Renal transport of Calcium, Phosphate and Magnesium (1).pdf

RENAL TRANSPORT OF CALCIUM, PHOSPHATE AND MAGNESIUM DR KADER ¡ Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. ¡ The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by...

RENAL TRANSPORT OF CALCIUM, PHOSPHATE AND MAGNESIUM DR KADER ¡ Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. ¡ The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. ¡ When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. ¡ Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. ¡ Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. INTRODUCTION ¡ Imbalances of calcium, phosphorus, and magnesium result in a number of serious clinical complications, including arrhythmias, seizures, and respiratory difficulties. ¡ The kidney plays a critical role in regulating serum levels of these ions. ¡ Regulation of calcium, phosphate, and magnesium occurs in different parts of the nephron and involves a number of different channels, transporters, and pathways. CALCIUM ¡ The total amount of calcium in the human body ranges from 1000 to 1200 g. ¡ Approximately 99% of body calcium resides in the skeleton; the other 1% is present in the extracellular and intracellular spaces. ¡ Although >99% of the total body calcium is located in bone, calcium is a critical cation in both the extracellular and intracellular spaces. ¡ Approximately 1% of the calcium in the skeleton is freely exchangeable with calcium in the extracellular fluid compartment. ¡ Serum calcium concentration is held in a very narrow range in both spaces. ¡ Calcium serves a vital role in nerve impulse transmission, muscular contraction, blood coagulation, hormone secretion, and intercellular adhesion RENAL TRANSPORT OF CALCIUM ¡ Total serum calcium consists of ionized, protein bound, and complexed fractions. ¡ The complexed calcium is bound to molecules such as phosphate and citrate. ¡ The ultrafilterable calcium equals the total of the ionized and complexed fractions. ¡ Normal total serum calcium is approximately 8.9–10.1 mg/dl (about 2.2–2.5 mmol/l). ¡ Calcium can be bound to albumin and globulins. ¡ For each 1.0-g/dl decrease in serum albumin, total serum calcium decreases by 0.8 mg/dl ¡ Acute alkalosis decreases the ionized calcium. Because both hydrogen ions and calcium are bound to serum albumin, in the presence of metabolic alkalosis, bound hydrogen ions dissociate from albumin, freeing up the albumin to bind with more calcium and thereby decreasing the freely ionized portion of the total serum calcium. RENAL TRANSPORT OF CALCIUM ¡ In humans who have a GFR of 170 liters per 24 hours, roughly 10 g of calcium is filtered per day. ¡ The amount of calcium excreted in the urine usually ranges from 100 to 200 mg per 24 hours; hence, 98%– 99% of the filtered load of calcium is reabsorbed by the renal tubules. ¡ Approximately 60%–70% of the filtered calcium is reabsorbed in the proximal convoluted tubule, 20% in the loop of Henle, 10% by the distal convoluted tubule, and 5% by the collecting duct. ¡ The terminal nephron, although responsible for the reabsorption of only 5%–10% of the filtered calcium load, is the major site for regulation of calcium excretion RENAL TRANSPORT OF CALCIUM RENAL TRANSPORT OF CALCIUM- PROXIMAL CONVOLUTED TUBULE ¡ The reabsorption of calcium in the proximal convoluted tubule parallels that of sodium and water. ¡ Proximal tubular calcium reabsorption is thought to occur mainly by passive diffusion and solvent drag. ¡ This is based on the observation that the ratio of calcium in the proximal tubule fluid to that in the glomerular filtrate is 1:1.2. ¡ The passive paracellular pathways account for approximately 80% of calcium reabsorption in this segment of the nephron. A small but significant component of active calcium transport is observed in the proximal tubules. ¡ The active transport of calcium proceeds in a two-step process, with calcium entry from the tubular fluid across the apical membrane and exit though the basolateral membrane. This active transport is generally considered to constitute 10%–15% of total proximal tubule calcium reabsorption and it is mainly regulated by parathyroid hormone (PTH) and calcitonin RENAL TRANSPORT OF CALCIUM- LOOP OF HENLE ¡ No reabsorption of calcium occurs within the thin segment of the loop of Henle. ¡ In the thick ascending limb of the loop of Henle, 20% of the filtered calcium is reabsorbed largely by the cortical thick ascending limb, through both transcellular and paracellular routes. ¡ In the thick ascending limb, the bulk of calcium reabsorption proceeds through the paracellular pathway and is proportional to the transtubular electrochemical driving force. RENAL TRANSPORT OF CALCIUM- DISTAL TUBULE ¡ In contrast with the proximal tubule and the thick ascending limb of the loop of Henle, the distal tubule reabsorbs calcium exclusively via the transcellular route. ¡ The distal convoluted tubule absorbs 5%–10% of the filtered calcium. Calcium absorption in this segment is active because it proceeds against a chemical and an electrical gradient. HORMONAL AND OTHER FACTORS REGULATING RENAL CALCIUM HANDLING PARATHYROID HORMONE ¡ PTH is a polypeptide secreted from the parathyroid gland in response to a decrease in the plasma concentration of ionized calcium. ¡ Therefore, the major physiologic role of the parathyroid gland is to regulate calcium homeostasis. ¡ PTH acts to increase the plasma concentration of calcium in three ways: 1. It stimulates bone resorption 2. It enhances intestinal calcium and phosphate absorption by promoting the formation within the kidney of 1,25(OH)2D 3. It augments active renal calcium absorption. ¡ These effects are reversed by small changes in the serum calcium concentration that lower PTH secretion. VITAMIN D ¡ Vitamin D3 (cholecalciferol) is a fat-soluble steroid that is present in the diet and also can be synthesized in the skin from 7-dehydrocholestrol in the presence of ultraviolet light. ¡ The hepatic enzyme 25-hydroxylase catalyzes the hydroxylation of vitamin D at the 25 position, resulting in the formation of 25-hydroxyvitamin D or calcidiol. ¡ 25-Hydroxyvitamin D produced by the liver enters the circulation and travels to the kidney, bound to vitamin D binding protein. ¡ In the kidney, tubular cells contain two enzymes (1α-hydroxylase and 24α-hydroxylase) that can further hydroxylate calcidiol, producing 1,25(OH)2D, the most active form of vitamin D, or 24,25-dihydroxyvitamin D, an inactive metabolite. ¡ Hence, the vitamin D hormonal system consists of multiple forms, ranging from cutaneous precursors or dietary components to the most active metabolite, 1,25(OH)2D, which acts upon the target organ receptors to maintain calcium homeostasis and bone health. However, the serum concentration of 25(OH)D, which is the precursor form of the biologically active vitamin D, is the best indicator of the overall vitamin D storage or status. SERUM CALCIUM ¡ Hypercalcemia is associated with an increase in urinary calcium excretion as a consequence of an increase in the filtered load and a decrease in the tubular reabsorption of calcium. ¡ Although hypercalcemia can decrease GFR by renal vasoconstriction, which tends to offset the increase in filtered load, hypercalcemia also causes a decline in tubular reabsorption of calcium by both PTH-dependent and -independent effects. ¡ Hypocalcemia decreases renal calcium excretion by decreasing the filtered load and enhancing the tubular reabsorption of calcium EXTRACELLULAR FLUID ¡ Expansion of the extracellular fluid is associated with an increase in sodium, chloride, and calcium excretion, whereas reciprocal effects are seen with volume contraction. ¡ The mechanisms of this effect are interrelated with the effects of sodium reabsorption and compensatory changes that occur as a result of volume expansion METABOLIC ACIDOSIS ¡ Acute and chronic metabolic acidosis can be associated with an increase in calcium excretion, independent of PTH changes. ¡ The calciuria may, in part, be due to the mobilization of calcium from bone, as the hydrogen ion is buffered in the skeleton; however, direct effects of acidosis on tubular calcium resorption also play a role PHOSPHORUS PHOSPHATE BALANCE ¡ At steady state, oral phosphorus intake is balanced by phosphate (Pi) excretion in the urine and faeces. ¡ Daily phosphorus intake varies between 700 and 2000 mg, depending on consumption of phosphorus-rich foods, such as dairy products. ¡ After absorption, phosphorus is transported across cell membranes as phosphate. ¡ Phosphate in the plasma or extracellular fluid undergoes one of three fates: 1. Transport into cells 2. Deposition in bone or soft tissue 3. Elimination predominantly by the kidneys. PHOSPHATE ¡ Within the body, the majority of phosphorus stores are in the bone. ¡ Although serum phosphate levels constitute