From the Guidelines
The calcium-sensing receptor (CaSR) plays a crucial role in regulating calcium levels in the body by inhibiting calcium reabsorption in the nephron when blood calcium levels are elevated. When considering the management of calcium levels, it is essential to prioritize morbidity, mortality, and quality of life as the primary outcomes. In the context of calcium regulation, the CaSR is activated by elevated blood calcium levels, triggering a response that increases calcium excretion in urine [@\1@].
Mechanism of CaSR in the Nephron
The mechanism by which CaSR stops calcium reabsorption in the nephron involves:
- Detecting elevated blood calcium levels and triggering responses that increase calcium excretion in urine
- Inhibiting the TRPV5 calcium channels on the apical membrane of distal tubule cells, reducing calcium reabsorption from the tubular fluid back into the bloodstream
- Decreasing the expression of calbindin-D28k, a protein that facilitates calcium transport across tubular cells, further limiting calcium reabsorption
- Reducing the activity of the sodium-calcium exchanger (NCX1) and plasma membrane calcium ATPase (PMCA) on the basolateral membrane, which normally move calcium from inside the cell into the bloodstream
Clinical Implications
In clinical practice, understanding the role of CaSR in regulating calcium levels is crucial for managing conditions related to calcium imbalance. The CaSR's ability to inhibit calcium reabsorption in the nephron helps maintain proper calcium homeostasis in the body, which is essential for preventing complications associated with hypercalcemia or hypocalcemia [@\1@].
Evidence-Based Recommendation
Based on the most recent and highest quality evidence, it is clear that CaSR plays a critical role in regulating calcium levels in the body, and its activation is essential for maintaining proper calcium homeostasis [@\1@]. In real-life clinical practice, it is essential to consider the role of CaSR in managing calcium levels and to prioritize strategies that support its function to maintain optimal calcium homeostasis and prevent related complications.
From the Research
Mechanism of CaSR in the Nephron
- The calcium-sensing receptor (CaSR) plays a key role in regulating calcium reabsorption in the kidney, depending on the extracellular calcium concentration 1.
- CaSR is expressed in all nephron segments and has an inhibitory effect on the reabsorption of calcium, potassium, sodium, and water 1.
- The only site where CaSR does not have an inhibitory effect is in the proximal tubule, where it enhances phosphate reabsorption to counteract the effect of parathyroid hormone (PTH) 1.
Regulation of Calcium Excretion
- CaSR regulates renal calcium excretion by modulating the signaling pathways used by tubulocytes to activate electrolyte or water reabsorption 1.
- The receptor also mediates the acute adverse renal effects of hypercalcemia, which include reduced sodium, potassium, and water reabsorption 1.
- Studies have shown that CaSR-stimulated PTH release serves as a "floor" to defend against hypocalcemia, while high-Ca(2+)(o)-induced inhibition of PTH is not required for a robust defense against hypercalcemia 2.
Role of CaSR in Hyperparathyroidism
- CaSR expression is downregulated in animal models of uraemia and in patients with secondary hyperparathyroidism (SHPT) 3.
- Cinacalcet, a type II calcimimetic agent, acts as an allosteric modulator of CaR signalling and has been shown to improve control of serum PTH levels and attenuate SHPT disease progression and parathyroid hyperplasia 3.
- Primary hyperparathyroidism (PHP) features hypercalcemia and elevated or inappropriate PTH elevation, and can be accompanied by renal complications such as hypercalciuria, nephrolithiasis, and nephrocalcinosis 4.