What causes hyperkalemic distal renal tubular acidosis (type IV)?

Updated: Sep 03, 2020
  • Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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The pathogenesis of hyperkalemic dRTA, the most common RTA, is ascribed to either of 2 mechanisms: (1) a voltage defect or (2) a K+ and H+ secretion rate defect due to aldosterone deficiency or resistance.

The voltage-related type is rarer and is thought to be caused by inadequate negative intratubular electrochemical potential at the cortical collecting duct. This, in turn, causes inadequate secretion of protons and potassium, with decreased trapping and excretion of ammonium and decreased excretion of potassium.

Inadequate voltage generation may be secondary to several factors, including (1) administration of certain drugs, such as amiloride; (2) structural defects that inhibit active sodium reabsorption, such as sickle cell nephropathy; (3) severe limitation of sodium reabsorption in the distal tubule because of proximal sodium avidity, secondary to diseases such as cirrhosis; and (4) increased epithelial permeability to chloride, causing increased reabsorption and preventing the formation of negative voltage linked to sodium reabsorption.

The more common form of hyperkalemic dRTA is due to aldosterone resistance or deficiency. Postulated mechanisms include the following:

  • Destruction of juxtaglomerular cells

  • Decreased sympathetic denervation of the juxtaglomerular apparatus (JGA)

  • Decreased production of prostacyclin, causing a decrease in renin-aldosterone production

  • Primary hypoaldosteronism

  • Secondary hypoaldosteronism from the long-term use of heparin

Aldosterone increases Na+ absorption and the negative intratubular electrochemical potential. It also increases luminal membrane permeability to potassium and stimulates basolateral Na+/K+/ATPase, [7] causing increased urinary potassium losses. Because aldosterone also directly stimulates the proton pump, aldosterone deficiency or resistance would be expected to cause hyperkalemia and acidosis. Another major factor in decreasing net acid excretion is the inhibition of ammoniagenesis due to hyperkalemia (which causes an intracellular alkalosis).

A study by Tseng et al indicated that in infants with urinary tract infection (UTI) but no identifiable risk factors for hyperkalemic dRTA, mutations in the gene NR3C2 may be a factor in the development of this form of RTA as a complication of UTI. [10]

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