Pediatric Nephrology

https://doi.org/10.1007/s00467-018-4142-9

EDUCATIONAL REVIEW

Renal aspects of metabolic acid–base disorders in neonates

Silvia Iacobelli 1,2 & Jean-Pierre Guignard 3

Received: 28 June 2018 / Revised: 29 October 2018 / Accepted: 6 November 2018

# IPNA 2018

Abstract
Acid–base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid–base balance is particularly
challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against
disturbances of acid–base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine
environment. This review article summarizes the physiology of acid–base regulation by the immature human kidney and
discusses disorders of acid–base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory
alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the
nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective
disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are
primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the
distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypoka-
lemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid–base
tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic
renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can
prevent some of the consequences of the disorders and improves the prognosis.

Keywords Acidemia . Alkalemia . Anion gap . Physiological approach . Tubular function . Immaturity . Bicarbonate . Growth
failure

Physiology of acid–base regulation

pH ¼ pK þ log10 ðbicarbonate ½HCO3 −   ½0:03  PCO2 Þ;
In a steady state, organic acids and proton generation are in where 0.03 represents the solubility factor of CO2 into the blood.
balance with their excretion and with bicarbonate production, In the adult, the plasma pH is normally kept between 7.35
and this allows the maintenance of the systemic arterial pH and 7.45. Any disorder tending to lower the pH < 7.35 is
between 7.35 and 7.45. The Henderson-Hasselbalch equation called acidosis, while a disorder tending to increase the pH
[1, 2] defines how the ratio of the major blood buffer, bicar- > 7.45 is called alkalosis. The acid–base disorder is considered
bonate (HCO3−), to partial pressure of arterial carbon dioxide as metabolic when the primary change is due to a variation in
(PCO2) maintains the pH at the physiological range: the plasma bicarbonate concentration, and respiratory when
the plasma PCO2 is primarily modified [3]. The concept of
base excess (BE) is used to estimate the amount of excess or
* Silvia Iacobelli deficit of bicarbonate in the system. A negative BE indicates a
silvia.iacobelli@chu-reunion.fr base deficit in the blood, and a positive BE an excess of base.
In case of acute changes of the extracellular pH, the respi-
1
Néonatologie, Réanimation Néonatale et Pédiatrique, CHU La ratory system, stimulated by the central nervous system, in-
Réunion, Site Sud, Saint Pierre, France duces variations in PCO2 which act as an immediate compen-
2
Centre d’Etudes Périnatales de l’Océan Indien, CHU La Réunion, satory response. The kidneys then modulate the final line of
Site Sud, EA 7388 Saint Pierre et Université de la Réunion, France regulation by the tubular reabsorption of bicarbonate and the
3
Lausanne University Medical School, excretion of fixed hydrogen ions. The normal range of BE is
CHUV-1011 Lausanne, Switzerland − 5 to + 5 mmol/L.
 Pediatr Nephrol

Acid–base regulation in the newborn infant furosemide increases urinary excretion of titratable acids
by direct stimulation of the collecting tubule; and (c) K+-
A tight control of pH is relatively efficient since birth. sparing diuretics decrease the excretion of H+ into distal
The compensatory mechanisms undergo, however, a mat- tubular fluid [10]. Finally, a recent study on very low
uration process during the transition from the fetal to the birth weight (VLBW) infants receiving early parenteral
extra-uterine environment. This maturation may be limit- nutrition according to new recent guidelines demonstrated
ed in newborns by low gestational age, diseases, drugs, that these babies were exposed to substantial acid–base
and therapeutic interventions. In the preterm infant, in disequilibrium during the first week of life, with a risk
particular, multiple factors may limit the ability to main- of developing significant metabolic acidosis secondary
tain acid–base homeostasis, such as decreased sensitivity to amino acid and lipid intake [11].
to PCO2, severe lung disease, immature glomerular filtra-
tion, and tubular function. The renal acidification capacity
can be decreased by several factors during postnatal life,
Metabolic acidosis
as summarized in Table 1 [4].
The renal bicarbonate threshold is low in newborn in-
Definition: BE ≤ 5 mmol/L, PCO2 = 35–45 mmHg, and pH <
fants, thus maintaining the plasma bicarbonate concentra-
7.35.
tion within the range of 20–22 mmol/L in the term infant
and in the range of 18–20 mmol/L in preterm infants.
Bicarbonate plasma concentrations as low as 14 mmol/L The serum anion gap
can be observed in extremely preterm infants [5]. Adult
values are achieved during the first year of life. This Calculation of the serum anion gap should be used to precisely
Bphysiological acidosis^ observed in neonates is neither characterize metabolic acidosis:
due to impaired function of carbonic anhydrase enzymes,
as their activity is comparable to that of healthy adults Serum anion gap
from the 26th week of gestation, nor to a limited renal ¼ Naþ −½Cl− þ HCO3 −  ðnormal value : 10–12 mEq=LÞ
capacity to excrete hydrogen ions. The state of relative
expansion of the extracellular fluid volume, as well as In metabolic acidosis with normal serum anion gap,
the disparate maturity of nephrons in preterm neonates, hyperchloremia compensates for the loss of bicarbonate by
is responsible for their difficulty to maintain higher levels the gastrointestinal tract (diarrhea, fistula or external drains,
of plasma bicarbonate. short bowel syndrome) or by the kidneys (deficient urinary
In preterm infants, the urinary excretion of titratable acids acidification by the renal tubules). Hyperchloremic metabolic
and ammonium is lower than in term ones. It increases as a acidosis with normal serum anion gap can also be induced by
function of gestational age, with a rapid maturation process, infusion of large volumes of normal saline and, as recently
that occurs within three postnatal weeks, whatever the gesta- described in VLBW infants, after inadvertently administering
tional age at birth [6]. Human studies indeed show that the excessive chloride by parenteral nutrition [12, 13].
renal mechanisms for preserving bicarbonate are normally Increased serum anion gap metabolic acidosis points to a
effective enough in preterm infants to compensate for the acid rise in the serum of an unmeasured anion, either endogenous
load delivered by milk intake [7]. (lactate, ketone bodies, organic acid) or exogenous. The
Several drugs administered in neonatal intensive care most frequent case during the neonatal period is that of
units can also affect acid–base balance: (a) both dopamine lactic acidosis due to perinatal hypoxia–ischemia, hemody-
[8] and carbonic-anhydrase inhibitors (acetazolamide) [9] namic disturbances during adaptation, septic shock, severe
lower the renal bicarbonate threshold by decreasing the respiratory distress syndrome, hypovolemia, or severe ane-
apical sodium ion (Na + –H + ) exchanger activity; (b) mia. Metabolic acidosis with increased anion gap is usually

Table 1 Renal factors and

determinant mechanisms which Proximal nephron Determinant mechanisms
limit the acidification capacity
during adaptation to extra-uterine Low glomerular filtration rate Reduced filtered load of HCO3−
life Extracellular volume expansion Low renal HCO3 threshold
Proximal tubule immaturity Apical Na+–H+ exchangers immaturity
Na+,K+–ATPase pumps immaturity
Distal nephron
Distal and collecting tubule immaturity Low excretion of titratable acids and ammonium salts
Pediatr Nephrol

present in acute and chronic renal failure, due to accumula- The presence of a positive value of urine anion gap indicates a
tion of fixed acids in the blood. defect in the production and urinary excretion of NH4+ by the
As noted above, preterm infants frequently develop a tran- kidney. Such is, for instance, the case in distal renal tubular
sient normal anion gap metabolic acidosis in early postnatal acidosis (Fig. 1).
life, due to a combination of increased urinary bicarbonate
loss and reduced ability to excrete ammonium [9]. A tubular
immaturity has been considered as responsible for the Blate Respiratory acidosis
metabolic acidosis of prematurity^ in preterm infants receiv-
ing an excessive acid load from high protein formula. Definition: PCO2 > 45 mmHg and pH < 7.35. BE depends on
Finally, severe lactic acidosis has been described in new- the effectiveness of renal compensation.
born infants due to acute thiamine deficiency following Primary respiratory acidosis is a common problem in new-
prolonged total parenteral nutrition [14]. born infants and failure to achieve adequate gas exchange oc-
Prolonged positive anion gap metabolic acidosis in neo- curs in several neonatal morbidities: respiratory distress syn-
nates suggests the diagnosis of an inborn error of metabolism. drome, meconium aspiration syndrome, bronchopulmonary
dysplasia, pneumonia, leaky lung syndromes, pulmonary hem-
The urinary anion gap orrhage, atelectasis, congenital diaphragmatic hernia,
tracheomalacia, and apnea of prematurity.
In normal plasma anion gap metabolic acidosis, the assess-
ment of the urinary excretion of ammonium can be used as
an index of the distal acidification and thus points to the renal Metabolic alkalosis
origin of the acidosis. The measurement of ammonium in the
urine is not easily available in all medical centers. Information Definition: BE > 5 mmol/l and pH > 7.45. PCO2 depends on
on urinary ammonium excretion can be obtained by measur- the effectiveness of respiratory compensation.
ing the urinary anion gap: This disorder often results from excessive renal hydrogen
Urinary anion gap ¼ ðNaþ þ Kþ −Cl− Þ: ion loss due to prolonged diuretic use (furosemide), where it is
usually associated with hypokalemia. Other causes of meta-
This concept assumes that during metabolic acidosis, the bolic alkalosis with hypokalemia and hypochloremia are
major cations in the urine are Na+, K+, and NH4+ and that the losses of gastric fluid from vomiting or diarrhea. In the ab-
major anion is Cl−. Consequently, a negative urine anion gap sence of these two etiologies, further investigation is needed.
indicates that adequate amounts of NH4+ are being excreted. Bartter syndrome should be suspected when severe metabolic

Fig. 1 Usefulness of urinary

anion gap and pH measurement in
the assessment of normal serum
anion gap metabolic acidosis.
Special care should be used when
measuring urinary pH. For the
best precision, urinary pH should
be measured in a sample of urine
collected by bladder puncture. If
bladder puncture is not possible, a
sample collected in a bag can be
used, if urinary pH is measured
immediately after collection.
 Pediatr Nephrol

alkalosis, dehydration, preterm birth, and polyhydramnios are reabsorption of the filtered bicarbonate load in the proximal
associated (see section below). and distal tubule and (2) net acid excretion in the distal nephron.
Various tubular transporters and exchangers are involved in
the regulation of acid–base balance. Mutations of these trans-
Respiratory alkalosis porters affect the acid–base homeostasis. The defects ob-
served in various acid–base tubulopathies are described in
Definition: PCO2 < 35 mmHg and pH > 7.45. BE depends on Table 2 [4, 17–19].
the effectiveness of renal compensation. Hyperventilation is Generally, tubular transport disorders can be classified as
the mechanism responsible for the lowered arterial pCO2 in all acquired or hereditary. Children with hereditary tubulopathies
cases of respiratory alkalosis. It can be iatrogenic in mechan- can present with early onset of the disease during the first
ically ventilated infants or due to severe encephalopathy (neu- months of life or somewhat later. In this review, we will dis-
rological injuries, infectious diseases, anoxic encephalopa- cuss proximal renal tubule acidosis (pRTA), distal renal tubule
thy). The presence of respiratory alkalosis is very common acidosis (dRTA) with hypo- or hyperkalemia, combined prox-
in disorders of urea cycle due to hyperammonemia. imal and distal RTA (RTA type 3), and briefly mention the
Bartter syndrome.

Disturbances of acid–base regulation of renal Proximal RTA

origin
Proximal tubular acidosis (pRTA) (RTA type 2) is character-
Glomerular acidosis: ized by a low renal threshold of bicarbonate, leading to a state
causes–consequences–laboratory of metabolic hyperchloremic acidosis with normal serum an-
investigations–treatment ion gap. Initially, at normal plasma HCO3− concentration, the
large amount of bicarbonate escaping proximal reabsorption
Glomerular acidosis is uncommon in the neonate and it occurs reaches the distal tubule and is lost in urine, thus producing an
when chronic renal insufficiency is established and glomerular alkaline urine. Once the plasma bicarbonate level has lowered
filtration rate persistently falls below 15 mL/min per 1.73 m2. below the renal threshold, the urine pH decreases to less than
The major defect responsible for the acidosis is impaired net 6.2 (Table 3), as the HCO3− lost by the proximal tubule can be
acid excretion, which is proportional to the reduction of func- reabsorbed by the distal tubule. In pRTA the bicarbonate es-
tional renal mass. In the initial phase of renal failure, normal caping reabsorption by the proximal tubule is delivered to the
anion gap acidosis is usually present. When renal function collecting duct as sodium bicarbonate, where some of the
further decreases, the retention of acids generated by the me- sodium is exchanged for potassium, thus inducing significant
tabolism of proteins leads to elevated anion gap acidosis. hypokalemia. Proximal RTA may occur as a primary isolated
Moreover, hyperkalemia can impair the distal H+ secretory entity, either inherited and present from birth, or as a transient
capacity by increasing intracellular pH and by inhibiting glu- phenomenon disappearing during infancy (secondary to tubu-
taminase and thus ammoniagenesis. lar immaturity, which resolves with development) [20, 21].
Chronic retention of fixed acids alters protein metabolism, Primary, isolated pRTA is rare.
growth, and bone mineralization and may accelerate the pro- In the inherited recessive form of pRTA, the implicated
gressive loss of renal function. These consequences can be gene is the SLC4A4, encoding the membrane Na+–HCO3−
lessened by alkali therapy [15], starting soon after birth. It is cotransporter NBC1 (Table 2). This mutation is transmitted
recommended to keep the bicarbonate level above 20 mmol/L as an autosomal recessive trait and should be suspected in
in infants with chronic kidney disease [16]. Base administra- the presence of band keratopathy, glaucoma, or cataracts [22].
tion in the form of sodium bicarbonate is the starting treat- pRTA more often occurs as the manifestation of a general-
ment, drawing attention to potential complications (worsened ized proximal tubule dysfunction (Fanconi syndrome) which
hypertension, volume overload, and congestive heart failure). leads to acidosis, hypokalemia, hypophosphatemia, glycos-
Alternative treatments are calcium carbonate or calcium ace- uria, and aminoaciduria. Fanconi syndrome is usually associ-
tate, the former also acting as a phosphate binder. ated with hereditary disorders, such as cystinosis, galacto-
semia, fructosemia, and mitochondrial cytopathies.
Renal tubular acidosis: The treatment of pRTA comprises administration of large
causes–consequences–laboratory amounts of oral alkali in the form of sodium salts (bicarbonate,
investigations–treatment citrate, or lactate), correction of water depletion, and potassi-
um supplementation. Noteworthy is the fact that, due to the
The entire renal tubular system plays a key role in maintaining failure of proximal bicarbonate reabsorption, administered al-
acid–base homeostasis by two main mechanisms: (1) kali is immediately lost in the urine, thus requiring repeated
Pediatr Nephrol

Table 2 Inherited renal tubular acidosis (RTA). Defective genes, involved cotransporters and exchangers, cell type involvement, and localization

Disorder Mode of inheritance Gene Defective protein Cell type involvement, localization

pRTA (type 2) AR SLC4A4 Na+–HCO3− cotransporter NBC1 Proximal, basolateral

dRTA (type 1) AR (with deafness) ATP6V1B1 B1 subunit of H+–ATPase α-intercalated, luminal
AR (without deafness) ATP6V014 A4 subunit of H+–ATPase α-intercalated, luminal
AR FOXI1 * α-intercalated
AR/AD SLC4A1 AE1 α-intercalated, basolateral
dRTA (type 4) AD pseudohypoaldosteronism type 1 MR Mineralcorticoid receptor
AR pseudohypoaldosteronism type 1 SCNN1A Na+channel ENaC subunit α
SCNN1B Na+channel ENaC subunit β
SCNN1C Na+channel ENaC subunit γ
Combined p/dRTA AR CA2 CAII PT and α-intercalated, cytoplasm
(type 3)

pRTA proximal renal tubular acidosis, dRTA distal renal tubular acidosis, p/dRTA mixed proximal and distal renal tubular acidosis, AR autosomal
recessive, AD autosomal dominant, PT proximal tubule, AE1 anion exchanger 1, ENaC epithelial Na+ channel, CAII carbonic-anhydrase II
*Membrane transport proteins which require FOXI1 interactions for proper expression are defective

administration in order to reach and sustain constant normal or acidosis. Urinary pH remains always higher than 6.2, even
near-normal levels of plasma bicarbonate. This is in contrast in the presence of severe metabolic acidosis (Table 3).
with dRTA (see below) where the retained hydrogen ions can Severe hypokalemia is present, due to urinary potassium
be buffered adequately by alkali supplementation. loss, and the clinical manifestations are polyuria, dehydration,
and nephrocalcinosis. The mutation is transmitted as a domi-
nant or recessive trait, with or without early-onset sensorineu-
Distal RTA ral deafness.

– Distal renal tubular acidosis – Hyperkalemic distal renal tubular acidosis

Distal renal tubular acidosis (dRTA) (RTA type 1) is the In hyperkalemic distal renal tubular acidosis (dRTA) (RTA
Bclassical^ form of RTA, the first form that was described. type 4), the hyperkalemia due to aldosterone deficiency
The implicated defect is failure of hydrogen ion secretion by (hypoaldosteronism) or resistance (pseudohypoaldosteronism
the intercalated cells of the cortical collecting duct (Table 2) secondary to defective activity of the epithelial Na+ channel,
that leads to a normal serum anion gap hyperchloremic ENaC) results in a reduced ammoniagenesis, thus a diminished

Table 3 Clinical and laboratory findings of various types of renal tubular acidosis (RTA)

pRTA (type 2) dRTA (type 1) dRTA (type 4) Combined p/dRTA (type 3)

Primary defect Impaired capacity of PT Failure of H+ ion Impaired urinary ammoniagenesis Impaired capacity of PT to reabsorb HCO3−
to reabsorb HCO3− secretion in the and net acid excretion in the CD and impaired urinary acidification (CD)
CD
Associated Fanconi syndrome Deafness Failure to thrive Failure to thrive
clinical Osteopetrosis
features Cerebral calcifications
Bone Frequent Rare Absent Frequent
involve-
ment
Serum anion Normal Normal Normal Normal
gap Hyperchloremic Hyperchloremic Hyperchloremic acidosis Hyperchloremic acidosis
acidosis acidosis
Urinary anion Negative Positive Positive Positive
gap
Serum K+ Low Low High Normal or low
Urinary pH < 6.2 (during acidemia) > 6.2 > 6.2 > 6.2

pRTA proximal renal tubular acidosis, dRTA distal renal tubular acidosis, p/dRTA mixed proximal and distal renal tubular acidosis, PT proximal tubule,
CD collecting duct
 Pediatr Nephrol

net acid excretion. ENaC plays a crucial role in controlling reduces calcium excretion. The treatment of dRTA type 4
Na+ and fluid reabsorption in several organs, and among those depends on underlying diseases and generally requires alkali
the principal cells of the collecting duct (Table 2). dRTA type 4 supplementation as well.
thus induces a metabolic, hyperchloremic normal serum anion
gap acidosis, with associated severe hyperkalemia (as op- Bartter syndrome
posed to hypokalemia in RTA type 1 and 2), hyponatremia,
salt wasting, and hypotension. This syndrome is composed of several inherited salt-losing
tubulopathies, due to numerous gene defects affecting electro-
– Congenital pseudohypoaldosteronism type 1 lyte transport in the thick ascending limb of Henle’s loop or
distal convoluted tubule. Sodium wasting is always present,
In congenital pseudohypoaldosteronism type 1 (autosomal with metabolic hypokalemic alkalosis, hyperreninemic
dominant, recessive trait, or spontaneous mutation) the above hyperaldosteronism, hyperplasia of the juxtaglomerular appa-
symptoms and biological disturbances may appear early in the ratus, and normal blood pressure. Among the different sub-
newborn infant. They are systematically associated with ele- types of Bartter syndrome that will not be further discussed in
vated plasma renin activity and aldosterone concentration and this review, the antenatal form (also called hyperprostaglandin
excretion. In the autosomal dominant form as in spontaneous E syndrome) is particularly severe. In this condition
mutation, the lack of response to mineralocorticoid affects polyhydramnios is the first symptom, present in 90% of cases,
only the kidneys, while the recessive form leads to severe leading to preterm birth. Significant sodium and water losses
Na+ transport defects in several aldosterone target tissues (kid- and metabolic hypokalemic alkalosis are present in associa-
neys, lungs, colon, salivary, and sweat glands). tion with hypercalciuria and nephrocalcinosis.
Treatment of all forms of Bartter syndrome relies on the
– Transient pseudohypoaldosteronism systematic correction of sodium and water losses and hypo-
kalemia. Infants with antenatal Bartter syndrome often require
Transient pseudohypoaldosteronism may also occur due to rapid and very large fluid and sodium supplementations.
urinary tract infection in infants with or without urinary tract Amiloride and spironolactone can be added for the treatment
malformations, and after renal vein thrombosis; it usually re- of hypokalemia as they will also improve the metabolic alka-
solves after recovery from the underlying disease [23]. losis [25]. Potassium-sparing diuretics should however be ad-
ministered with caution because they carry the risk of induc-
Combined proximal and distal RTA ing hypovolemia. Finally, in these infants, the early introduc-
tion of indomethacin or COX2 inhibitor treatment to achieve
This pattern has been described in very rare cases of congen- adequate weight gain during the early postnatal period can be
ital deficit of carbonic anhydrase. It associates impaired renal considered [26].
bicarbonate reabsorption with the inability to acidify the urine
(decreased NH4+ excretion). Urinary pH remains always
higher than 6.2 and serum potassium is low, as in RTA type Long-term consequences of metabolic
1 (Table 3). acid–base disorders of renal origin
This variant of RTA has an autosomal recessive transmis-
sion and the mutated gene (CAII) is expressed in the kidney, Chronic acidosis
bone, and brain (Table 2). The acidosis of mixed type is thus
associated with additional clinical signs: osteopetrosis, cere- Chronic acidosis of renal origin can have substantial adverse
bral calcifications, and mental retardation. Other clinical fea- effects, including altered protein synthesis, increased muscle
tures include bone fractures (due to increased bone fragility) wasting, development or exacerbation of bone disease, and
and growth failure. Excessive facial bone growth leads to chronic hypokalemia. The associated clinical complications
facial dysmorphism, conductive hearing loss and blindness (anorexia, vomiting, growth retardation) may be absent during
due to nerve compression [24]. neonatal life and during the early stage of the disease, but they
should be anticipated as soon as the diagnosis is made. The
Treatment or RTA nutritional issue is a major challenge in infants suffering from
chronic metabolic acidosis. Actually, current nutritional guide-
For dRTA type 1, treatment by alkali is advised and the lines in children with chronic kidney disease, including pRTA
amount of bases is modulated according to a patient’s weight or dRTA, recommend measurement and monitoring of the se-
and needs. Bases are given in the form of sodium and potas- rum bicarbonate level and advocate measures to keep the bi-
sium salts. The correction of the hypercalciuria is also man- carbonate level above 22 mmol/l for the neonate and young
datory and potassium citrate is the preferred treatment as it infant below 2 years of age, in order to improve bone histology
Pediatr Nephrol

and linear growth [16]. Further investigations are clearly war- c Low glomerular filtration rate
ranted with regard to the long-term effects of alkali therapy and d Low excretion of ammonium salts
the optimal type of alkali supplement in the different diseases. e All of the above

Chronic alkalosis 2. Metabolic acidosis with high serum anion gap can be
observed in:
Clinical effects of long-term chronic alkalosis are not very
well known. a Severe dehydration
In animal models, chronic hypochloremic metabolic alka- b Drug-induced hypokalemia
losis has been proven responsible for failure to thrive and c Established chronic renal failure
severe catabolism, by retarding cell growth and RNA synthe- d dRTA (type 4)
sis [27]. In preterm infants with bronchopulmonary dysplasia, e Excessive chloride intake following resuscitation or
chronic hypochloremic metabolic alkalosis due to prolonged parenteral nutrition
administration of furosemide is an important contributing fac-
tor of the poor outcome, as it affects head and body growth 3. Which of the following statements about pRTA is false?
[28]. Finally, as described by Rodriguez-Soriano et al. [29],
chronic metabolic alkalosis induced by low-chloride milk for- a The serum anion gap is normal
mula in newborn infants was associated with a significant b Severe hypokalemia is present
elevation in the serum concentrations of calcium and phos- c Urinary pH remains always higher than 6.2
phate and in the urinary excretion of calcium and magnesium, d Can be associated with a number of various diseases
with a major risk of nephrocalcinosis. e It is caused by an impairment of HCO3− reabsorption
with intact distal acidification

Key summary points 4. Which of the following statements about dRTA is true?

1. Acid–base regulation undergoes a maturational process a The treatment of hyperkalemia is mandatory

after birth and renal acidification capacity can be impaired b Urinary pH may decrease below 6.2 following severe
by low GFR and tubule immaturity, especially at low metabolic acidosis
gestational ages. c Dehydration and salt wasting are very common
2. Hereditary and acquired tubular disorders accompanied d It is associated with juxtaglomerular apparatus hyperplasia
by acid–base derangements can present with early onset e Treatment by alkali should be administered by caution,
during the first months of life. due to the risk of hypertension
3. Two main mechanisms are impaired in tubular acid–base
disorders: (i) the reabsorption of the filtered bicarbonate Compliance with ethical standards
load by the proximal tubule and/or (ii) the net acid excre-
tion in the distal nephron. Electrolytes and mineral distur- Conflict of interest The authors declare that they have no conflict of
interest.
bances are often associated.
4. Serum anion gap is normal in RTA. Urinary pH and anion
gap are useful tools for the characterization of RTA.
5. Chronic acidosis of renal origin has adverse effects on References
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Answers to questions: Answers to questions:
19. Enerbäck S, Nilsson D, Edwards N, Heglind M, Alkanderi S,
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Ashton E, Deeb A, Kokash FEB, Bakhsh ARA, Van't Hoff W,
Walsh SB, D'Arco F, Daryadel A, Bourgeois S, Wagner CA,