TO THE EDITOR:
We have observed hypernatraemia and hypokalaemia with normal serum urea
and creatinine associated with new-onset hypertension among COVID-19
patients. We assessed the renin-angiotensin-aldosterone system (RAAS) of
2 patients during the pandemic and found elevated urinary potassium
(without causal medications) and hyporeninaemic hypoaldosteronism in
both.
We fully investigated a fit 74-year-old woman with COVID-19 who
developed hypertension (peak blood pressure (BP) 195/120 mmHg),
hypokalaemia (range 2.7–3.2 mmol/L) and hypernatraemia (range 150-166
mmol/L) during the first week of admission. There was metabolic
alkalosis with pH 7.50, bicarbonate 31mmol/L, partial pressure of carbon
dioxide 5.3 kPa. Adjusted calcium and serum magnesium were normal.
Urinary potassium (K+) was 19.72 mmol/L and 24.46 mmol/L (0-10) on 2
occasions. Plasma renin was <0.2 nmol/L/hr (0.5-3.5) and
aldosterone <60 pmol/L (60-250).
Congenital forms of hypertension, glucocorticoid resistance and syndrome
of apparent mineralocorticoid excess were excluded. There were no
features of hypothalamic-pituitary dysfunction.
She was treated with amiloride 5mg daily increased to 7.5mg after 3 days
with normalisation of serum/urinary K+ and BP within 1 week (Table).
After 3 weeks amiloride was withdrawn and she remained normotensive.
Plasma renin and aldosterone levels remained normal thereafter.
Transient hyporeninaemic hypoaldosteronism may be related to
dysregulated sodium (Na+) channel (ENaC) pathophysiology similar to that
in Liddle’s syndrome. Enhanced ENaC activity (highly selective for Na+
over K+) leads to Na+ retention in the distal nephron and K+ and
hydrogen ion secretion to maintain tubular neutrality. This results in
intravascular volume expansion and hypokalaemic metabolic alkalosis.
This hypothesis is supported by reversibility of electrolyte
abnormalities and hypertension with the diuretic amiloride which
inhibits Na+ reabsorption by selectively blocking this channel
[1,2].
Normalisation of the RAAS during convalescence favour an immediate,
self-limiting pathological response related to COVID-19 with a direct
effect on ENaC homeostasis leading to a distal tubulopathy.
Viral- angiotensin converting enzyme 2 (ACE2) binding and its
degradation in COVID-19 may provide the mechanism. Chen et al. reported
high prevalence of hypokalaemia which was difficult to correct because
of ongoing renal loss arising from ACE2 degradation. They suggested that
reduced counteractivity of ACE2 against ACE1 resulted in disordered RAAS
activity and that the end of renal loss of K+ reflected the end of
disruption on the RAAS [3]. Our findings support this.
Viral-ACE2 binding may promote Na+ resorption and hypertension via 2
distinct mechanisms which both enhance ENaC activity. Firstly, through
increased angiotensin II (AngII) which directly stimulates ENaC activity
[7]. ACE2 is abundant in renal tubular epithelium and its
downregulation through viral binding increases AngII which in turn
increases ENaC activity. And secondly, through increased aldosterone
expression. Expression of ACE2 is the principal counter-regulatory
mechanism of the RAAS and its downregulation amplifies the ACE-AngII
pathway which stimulates aldosterone secretion and augments ENaC
activity [4]. Both processes result in Na+ resorption with
hypertension and distal tubulopathy with K+ secretion. The first
“aldosterone-independent” process is the probable underlying mechanism
here and hyporeninaemic hypoaldosteronism reflects appropriate RAAS
suppression in response to hypertension and hypokalaemia.
Clinicians should consider investigating the RAAS when faced with
unexplained hypokalaemia and hypernatraemia in COVID-19 patients who
develop severe hypertension and these patients could be trialled with
amiloride.