Molecular mechanisms of loop diuretics on renal calcium and magnesium transport

In connection with the special series on membrane proteins, epithelial transport, and kidney physiology, we here explore the molecular mechanisms of how loop diuretics act on the kidney and how they influence renal calcium and magnesium transport. Loop diuretics are an important class of compounds that remain a cornerstone for the treatment of adult and pediatric patients with fluid retention due to heart failure, kidney disease, and cirrhosis. Although commonly employed in clinical medicine, their mode of action leads to alterations in mineral balance. Many loop diuretics belong to the group of 4-sulfamoyl benzoic acid derivatives. This class includes furosemide, bumetanide, torasemide, and benzmetanide. Additionally, ethacrynic acid is a nonsulfonamide alternative.1 The loop diuretic furosemide is the most commonly employed in clinical practice. Loop diuretics are a potent class of drugs whose primary site of action is the thick ascending limb (TAL) in the loop of Henle. They act by inhibiting the furosemide-sensitive NKCC2 cotransporter, encoded by the SLC12A1 gene (Figure 1). Loop diuretics primarily exist in the circulation, bound to plasma proteins, and are mainly secreted into the luminal fluid via anion transporters in the proximal tubule.2 From here, they move with luminal fluid to the TAL, where they bind and inhibit the NKCC2 transporter, which is responsible for the reclamation of sodium and chloride from the TAL, resulting in a significant natriuretic response.3 In addition to salt wasting, loop diuretics further diminish the osmotic gradient in the kidney by restricting interstitial sodium chloride accumulation in the medullary interstitium, thereby limiting urinary concentrating capacity and consequently markedly increasing urine volume. The TAL is an important site for reabsorbing both calcium and magnesium, with this segment being responsible for reclaiming 25% of filtered calcium and 60% of filtered magnesium.4 Divalent cation reabsorption occurs via the paracellular pathway in the cortical portion of the segment, in a process that is critically dependent on the formation of a lumen-positive voltage gradient.4 The electrical gradient is created by the transport of sodium, potassium, and chloride ions in the TAL. This process is driven by the coordinated interaction of the NKCC2 cotransporter, ROMK, CLC-Kb channels, and the Na+/K+-ATPase (Figure 1A).4 The transepithelial voltage generated by this process is critical for the paracellular reclamation of calcium and magnesium. Claudins, which are tight junction proteins, in particularly CLDN16 and CLDN19, allow the permeation of calcium and magnesium from this segment. This is illustrated in patients with pathogenic variants in these genes who have familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC).5, 6 The syndrome is characterized by marked renal losses of calcium and magnesium, leading to hypomagnesemia and calcium deposits in the kidneys (nephrocalcinosis).5, 6 Administration of loop diuretics inhibits NKCC2, a primary contributor to the generation of the lumen-positive transepithelial voltage in the TAL. Collapsing the electric gradient is therefore expected to cause a marked loss of calcium and magnesium in urine and potentially secondary alterations in systemic mineral balance (Figure 1B). This is reflected to some degree in patients and experimental animals receiving the compounds. In experimental animals, loop diuretics induce both calciuria and magnesiuria.1 In patients, the administration of loop diuretics results in a significant loss of calcium and magnesium.1, 7, 8 Although hypomagnesemia is a common side effect in patients being treated with loop diuretics, hypocalcemia is rarely reported, perhaps due to strict regulation by calciotropic hormones.1 Nevertheless, urinary wasting of divalent cations may depend on the dose and schedule, and hence the degree to which the transepithelial voltage in the TAL is reduced. Similarly, changes in overall mineral balance may be more penetrant in patients with preexisting calcium and magnesium imbalances.1 Pathogenic variants in NKCC2, ROMK, CLC-Kb, or Barttin that disrupt TAL transport result in different forms of Bartter syndrome. While the disease manifests with consistent features including low blood pressure, metabolic alkalosis, and hypokalemia secondary to renal salt wasting, urinary calcium and magnesium wasting are present to varying degrees depending on the pathogenic variant. Antenatal Bartter syndrome due to pathogenic variants in NKCC2 and ROMK causes significant calcium losses and nephrocalcinosis; however, alterations in magnesium levels are rarely seen.9 Conversely, individuals with classical Bartter syndrome, due to CLCNKB variants, commonly experience hypomagnesemia, while hypercalciuria and nephrocalcinosis are less commonly observed.10 These differences could stem from CLC-Kb being expressed in the distal convoluted tubule (DCT), a critical site of magnesium transport, and because of a milder disruption in TAL transport resulting in less calcium losses. Mice lacking Cldn16 develop features that mimic FHHNC with urinary wasting of calcium and magnesium. Interestingly, when Cldn16-deficient animals were treated with furosemide, hypercalciuria was blunted, likely due to compensatory mechanisms activated in the DCT and connecting tubule, which were not seen in wild-type mice receiving similar treatment.11 Whether furosemide could be employed therapeutically to limit hypercalciuria and the progression of nephrocalcinosis and renal failure in FHHNC patients while minimizing dehydration remains to be tested, but it could be a welcome therapy for these patients. Henrik Dimke: Conceptualization; visualization; writing – original draft; writing – review and editing. R. Todd Alexander: Writing – review and editing; visualization; writing – original draft. Danmarks Frie Forskningsfond Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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