Hypercalciuria in Familial Hyperkalemia and Hypertension with KLHL3 Mutations

Abstract

Background: Familial hyperkalemia and hypertension (FHHt) is a rare genetic disorder manifested by hyperkalemia and early hypertension. Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are components of the Ubiquitin system. It was not reported whether these latter mutations are accompanied by hypercalciuria. Methods: We compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations, and in their unaffected family members, and in affected subjects with FHHt and WNK4 Q565E mutation. Results: Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified. Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second. Affected subjects had hypercalciuria. UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001)). Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation (0.608 ± 0.196 (n = 10) mmol Ca per mmol creatinine versus 0.860 ± 0.295 (n = 29), respectively (p = 0.0168)). Conclusions: FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension. The similar phenomena observed for FHHt caused by WNK4 mutations fits the other evidence that WNK4 mutations are activating, and the aberrant mechanism of calcium handling by the kidney in FHHt.

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter

“…Family 1 consists of 2 clinically affected subjects with FHHt and their 10 relatives. Family 2 is an expansion of a family previously described by us [13] , adding 13 members to the 7 members with FHHt previously described.…”

“…In addition, a major expansion of another already reported family with FHHt and a dominant KLHL3 mutation, Q309R, is described [13] .…”

“…This is an expansion of the family adding 13 new members to the 5 affected members and 2 unaffected members previously reported [13] . All of the affected subjects in generation II were known to be hypertensive when examined by us, and were treated by a combination antihypertensive therapy, usually including thiazide diuretics.…”

Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase

“…The disease is inherited in an autosomal dominant way, except for recessive transmission in some cases caused by KLHL3 mutations (Boyden et al 2012). In addition to hyperkalemia and hypertension associated with Na retention, FHHt is characterized by hypercalciuria (Mayan et al 2002(Mayan et al , 2015 but normomagnesuria rather than hypomagnesuria (Mayan et al 2002). All the abnormalities are corrected by low doses of thiazides (Mayan et al 2002).…”

“…In addition to hyperkalemia and hypertension associated with Na retention, FHHt is characterized by hypercalciuria (Mayan et al. , ) but normomagnesuria rather than hypomagnesuria (Mayan et al. ).…”