostic features are summarized in Table 1. Tel: +34 985103585; e-mail: fsantos@[Link]
Recent comprehensive reviews on these forms of Curr Opin Pediatr 2017, 29:206–210
&
RTA are available in the literature [2 ]. DOI:10.1097/MOP.0000000000000460

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 Renal tubular acidosis Santos et al.

bicarbonate due to the alkali needs of growing bones

KEY POINTS and the transient associated reduction in proximal
 Clinical and biochemical manifestations as well as tubular reabsorption of bicarbonate that may occur
genetic analysis serve to characterize the four types of in infants with distal RTA. Infants and children with
primary renal tubular acidosis in children. proximal type 2 RTA need much greater amounts of
alkali because of their high fractional excretion of
 The measurement of urinary ammonium is important for
bicarbonate. These patients with type 2 RTA usually
an accurate diagnosis of RTA. Indexes in urine
developed to indirectly estimate ammonium need to be have generalized proximal tubular dysfunction (i.e.
validated in infants and children. Fanconi syndrome) and therefore require a more
complex treatment.
 Incomplete forms of distal type 1 RTA can be detected The current review updates recent and updated
by subtle defects in the ability to acidify the urine. The
information on the underlying molecular defect and
clinical interest of this diagnosis in pediatric population
is questionable. discusses critical issues for the appropriate diagnosis
of primary RTA-based on clinical and biochemical
findings.

vomiting, diarrhea, dehydration, polyuria and fail-

ure to thrive. Nephrocalcinosis develops early in GENETIC BASIS
infants with distal type 1 RTA so that it can be Table 2 lists the genes and proteins having loss-of-
detected by ultrasound within the first weeks of life. function mutations known to be involved in the
In type 4 RTA, the hyperkalemia, often associated & &&
genesis of primary RTA [4 ,5 ]. As for distal type 1
with chronic renal failure, may be the most prom- RTA, in 10% of 52 cases analyzed in the RenalTube
inent clinical manifestation. database ([Link]), a website-based col-
Treatment of RTA patients requires sustained laborative multicenter effort aimed at the study of
alkali supplementation, habitually provided as primary tubular disorders [6], the underlying patho-
sodium bicarbonate or potassium citrate, aiming genic variant has not been found so far. This requires
to normalize blood pH and bicarbonatemia. Adult the confirmation of the clinical diagnosis, some-
patients with distal RTA are well controlled by the times made not on the basis of strict criteria as
administration of 2–3 mEq/day of alkali. However, commented below and also supports the suggestion
pediatric patients may require higher amounts of that additional genes are responsible for the disease.

Table 1. Differential clinical and biochemical characteristics in the four types of primary renal tubular acidosis, which all are
hyperchloremic normal serum anion gap persistent metabolic acidosis
Biochemical features
Plasma Urinary Urinary FE of Other data
RTA Clinical manifestations potassium acidificationa ammonium HCO3
Type 1, distal RTA Dehydration. Growth Low/normal Defective Low Normal Hypocitraturia,
retardation hypercalciuria
Nephrocalcinosis and urolithiasis
b
Deafness
b
Hemolytic anemia
Type 2, In the context of syndromes with Low/normal Preserved Normal Very high
proximal RTA generalized proximal tubular
dysfunction. Isolated, very rare
b
Ocular anomalies
b
Neurological symptoms
b
Type 3 Osteopetrosis Low/normal Defective Low High
b
Cerebral calcification
Type 4 Pseudohypoaldosteronism or High Preserved Low High Low GFR
hypoaldosteronism

FE of HCO3: urinary fractional excretion of bicarbonate anion with simultaneous normal bicarbonatemia. GFR, glomerular filtration rate.
a
Assessed by minimal urinary pH achieved in the setting of spontaneous or acid load (NH4Cl) induced metabolic acidosis or following the administration of
furosemide or by urine-blood pCO2 measured in the presence of normal bicarbonatemia.
b
Associated in some cases with the RTA, according to the mutated gene responsible for the disease (Table 2).

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Nephrology

Table 2. Genetic and molecular basis of the different types of primary renal tubular acidosis

RTA Mutated gene OMIM number Defective protein Inheritance


Type 1 ATP6V1B1 192132 Hþ-ATPase, V1 subunit B1 isoform AR
 þ
ATP6V0A4 605239 H -ATPase subunit, V0 subunit A4 isoform AR
SLC4A1 þ109270 Kidney Cl/HCO3 exchanger (kAE1) AD or AR

Type 2 SLC4A4 603345 Kidney Naþ/HCO3 cotransporter (NBCe1) AR

CLCN7 602727 Hþ/Cl exchange transporter 7 (CLCN7) AD with VE

CA2 611492 Carbonic anhydrase II AR

SLC2A2 138160 Solute carrier family 2, member 2; (SLC2A2) AR or AD

CTNS 606272 Cystinosin (CTNS) AR

FAH 613871 Fumarylacetoacetate hydrolase (FAH) AR

TAT 613018 Tyrosine aminotransferase (TAT) AR

HPD 609695 4-hydroxyphenylpyruvate dioxygenase (HPD) AD or AR

ATP7B 606882 ATPase, Cu (2þ)-transporting, beta polypeptide (ATP7B) AR

GALT 606999 Galactose-1-phosphate uridylyltransferase (GALT) AR

CLCN5 300008 Chloride channel 5 (CLCN5) XLR

OCRL 300535 OCRL gene (OCRL) XLR

Type 3 CA2 611492 Carbonic anhydrase II AR

Type 4 NR3C2 600983 Nuclear receptor subfamily 3, group C, member 2 (NR3C2) AD

SCNN1A 600228 a subunit of sodium channel, nonvoltage-gated 1 (SCNN1A) AR

SCNN1B 600760 b subunit of sodium channel, nonvoltage-gated 1 (SCNN1B) AR

SCNN1G 600761 g subunit of sodium channel, nonvoltage-gated 1 (SCNN1G) AR

WNK 4 601844 With-no-lysine kinase member 4 (WNK4) AD

WNK1 605232 With-no-lysine kinase member 1 (WNK1) AD

KLHL3 605775 Kelch-like protein 3 (KLHL3) AR

KLHL3 605775 Kelch-like protein 3 (KLHL3) AD

CUL3 603136 Cullin 3 (CUL3) AD

Underlined entries corresponds to syndromic forms of proximal type 2 RTA. AD, autosomal dominant; AR, autosomal recessive; OMIM, Online Mendelian
Inheritance in Man database; VE, variable expressivity; XLR, X-linked recessive.

Various potential candidate genes for human distal stones, epilepsy and blindness. As shown in consan-
type 1 RTA have been proposed because their inac- guineous families with congenital anomalies of the
tivation has caused RTA in mice, but there is no kidneys and urinary tract, exome sequencing can
evidence that these genes cause the disease in lead to the detection of syndromes not formerly
&
humans [2 ]. Analysis by next-generation sequenc- identified because of atypical phenotypical mani-
ing (NGS) of DNA from 10 patients with primary festations or even to the diagnosis of unsuspected
&&
distal RTA disclosed the mutation in nine and primary tubular disorders [7 ].
suggested that compound heterozygosity of known
&
mutations may be present in exceptional cases [4 ], a
hypothesis that needs to be validated by further CORRECT CLINICAL DIAGNOSIS OF
functional experiments. The extended use of exome PRIMARY DISTAL RENAL TUBULAR
sequencing will likely result in the discovery of new ACIDOSIS
genes responsible for RTA, particularly when RTA Type 1 distal RTA is the most common form of
occurs in association with other apparently unre- primary RTA in Western countries. It is character-
lated renal or extrarenal manifestations. In this ized by the inability to maximally decrease urine pH
and enhance urinary ammonium (NH4þ) excretion
&&
regard, Piret et al. [5 ] have recently reported a
case of proximal RTA secondary to a missense in the presence of sustained hyperchloremic meta-
mutation (c.643G > A; p.Gly215Arg) in the gene bolic acidosis, hypokalemia, early development of
encoding the chloride/proton antiporter 7 (gene nephrocalcinosis and frequent association with
CLCN7, protein CLC-7) in a family with autoso- nerve deafness [1]. It is of note that primary distal
mal-dominant osteopetrosis associated with renal RTA is a permanent condition that cannot be

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 Renal tubular acidosis Santos et al.

reliably diagnosed on the basis of an episode of INCOMPLETE DISTAL RENAL TUBULAR

transient metabolic acidosis and simultaneous uri- ACIDOSIS
nary pH above 5.5, as often occurs [8]. The diagnosis Normal kidneys respond to metabolic acidosis, either
of distal RTA requires the accurate determination of spontaneous or induced by ammonium chloride or
blood pH and bicarbonate concentration by using a another acidifying agent, by decreasing urinary pH
blood gas analyzer, the measurement of pH in fresh below 5.5. The ability to acidify the urine can also be
urine samples using a pH meter and the assessment explored by administration of furosemide that does
of titratable acid excretion and, especially, NH4þ in not cause acidosis but augments distal nephron
urine collected during acidosis. The amount of sodium delivery and increases the lumen-negative
titratable acid is more or less fixed but the normal electrical gradient favoring Hþ secretion [1]. The
kidneys respond to chronic metabolic acidosis by inability of the kidneys to achieve a urine pH lower
markedly increasing the elimination of NH4þ. In than 5.5 is usually considered as a defect in urinary
distal RTA, the NH4þ excretion is reduced due to acidification and indicative of underlying incom-
impaired trapping of ammonia (NH3) in the collect- plete distal RTA in patients without spontaneous
ing duct subsequent to the defective Hþ secretion metabolic acidosis or acidemia. This assumption
[3]. Unfortunately, the determination of urinary has mostly been made in adults with osteoporosis,
NH4þ is not available in the majority of hospital chronic interstitial nephritis, kidney calcium phos-
clinical laboratories, and, subsequently, appropriate phate stones, medullary sponge kidney or lithium
&
reference normative data for the elimination of therapy [13,14]. Shavit et al. [15 ] have recently pro-
NH4þ in acidotic children with healthy kidneys posed that a normal response to the furosemide þ -
are not available. Indices proposed to indirectly fludrocortisone test [16] can be used as a screening
estimate the amount of NH4þ in urine, such as method to exclude distal RTA in adult patients with
the urine anion gap or osmolal gap, provide a rough recurrent kidney stone formation or nephrocalcino-
estimation of the amount of NH4þ, have limitations sis, whereas an abnormal urinary acidification fol-
in the clinical interpretation and, in addition, are lowing furosemide þ fludrocortisone administration
not frequently reported in publications describing needs to be confirmed by a subsequent ammonium
pediatric cases of RTA. Urine anion gap is calculated chloride test. In children, Sharma et al. [17] diagnosed
by the formula Naþ þ Kþ – Cl, and negative values incomplete distal RTA by the coexistence of blood pH
are supposed to reflect high concentrations of uri- greater than 7.30, serum bicarbonate greater than
nary NH4þ unless significant amounts of bicarbon- 18 mEq/l and urinary pH higher than 5.5 despite
ate, for instance, if the urinary pH is greater than 6.5, systemic acidosis induced by oral ammonium
or other organic anions are present in the urine [9]. chloride in 17 out of 40 Indian patients who under-
Sulyok and Guignard [10] showed a poor correlation went surgical correction of posterior urethral valves.
between urinary NH4þ and urinary anion gap in The height of these children improved with sustained
neonates and infants during the first weeks of life. sodium bicarbonate treatment. Thus, there are
Additional studies are necessary in pediatric popu- patients with acquired tubulointerstitial kidney dis-
lation to analyze this correlation in different clinical eases who are unable to maximally acidify the urine
situations. Likewise, a urinary osmolal gap, calcu- when challenged by different acidifying stimulus but
lated by the formula: do not develop metabolic acidosis. Some individuals

do not acidify the urine after furosemide þ fludrocor-
Measured urine osmolality  2 Naþ þKþ
fludrocortisone but they do it normally when chal-
urea nitrogen ðmg=dlÞ &
lenged by ammonium chloride [15 ]. This raises the
þ
2:8 issue of urinary acidification needing to be carefully
glucose ðmg=dlÞ assessed in the clinical setting, and factors such as
þ urine osmolality as well as sodium and NH4þ con-
18
centrations need to be taken into consideration for a
with a value below 100 has been proposed as indica- correct interpretation of the ability to achieve a min-
tive of defective NH4þ elimination in metabolic imal urinary pH.
acidosis [11] but more clinical studies are needed It is known that the measurement of urine pCO2
to confirm whether the urinary osmolality gap is an when the urinary pH is higher than that of blood is a
appropriate index of urinary NH4þ concentration in sensitive index of distal nephron Hþ secretion so
infants and children. Unpublished preliminary data that the urine minus blood pCO2 difference should
from our hospital’s clinical laboratory indicate that be greater than 20 mmHg in normal individuals
technical modifications proposed to facilitate the [3,18]. Interestingly, Zhang et al. [19] recently
measurement of NH4þ in urine [12] can reliably be reported two members of a family heterozygous
used in samples from pediatric patients. for a mutation in the Hþ-ATPase, V1 subunit B1

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Nephrology

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&& of outstanding interest
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Acknowledgements &

of the simultaneous furosemide and fludrocortisone test with the short

We thank the Molecular-Genetics Laboratory of the ammonium chloride test. Nephrol Dial Transplant 2016; 0:1–7.
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Financial support and sponsorship ammonium chloride. Kidney Int 2007; 71:1310–1316.
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There are no conflicts of interest. Physiol Renal Physiol 2014; 307:F1063–F1071.

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