What are the genetic forms of type 4 renal tubular acidosis (RTA)?

Updated: Oct 10, 2018
  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Answer

Although type 4 RTA occurs sporadically, familial forms have been reported. The genetic forms are called PHA; PHA type 1 is characterized by hypotension with hyperkalemia and acidosis and includes an autosomal recessive and autosomal dominant form. PHA type 2 is characterized by hypertension with hyperkalemia and acidosis and is also known as Gordon syndrome and familial hyperkalemic hypertension. Note the following:

  • Autosomal recessive PHA type 1: Homozygous mutations in the alpha, beta, or gamma subunits (gene symbols SCNN1A, SCNN1B, and SCNN1G) of the collecting duct epithelial sodium channel cause a syndrome that manifests in infancy with severe salt wasting, hypotension, hyperkalemia, and acidosis. A pulmonary syndrome characterized by recurrent respiratory infections, chronic cough, and increased respiratory secretions has also been noted in some individuals.

  • Autosomal dominant PHA type 1: Heterozygous mutations in the mineralocorticoid receptor lead to a milder phenotype that is restricted to the kidneys. Unlike the autosomal recessive form, the clinical symptoms improve with age.

  • Gordon syndrome (PHA type 2): This disorder is characterized by hypertension and hyperkalemia with variable degrees of metabolic acidosis. There are at least 5 genetic loci associated with this disease. Heterozygous mutations in 1 of 2 kinases, WNK1 or WNK4, or in the CUL3 gene cause this syndrome. Heterozygous or homozygous mutations in the KLHL3 genecause an autosomal dominant or recessive form of this syndrome. A fifth locus on band 1q has been described, but the genetic defect at this locus has not yet been identified.

Table. Comparison of Types 1, 2, and 4 RTA (Open Table in a new window)

Characteristics

Proximal (Type 2)

Distal (Type 1)

Type 4

Primary defect

Proximal HCO3 - reabsorption

Diminished distal H+ secretion

Diminished ammoniagenesis

Urine pH

< 5.5 when serum HCO3 - is low

>5.5

< 5.5

Serum HCO3 -

>15 mEq/L

Can be < 10 mEq/L

>15 mEq/L

Fractional excretion of HCO3 - (FEHCO3)

>15-20% during HCO3 - load

< 5% (can be as high as 10% in children)

< 5%

Serum K+

Normal or mild decrease

Mild-to-severe decrease*

High

Associated features

Fanconi syndrome

...

Diabetes mellitus, renal insufficiency

Alkali therapy

High doses

Low doses

Low doses

Complications

Osteomalacia or rickets

Nephrocalcinosis, nephrolithiasis

...

*K+ may be high if RTA is due to volume depletion.


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