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Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations
Haim Mayan1, Vered Carmon, Kira Oleinikov
1Department of Medicine E, Sheba Medical Center, Tel Hashomer, Israel.
Insights
Familial hyperkalemia and hypertension (FHHt) with KLHL3 mutations is linked to hypercalciuria. This genetic disorder affects kidney calcium handling, similar to WNK4 mutations.
Area of Science:
- Nephrology
- Genetics
- Endocrinology
Background:
- Familial hyperkalemia and hypertension (FHHt) is a rare genetic disorder characterized by hyperkalemia, hypertension, and hypercalciuria.
- Mutations in WNK4, WNK1, KLHL3, and CUL3 genes have been identified as causes of FHHt.
- The association between KLHL3 mutations and hypercalciuria in FHHt has not been previously reported.
Purpose of the Study:
- To investigate the presence of hypercalciuria in patients with FHHt caused by KLHL3 mutations.
- To compare urinary calcium excretion in affected individuals with KLHL3 mutations versus unaffected family members and patients with WNK4 mutations.
Main Methods:
- Compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations and their unaffected family members.
- Also compared UCa in affected subjects with FHHt and WNK4 Q565E mutation.
Main Results:
- Two new families with FHHt and KLHL3 mutations (Q309R and R528H) were identified, presenting with short stature or transient tachypnea of the newborn.
- Affected subjects with KLHL3 mutations exhibited significantly higher UCa levels compared to unaffected family members (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca/mmol creatinine, p < 0.0001).
- Hypercalciuria in FHHt with KLHL3 mutations was less severe than in FHHt with WNK4 Q565E mutation (0.608 ± 0.196 vs. 0.860 ± 0.295 mmol Ca/mmol creatinine, p = 0.0168).
Conclusions:
- FHHt caused by KLHL3 mutations is associated with hypercalciuria, in addition to hyperkalemia and hypertension.
- The findings suggest a shared aberrant mechanism of kidney calcium handling in FHHt, regardless of whether it is caused by KLHL3 or WNK4 mutations.
- KLHL3 mutations contribute to the spectrum of genetic causes for FHHt with hypercalciuria.
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.
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