6. S L I D E 5
Algorithm for the clinical evaluation of non–anion gap metabolic acidosis.
Jonathan Pelletier et al. Pediatrics in Review 2017;38:537-
539
7. S L I D E 6
Juan Rodríguez Soriano JASN 2002;13:2160-2170
Type 1 – Distal RTA
8. S L I D E 7
Acquired causes
• Medications
– Amphotericin B.
– Lithium
– NSAIDs
– Ifosfamide
• Autoimmune disorders
– Systemic lupus erythematosus
– Sjögren syndrome
– Rheumatoid arthritis
• Hypercalciuric conditions
– Hyperparathyroidism
– Vitamin D intoxication
• Obstructive uropathy
9. S L I D E 8
Genetic causes of distal RTA
Gene
Gene
location
Protein Features
Autosomal recessive
with deafness
ATP6V1B1 2p13
B1 subunit of H-
ATPase
Presents in infancy with severe metabolic
acidosis, poor growth, rickets, and
nephrocalcinosis
Autosomal recessive
without deafness
ATP6V0A4 7q33-q34
a4 subunit of H-
ATPase
Presents in infancy with severe metabolic
acidosis, poor growth, rickets, and
nephrocalcinosis
Autosomal dominant SLC4A1 17q21-q22
Chloride-
bicarbonate
exchanger
Presents later in life (eg, adolescence and
adulthood) with mild/moderate metabolic
acidosis, hypercalciuria, nephrolithiasis or
nephrocalcinosis, osteomalacia, and
erythrocytosis; may be associated with
hereditary spherocytosis and ovalocytosis
10. S L I D E 9
• 18 patients from four families
• All were heterozygous for mutations in
red cell HCO3-/Cl- exchanger, band 3
(AE1, SLC4A1) genes.
• 10 mild acidosis (bicarbonate 15 to 21).
All had nephrocalcinosis.
• 8 impaired urinary acidification, but
not acidotic (bicarbonate ≥ 22).
(incomplete distal RTA).
• 12 normal K
• 5 K 3.0 to 3.4
• 1 severe hypokalemia (~2).
13. S L I D E 12
Treatment
• Alkali therapy (e.g. Na-bicarbonate or Na-citrate)
– Younger children require higher doses (as much as 4 to 8 meq/kg per
day in divided doses) because the rapidly growing skeleton generates
an additional acid load.
• This prevents poor growth, rickets, nephrocalcinosis, and reduces
inappropriate urinary potassium losses.
• K-citrate or polycitra (Na-citrate & K-citrate) for hypokalemia not
corrected with bicarbonate therapy
14. S L I D E 13
Prognosis
• Prognosis is excellent if diagnosed and treated early
• Delayed or untreated will lead to poor growth, rickets,
nephrocalcinosis, and CKD
• CKD
– Nephrocalcinosis
– Persistent hypokalemia,
– Progressive tubulointerstitial damage
– Repeated episodes of dehydration and AKIs
15. S L I D E 14
Juan Rodríguez Soriano JASN 2002;13:2160-2170
Type 2 – Proximal RTA
16. S L I D E 15
Isolated proximal RTA
Transient or sporadic proximal RTA:
• Usually present within the first year of life with tachypnea, growth
failure, recurrent vomiting, and feeding difficulties
• Extended functional immaturity of the proximal sodium-hydrogen
exchanger, -> age-based decrease in bicarbonate reabsorption
capacity
• Alkali therapy:
– Excellent outcome
– Can be discontinued after several years without recurrence of RTA
17. S L I D E 16
Inherited Isolated Proximal RTA
Gene
Gene
location
Protein Features
Autosomal
recessive
SLC4A4 4q21
Sodium
bicarbonate
cotransporter
(NBC)
Severe hypokalemic,
hyperchloremic, metabolic
acidosis, growth retardation,
and ocular abnormalities
(glaucoma, cataracts, and band
keratopathy)
Autosomal
dominant
Unknown Unknown Unknown
Short stature and metabolic
acidosis
20. S L I D E 19
Fanconi syndrome
Growth failure
Episodes of hypovolemia
Persistent acidosis
Chronic hypokalemia
Rickets
Hypophosphatemia
Proteinuria
Glucosuria
21. S L I D E 20
Genetic conditions associated with Fanconi syndrome
Cystinosis
Tyrosinemia
Hereditary fructose intolerance
Galactosemia
Glycogen storage disease (type I)
Wilson disease
Lowe syndrome
22. S L I D E 21
Acquired causes of Fanconi syndrome
Drugs
• Aminoglycosides
• Cisplatin
• Valproic acid
Heavy metals
• Lead
Vitamin D deficiency
Renal transplantation
Paroxysmal nocturnal hemoglobinuria
23. S L I D E 22
Treatment of Proximal RTA
• Treat underlying cause (e.g. stop medications)
• Alkali therapy
– More difficult to treat than dRTA (10 to 15 meq/kg per day
compared to 1 to 2 meq/kg per day for dRTA)
• Phosphate and vitamin D supplementation for
hypophosphatemia
• Thiazide diuretic (mild volume depletion -> enhance
proximal reabsorption of sodium and bicarb will follow)
24. S L I D E 23
• CA2 is a widely expressed gene
Type 3 – Mixed RTA
Gene Gene location Protein Features
Autosomal
recessive
Carbonic
anhydrase II
8q22
Carbonic
anhydrase II
Mixed RTA, osteopetrosis,
cerebral calcification, and
mental retardation
25. S L I D E 24
Type 4 – Hypoaldosteronism
• Hyperkalemia
• Hyponatremia
• Mild acidosis
• Failure to thrive
Collecting tubule principal cells
26. S L I D E 25
Common causes of Hypoaldosteronism
• Most commonly in pediatrics due to medications:
– NSAIDs
– ACEi, ARBs, DRIs
– CNI (cyclosporine and tacrolimus)
– K-sparing diuretics (e.g. spironolactone)
– Chronic heparin therapy (impairs aldosterone synthesis)
• Primary adrenal insufficiency
• HIV
• Severe illness
• Inherited disorders
– Congenital hypoaldosteronism (21-hydroxylase deficiency and isolated
hypoaldosteronism)
– Pseudohypoaldosteronism type 2 (Gordon's syndrome)
27. S L I D E 26
Treatment
• Treat underlying cause (e.g. stop medications)
• Mineralocorticoid or glucocorticoid replacement
therapy based on the underlying etiology
Algorithm for the clinical evaluation of non–anion gap metabolic acidosis. RTA=renal tubular acidosis. (Modified with permission from Gbadegesin R, Foreman W. Renal tubular acidosis. In: Chand DH, Valentini RP, eds. Clinician's Manual of Pediatric Nephrology. 1st ed. Singapore: World Scientific Publishing Co; 2011.)
Figure 2. Schematic model of H+ secretion in cortical collecting tubule. The main pump for luminal H+ secretion in the α type-intercalated cell is a vacuolar H+-ATPase. A H+,K+-ATPase is also involved in H+ secretion. Intracellularly formed HCO3− leaves the cell via Cl−-HCO−3 exchange, facilitated by an anion exchanger (AE1). Cytoplasmic carbonic anhydrase II (CA II) is necessary to secrete H+.
The use of lipid formulations of amphotericin B avoids tubular damage and RTA.
Lithium can cause an incomplete distal RTA with impairment of urine acidification but typically does not cause metabolic acidosis.
Distal RTA may be present in patients with obstructive uropathy due to diminished sodium reabsorption by the principal cells of the distal renal tubule
Recessive distal RTA with deafness; bilateral sensorineural hearing loss (SNHL) that typically begins in infancy. Treatment of acidosis prevents poor growth, rickets, and nephrocalcinosis but does not improve or prevent ongoing hearing loss.
Recessive distal RTA without deafness: This gene product is also expressed in the inner ear, although most children with ATP6V0A4 gene mutations have normal hearing based upon audiometric screening, there are cases with sensorineural hearing loss
Next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype.
CKD almost always after pubertal growth spurt, probably because of compensatory hyperfiltration of functioning nephrons during childhood.
Figure 1. Schematic model of HCO3− reabsorption in proximal convoluted tubule. The processes occurring are H+ secretion at the luminal membrane via a specific Na+- H+ exchanger (NHE-3) and HCO3− transport at the basolateral membrane via a 1 Na+-3 HCO3− cotransporter (NBC-1). Cytoplasmic carbonic anhydrase II (CA II) and membrane-bound carbonic anhydrase IV (CA IV) are necessary to reabsorb HCO3−.
In children, isolated proximal RTA is rare
Autosomal recessive proximal RTA: rare disorder with reported cases from Europe and Japan
Report an Israeli family with isolated pRTA, inherited in AD fashion with no gene found
They studied the following genes: CA II, CA IV, CA XIV, NCB1, Na + /H + exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl − /HCO −3 exchanger, SLC26A6
All negative
Treatment of the metabolic acidosis is more difficult in proximal RTA than in distal RTA because raising the serum bicarbonate concentration will increase the filtered bicarbonate load above the proximal tubule's reduced reabsorptive capacity, resulting in a marked bicarbonate diuresis. Thus, in contrast to the 1 to 2 meq/kg per day of alkali therapy required for treatment of distal RTA, 10 to 15 meq/kg per day of alkali may be required in patients with proximal RTA to stay ahead of urinary bicarbonate losses
The entry of filtered sodium into these cells is mediated by selective sodium channels in the apical (luminal) membrane; the energy for this process is provided by the favorable electrochemical gradient for sodium (cell interior electronegative and low cell sodium concentration). Reabsorbed sodium is pumped out of the cell by the Na-K-ATPase pump in the basolateral (peritubular) membrane. The reabsorption of cationic sodium makes the lumen electronegative, thereby creating a favorable gradient for the secretion of potassium into the lumen via potassium channels in the apical membrane. Aldosterone (Aldo), after combining with the cytosolic mineralocorticoid receptor (Aldo-R), leads to enhanced sodium reabsorption and potassium secretion by increasing both the number of open sodium channels and the number of Na-K-ATPase pumps.
