Classification of pseudohypoaldosteronism type II as type IV renal tubular acidosis: results of a literature review

Abstract

Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the aid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K + ) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl -) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cland HCO3levels showed significant correlations with K + levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.

The TMEM16A channel as a potential therapeutic target in vascular disease

“…Hypochloraemia ([Cl − ] e < 96 mM) is observed in patients with chronic cardiac failure and is associated with higher risk of mortality in patients with acute or chronic heart failure [ 32 , 33 , 34 , 35 ]. Hyperchloremia ([Cl − ] e > 110 mM), which accompanies a range of kidney disturbances, is an independent predictor for hypertension [ 36 , 37 ], and positively associated with increased mortality rate of hospitalised patients [ 34 ]. These conditions are expected to impact E Cl and thus the magnitude of TMEM16A currents.…”