Calcineurin inhibitors (CNIs) are immunosuppressive drugs, which are used widely to prevent rejection of transplanted organs and treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria, and acidosis often complicate their use1,2. These side effects resemble familial hyperkalemic hypertension (FHHt), a genetic disease characterized by overactivity of the renal sodium chloride co-transporter (NCC), and caused by mutations in WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC, and the NCC regulatory kinases WNK3, WNK4, and SPAK. The functional importance of NCC in this response was demonstrated by showing that tacrolimus did not affect blood pressure in NCC knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice over-expressing NCC. Moreover, hydrochlorothiazide reversed tacrolimus-induced hypertension. In kidney transplant recipients treated with tacrolimus, fractional chloride excretion in response to bendroflumethiazide was greater than in controls, and renal NCC abundance was also greater, extending these observations to humans. Together, these findings indicate that tacrolimus-induced hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.

Box 1 | Prevailing attitudes of medical professionals emerging from public review and participant survey Agreement with goal of standardizing nomenclature, with acknowledgment of challenges Regarded multiplicity of terms and lack of adherence to established definitions as confusing and potentially leading to errors Anticipated that a standardized nomenclature would help foster consistency in trial design, execution, and reporting Judged consistency between terms used in scholarly and patient communities to be an important goal, but not one overriding the need for precision and efficiency Journal editors strongly agreed that having a more standardized nomenclature for kidney disease would be useful for their journals, but they anticipated time constraints of journal personnel to be the biggest barrier to implementation Qualified endorsement of replacing "renal" with "kidney" Felt that foregrounding "kidney" would be easier for patients and their families Perceived a greater likelihood of raising awareness, attracting funding, and influencing public policy with consistent use of "kidney" Cautioned against a wholesale switch because "renal" may be less awkward in some contexts and may be necessary in others (e.g., ESRD as a CMS definition) Dissatisfaction with "end-stage" as a descriptor of kidney disease Recognized that this wording can be demoralizing and stigmatizing for patients Considered the implication of imminent death to be outdated Frustrated by imprecision in its use (ranging from being a synonym for dialysis patients to a descriptor of patients with kidney failure with or without kidney replacement therapy) Recognition of the need for ongoing attention to nomenclature issues Noted that standardization of nomenclature is dependent on uptake of consensus definitions B where definitions are in flux or are more contentious, standardization of that nomenclature set may be premature B enhancing adoption of definitions requires continued effort Highlighted the need for harmonization with ongoing, broader-scope ontology efforts Expected that improved understanding of molecular mechanisms will lead to more-precise definitions and nomenclature CMS, Centers for Medicare & Medicaid Services; ESRD, end-stage renal disease.

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Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg2+ by the thick ascending limb of Henle’s loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg2+ wasting, as evidenced by an inappropriately high fractional Mg2+ excretion. Familial renal Mg2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns–Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.