鈣 – Calcium

作者/講者: 王舜禾醫師

整理: 楊澤斌醫師

校稿: Ian YC Chen, MD

上次校閱: 2018/08/2ˋ

Lab data 中，鈣 (Ca) 後面的 normal range 是在 albumin = 4g/dL 下的數值。

Ca 的矯正公式是讓我們算出當病人 albumin=4 g/dL 的時候他的血鈣會是多少，以便跟 normal range 做比較。

正常狀況下細胞外面的 Ca 比細胞內的 Ca 多很多，所以人體的機制會把血 Ca 控制在很精準的範圍內。

磷 (P) 在細胞內外濃度就沒差那麼多。

Ca-sensing receptor 受 pH 值影響 ==> 血液變鹼時 (alkalosis)，血鈣會降低

副甲狀腺受細胞外液的 Ca 影響。

副甲狀腺受細胞外液的 Ca 影響，身體對低血鈣很敏感，當血 Ca 降低一點的時候 intact parathyroid hormone (iPTH) 就會馬上飆升。

血鈣升高時 iPTH 濃度反而沒有很大的改變。

Paraneoplastic syndrome: squamous cell carcinoma 可能分泌 parathyroid hormone-related protein (PTHrP) 造成高血鈣 (hypercalcemia)

Postpartum osteoporosis: 乳房分泌 PTHrP==> 骨頭裡的 Ca 被釋放至血液中，供小嬰兒成長

PTH 作用在 osteoblast 上，分泌 RANK-L 和 M-CSF，進而刺激 osteoclast 成熟去分解骨頭，造成血中 Ca 和 P 上升。

Calcium reabsorption and calcium-sensing receptor in the nephron.

(A) Proximal tubule: 50%–60% of filtered Ca²⁺ is reabsorbed paracellularly. Luminal calcium-sensing receptor (CSR) activation counteracts parathyroid hormone (PTH)-mediated Pi excretion, thereby promoting Pi conservation.

(B) Thick ascending limb: 30%–35% of filtered Ca²⁺ is reabsorbed paracellularly. Basolateral CSR inhibits potassium excretion via renal outer medullary potassium channel (ROMK), diminishing Ca²⁺ (as well as magnesium) reabsorption. Diminished potassium exit also reduces NaCl reabsorption via NKCl2, analogous to the effect of loop diuretics.

(C) Distal convoluted tubule: 10% of filtered Ca²⁺ is reabsorbed transcellularly. Basolateral CSR inhibits plasma membrane calcium ATPase (PMCA), thereby inhibiting transcellular Ca²⁺ reabsorption.

(D) Collecting duct: in the principle cells, activation of CSR inhibits retention of aquaporin-2 in the luminal-surface of the plasma membrane, thereby inhibiting antidiuretic hormone-mediated water conservation, causing renal water wasting. In the intercalated cells, CSR promotes the activity of proton pump (H+-ATPase), enhancing urine acidification, thereby minimizing the risk of Ca²⁺ × Pi supersaturation.

Nutrients. 2013 Jun; 5(6): 1913–1936.

Pi : inorganic phosphate

PTH 在 proximal tublue 抑制 Na-P cotransporter，促進排 P 的作用。

PTH 在 proximal tublue 也會促進 CYP27B1(1α-hydroxylase)，讓 25-OH VitD 變成1,25-OH2 VitD。

Localization of the calcium-sensing receptor (CaSR) in the kidney tubule.

a | CaSR expression and function in the proximal tubule. The CaSR blunts the phosphaturic action of parathyroid hormone (PTH), inhibits the activity of CYP27B1 (25-hydroxyvitamin D3 1α-hydroxylase), and promotes acidification via the sodium–hydrogen exchanger SLC9A3, which in turns drives Na⁺ accumulation in the interstitium and solute reabsorption.

b | CaSR in the thick ascending limb (TAL). Hypercalcaemia activates the CaSR in the TAL, which leads to inhibition of the renal outer medulla K⁺ (ROMK) channel, thereby preventing apical K⁺ recycling — the rate-limiting step for Na-K-Cl cotransporter (SLC12A1) activity. This effect leads to a loss of the driving force for paracellular cation reabsorption. Thus, hypercalcaemia mimics the effects of loop diuretics and recapitulates Bartter syndrome types 1 and 2 phenotypes, ascribed to mutations in the genes encoding SLC12A1 and ROMK, respectively. This effect is also mimicked by activating mutations in the CaSR gene that causes type 5 Bartter syndrome with hypercalciuria, hypokalaemic alkalosis and hyper-reninaemic hyperaldosteronism. Bartter syndrome types 3 and 4 are caused by mutations in the genes encoding the basolateral Cl− channel, CLCKB, or its auxiliary subunit, Barttin, respectively. CaSR activation also directly regulates paracellular permeability via NFATc1–miRNA–CLDN14 signalling.

c | CaSR in the distal convoluted tubule (DCT). At the apical membrane, the CaSR is biochemically associated with the 1,25(OH)2D3-regulated transient receptor potential cation channel subfamily V member 5 (TRPV5). Increased Ca²⁺ delivery to the DCT results in CaSR activation and increased apical Ca²⁺ entry via TRPV5. Intracellularly, calbindin–D28K (CALB1) delivers Ca²⁺ to the basolateral membrane where Ca2+ exits the cell via active mechanisms (ATP2B1 and SLC8A1). The CaSR also decreases the surface expression of the K⁺ channel KCNJ10, which results in inhibition of NaCl2 reabsorption.

d | CaSR in the collecting duct. In the presence of an antidiuretic stimulus, Ca2+ concentrations in the pre-urine can become super-saturating, potentially leading to Ca²⁺ stone formation. When the luminal Ca²⁺ concentration becomes critically high it activates the apical CaSR which, in principal cells, blunts vasopressin-mediated apical insertion of the aquaporin 2 (AQP2) water channel and the rate of water reabsorption. In intercalated cells, CaSR activation leads to luminal acidification. Overall, these two effects result in the production of a dilute, acidified urine, which reduces the risk of nephrolithiasis. 20-HETE, 20-hydroxyeicosatetraenoic acid; ATP2B1, plasma membrane calcium-transporting ATPase 1; AQP, aquaporin; AVP, arginine vasopressin; Cld, claudin; miRNA, microRNA; NFAT, nuclear factor of activated T cells; SLC8A1, sodium–calcium exchanger 1; SLC12A3, solute carrier family 12 member 3; PTH1R, parathyroid hormone 1 receptor; SLC4A4, sodium bicarbonate cotransporter 1.

Nat. Rev. Nephrol. doi:10.1038/nrenph.2016.59

PTH 在 thick ascending limb 會間接促進 NKCC2 pump 和 ROMK 作用，ROMK 讓 K 往尿中打，造成外面的陽離子比較多，細胞就會回收 Ca、Mg 回來讓電荷平衡 (回收 Ca)。

PTH 在 distal tubule 會經由增加 cAMP、打開 TRPV5 channel，讓 Ca 從尿中回收進來，再經由 ATP pump 或 Na-Ca exchange transporter 把 Ca 運到血中。

使用 furosemide 時，抑制了 NKCC2，導致流過 distal tubule 的尿中 Na 濃度變高，distal tubule cell 中的 Na 濃度也會增高，導致 Na-Ca exchange transporter 無法把 Na 從血中打進 tubule cell，Ca 也就很難回到血中，造成低血鈣。

使用 thiazide 時，抑制了 distal tublue 的 Na-Cl cotransporter，造成 distal tubule cell 中的 Na 濃度變低， Na-Ca exchange transporter 就更容易把 Ca 打到血中，造成高血鈣。

Mechanisms of renal calcium transport

In the thick ascending limb of Henle’s loop, the creation of a lumen poparathyroid hormone and 1,25(OH)2D3sitive voltage tends to drive Ca²⁺ and Mg²⁺ through a paracellular path and thereby produces a high rate of reabsorption of the divalent ions. The CaSR modulates this transport activity by altering rates of K efflux and thereby contributing to the lumen positive voltage. In the distal convoluted tubule, a three-step process facilitates active and transcellular Ca²⁺ transport. The first step is entry of luminal Ca²⁺ at the apical side of the cell through the TRPV5 channel. Subsequently, calbindin, a calcium binding protein buffers Ca²⁺ and the Ca²⁺ diffuses to the basolateral membrane. At the basolateral membrane, Ca²⁺ is extruded by across the basolateral membrane by NCX. This process is controlled by calciotropic hormones, including parathyroid hormone and 1,25(OH)2D3.

Abbreviations:

NKCC, sodium potassium-2-chloride co-transporter;

ROM-K, renal outer medullary potassium channel;

CaSR, calcium sensing receptor;

NaKATPase, sodium potassium ATPase;

+, stimulates;

−, inhibits;

NCC, sodium chloride co-transporter;

NCX, sodium calcium exchanger;

TRPV5, transient receptor potential vanilloid membrane calcium channel

Nutrients 2013, 5(12), 4880-4893