Dangerous hyperkalemia in a newborn: Answers

The first differential considered was late onset sepsis with acute kidney injury (AKI) and dyselectrolytemia. Since this newborn had hyperkalemia with hyponatremia, out of proportion to his AKI and sepsis, congenital adrenal hyperplasia (CAH-salt wasting type) was also considered. CAH due to 21-hydroxylase deficiency leads to decreased cortisol and aldosterone which may present clinically like aldosterone resistance. In girls, virilization may be seen while in boys only increased pigmentation may be noted, which was absent in this child.

Other inborn errors of metabolism and pseudo-hypoaldosteronism (PHA) [primary or secondary] were also considered as rare differentials, which could be confirmed on investigations. Secondary/transient PHA occurs in the setting of obstructive urinary tract malformation or a urinary tract infection and usually gets corrected after adequate fluid resuscitation and management of infections [1], while other types of PHA are genetically mediated disorders of tubular transport of potassium and sodium.

Type 4 renal tubular acidosis (RTA) and was also considered in view of deranged renal functions and hyperkalemia, but it occurs in setting of obstructive uropathy or diabetic nephropathy, which were absent in the child.

Sepsis induced AKI as a primary cause for his illness was ruled out as the child continued to have severe hyperkalemia despite improvement in sepsis and initial resuscitation.

His cortisol level was 15.94 μg/dl (normal 2–11 μg/dl); 17 –OH progesterone was 8.13 ng/dl (3–90 ng/dl) which ruled out CAH. Serum ammonia, lactate, and blood sugar were normal which ruled against inborn errors of metabolism.

RTA type 4 and secondary or transient PHA was ruled out as renal dysfunction improved after correcting the initial shock and fluid bolus, and ultrasound of kidneys and urinary tract did not reveal any obstructive pathology.

Serum aldosterone was 171.1 ng/dl (normal range 2.52–39.2 ng/dl) and serum renin was 6.11 ng/ml (normal range 0.15–2.33 ng/ml), favoring a diagnosis of PHA, likely of genetic etiology as secondary and transient forms were ruled out.

Among the various types of PHA that are described, the PHA type 1 may be (a) systemic/multiple site form or (b) renal limited. The former occurs due to defects in epithelial sodium channel (ENaC) or defective mineralocorticoid receptor at multiple sites. Since the ENaC is expressed in all epithelial tissues, it is associated with widespread systemic manifestations, like recurrent pulmonary infections [1, 2]. One may find a high sweat or salivary sodium level which provides a clue to multisystem involvement. This helps to differentiate it from the renal limited form, which occurs due to defects in receptors for mineralocorticoid on tubular epithelial cells.

Since our patient had involvement of skin as well as respiratory system, such as recurrent chest and skin infections, the possibility of type 1 autosomal recessive variant of PHA was considered, which could be confirmed further by performing a genetic analysis [3].

PHA occurs due to renal tubular unresponsiveness to the action of aldosterone. Aldosterone acts on the aldosterone receptor and then through nuclear transcription pathways, and increases the activity of basolateral Na/K ATPase, luminal expression of epithelial sodium channel (ENaC) and the activity of luminal renal outer medullary potassium (ROMK) channels (Fig. 1). A defective mineralocorticoid receptor function or a failure of ENaC would lead to sodium wasting and failure of potassium excretion.

Multiple site type 1 PHA (ar-PHA1) is inherited as an autosomal recessive trait due to mutations in SCNN1A located in 12p13.31, SCNN1B, and SCNN1G, both situated in the locus 16p12.2. Each of these three genes is responsible for making one of the subunits of the ENaC protein complex [4]. When homologous mutations are introduced into alpha, beta, or gamma subunits of ENaC, they all bring about a change in sodium channel gating, causing a reduction in sodium channel opening probability [5].

Various mutations have been described worldwide in coding regions of ENaC subunit genes. Most of these cases are attributed to mutations in the alpha subunit gene (SCNN1A). In the present case, a known homozygous mutation in the SCNN1B gene was identified, which is relatively uncommon, as well as a new variant [1].

In the acute phase of illness, the child may require adequate fluid resuscitation, supportive measures for hyperkalemia and even transient dialysis for management of refractory hyperkalemia. For AD-PHA, only sodium supplementation may be required that generally becomes unnecessary by 3 years of age, which may be due to maturation of renal salt conserving ability. In children with AR-PHA, management entails lifelong salt supplementation and intensive monitoring for management of systemic features like respiratory complications [6]. The requirement of sodium may sometimes be very high, reaching up to 15–20 g a day [1]. A diet low in potassium, or measures to reduce potassium content of foods should be instituted for every child [7]. The use of potassium binding resins, like sodium polysterene, helps to excrete large amounts of potassium. In refractory cases, indomethacin may be used to reduce loss of sodium in urine, as it helps inhibit prostaglandin synthesis [6]. Though fludrocortisone is effective in congenital adrenal hyperplasia, the same is not true for PHA as the defective ENaC channel causes resistance to both aldosterone and fludrocortisone.