Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Question 1

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 1

Clinical manifestations:

Rare autosomal-dominant, heterogeneous syndrome

Electrolyte abnormalities occur as early as infancy: hyperkalemia (low renal K+ excretion), metabolic acidosis, hypercalciuria (osteoporosis)

Question 2

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 2

HTN:

May not be detected until two to four decades later

All patients will eventually develop HTN in adulthood.

Question 3

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 3

Kidney function is normal in most cases.

Low plasma renin and low-to-normal serum aldosterone levels despite normal adrenal function

Question 4

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Primary Defects:

Answer 4

Increased sodium chloride cotransport (NCC) expression and activity due to mutations of its regulatory molecules:

Increased Na+ reabsorption at NCC leads to reduced Na+ delivery to collecting tubules, hence reduced K+ excretion (hyperkalemia) and reduced H+ excretion (metabolic acidosis). See renal tubular acidosis section for mechanisms of how low Na+ delivery to collecting tubules can lead to hyperkalemia and metabolic acidosis.

Hyperkalemia also contributes to reduced H+ excretion (via reduced ammoniagenesis).

Question 5

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 5

Increased paracellular chloride reabsorption

Increased NaCl reabsorption above leads to volume expansion, HTN, and inhibition of RAAS, hence low renin ± low aldosterone levels. Low aldosterone levels can also contribute to hyperkalemia and metabolic acidosis.

Question 6

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 6

Reported mutations of NCC regulatory molecules leading to FHH: With-no-lysine kinases 1 to 4 (WNK 1-4) 1-4, Kelch-like 3 (KLHL3) and Cullin 3 (CUL3)

Question 7

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 7

WNK1 gain-of-function mutation enhances NCC activity

Question 8

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 8

Loss of function mutation of WNK4:

Enhances NCC activity and distal convoluted tubular (DCT) hyperplasia, thus Na+ retention.

Mutated WNK4 enhances ROMK endocytosis, reduces K+ excretion, and causes hyperkalemia.

Question 9

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 9

Loss of function mutation of WNK4 cont’d:

Mutations in WNK4 also downregulate the transient receptor potential V5 channel (TRPV5, calcium channel) and decrease Ca2+ reabsorption in DCT, thus hypercalciuria and osteoporosis.

Question 10

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 10

KLHL3 and CUL3 mutations: Mutations in KLHL3 or CUL3 can lead to impaired ubiquitination of NCC, a process whereby NCC is normally internalized and degraded. Impaired removal of NCC from apical membrane leads to increased Na+ reabsorption at DCT, hence HTN.

Question 11

Summary of molecular mutations leading to the clinical PHAII syndrome:

Mutations of WNK1-4:

Answer 11

↓ROMK → ↓K+ secretion → hyperkalemia, reduced ammoniagenesis, metabolic acidosis.

Question 12

Summary of molecular mutations leading to the clinical PHAII syndrome:

Mutations of WNK1-4:

Answer 12

↑NCC activity → ↑Na+ reabsorption → HTN, volume expansion induced, hyporenin/hypoaldosteronism → hyperkalemia, metabolic acidosis

Question 13

Summary of molecular mutations leading to the clinical PHAII syndrome:

Mutations of WNK1-4:

Answer 13

↑NCC activity → reduced Na+ delivery to cortical collecting tubule (CCT) → ↓K+ and H+ secretion → hyperkalemia, metabolic acidosis

Question 14

Summary of molecular mutations leading to the clinical PHAII syndrome:

Mutations of WNK1-4:

Answer 14

↑paracellular Cl– reabsorption → ↓lumen electronegativity for optimal K+ secretion → hyperkalemia

Question 15

Summary of molecular mutations leading to the clinical PHAII syndrome:

Mutations of WNK1-4:

Answer 15

↓TRPV5 activity → ↓Ca2+ reabsorption in DCT/CT → hypercalciuria → osteoporosis

Question 16

Familial Hyperkalemic HTN, a.k.a. Pseudohypoaldosteronism Type II, Gordon Syndrome

Answer 16

Treatment:

Chronic low salt diet

Thiazide diuretics