Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium PDF

Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium CHAPTER 30 ▪ Extracellular fluid: 4.2 mEq/L ▪ seldom rising or falling more than ±0.3 mEq/L ▪ many cell functions are sensitive to changes in extracellular fluid potassium concentration ▪ an increase in plasma potassium concentratio...

Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium CHAPTER 30 ▪ Extracellular fluid: 4.2 mEq/L ▪ seldom rising or falling more than ±0.3 mEq/L ▪ many cell functions are sensitive to changes in extracellular fluid potassium concentration ▪ an increase in plasma potassium concentration of only 3 to 4 mEq/L can cause cardiac arrhythmias ▪ Higher concentrations can lead to cardiac arrest or fibrillation ▪ Potassium is reabsorbed in the proximal tubule and in the ascending loop of Henle, so only about 8 percent of the filtered load is delivered to the distal tubule Distribution of calcium in the body ▪ Total body content of calcium is 1,000-1,200 g ▪ 99% of the body calcium resides in bone ▪ 1% of this is freely exchangeable with the calcium in extracellular fluids ▪ ~0.9% total body calcium is intracellular ▪ ~0.1% is present in the extracellular fluid volume Chemical Anatomy of Serum Calcium ▪ Total serum calcium (8.4-10.2 mg/dl) is composed of three distinct “compartments”: 1. Ionized (48%), physiologically active in muscle contraction, blood coagulation and intracellular adhesion 2. Protein bound (46%): ▪ Albumin: hypoalbuminemia may result in falsely low levels (may correct by adding 0.8 for the reduction of albumin by 1 unit below 4 g/dL) 3. Complexed with inorganic compounds (7%) e.g. citrate or phosphate  Calcium flux between body compartments Judith Blaine et al. CJASN doi:10.2215/CJN.09750913  Intestinal Calcium Absorption Transcellular transport mechanisms ▪ Two major mechanisms for Ca absorption: 1. Between cells (paracellular): ▪ Passive ▪ Quantitative significant when intake is high 2. Through cells: ▪ Active ▪ Influenced by calcitriol ▪ Calbindin: acts as an intracellular sink to reduce the microvilli [Ca] Judith Blaine et al. CJASN doi:10.2215/CJN.09750913 Renal Regulation of Calcium Balance ▪ Only the ionized and the complexed calcium may be directly affected by the kidneys ▪ Filtered load 10g of calcium a day ▪ Normally only 200mg are found in the urine ▪ 98-99% are absorbed by the kidneys ▪ Where is the calcium absorbed?  Renal Handling of Calcium ▪ Different segments of the nephron are tasked with calcium reabsorption 1. 60-70% proximal convoluted tubule 2. 20% cortical segments of the loop of Henle 3. 10% distal convoluted tubule 4. 5% collecting duct Judith Blaine et al. CJASN doi:10.2215/CJN.09750913 Segment Specific Mechanisms of Calcium Re-absorption: PT ▪ Proximal tubule: ▪ Passive diffusion (80% paracellular) ▪ Active transport (10-15%) Segment Specific Mechanisms of Calcium Re-absorption: TAHL ▪ Thick ascending loop of Henle: ▪ A paracellular mechanism accounts for the transport of calcium in this segment Segment Specific Mechanisms of Calcium Re-absorption: CD ▪ Collecting Duct: ▪A transcellular mechanism accounts for the transport of calcium in this segment Mechanisms of calcium absorption per segment (summary) Factors that affect renal regulation of calcium Increase Calcium Absorption Decrease Calcium Absorption ▪ Hyperparathyroidism ▪ Hypoparathyroidism ▪ Calcitriol ▪ Low calcitriol levels ▪ Hypocalcemia ▪ Hypercalcemia ▪ Volume contraction ▪ Extracellular fluid ▪ Metabolic alkalosis expansion ▪ Metabolic acidosis ▪ Thiazides diuretics ▪ Loop diuretics Hormonal Regulation of Calcium Homeostasis ▪ Involves two hormones: ▪ PTH (produced by parathyroid glands) ▪ Calcitriol (produced by the kidneys) ▪ Actions in three organs: ▪ Bone ▪ Intestine ▪ Kidneys ▪ Calcium Sensing Receptor is the key sensor coordinating the various feedback loops in kidneys and parathyroid glands PTH ▪Major physiological regulation of calcium level ▪Secreted by the parathyroid glands in response to hypocalcemia, hyperphosphatemia, and/or ↓ calcitriol ▪Changes in serum calcium are the primary stimulus (sensed by the Calcium Sensing Receptor) ▪Expression in parathyroid glands tightly regulated at the translation and transcription levels PTH ▪It increases serum calcium by three different mechanisms: 1. Stimulates bone resorption 2. Enhances GI absorption of calcium and phosphorus by stimulating renal production of calcitriol 3. Augments renal calcium reabsorption Vitamin D Nomenclature ▪ Vitamin D: cholecalciferol (from UV radiation) and/or ergocalciferol (dietary sources) ▪ 25-Hydroxyvitamin D: the 25-hydroxylated metabolites of vitamin D; also known as ercalcidiol or calcidiol; abbreviated as 25(OH)D ▪ Calcitriol: 1,25-dihydroxycholecalciferol; abbreviated as 1,25(OH)2D3 ▪ Vitamin D analogs: derivatives of vitamin D2 and vitamin D3, of which the clinically investigated synthetic derivatives include doxercalciferol, paricalcitol, alfacalcidol, falecalcitriol, and 22-oxacalcitriol (maxacalcitol)  Figure 2 Vitamin D metabolism and action T1/2 ~ 3 wks: used to assess stores  Alterations in Calcium Balance Have Clinical Consequences Hypocalcemia Hypercalcemia ▪ Excess PTH production (primary ▪ Lack of PTH: hyperparathyroidism) ▪ Hereditary/acquired ▪ Excess calcitriol (vitamin D intoxication, hypoparathyroidism sarcoidosis) ▪ Lack of Vitamin D ▪ Increased bone resorption (humoral hypercalcemia of malignancy due to ▪ Increased calcium complexation PTHrP, immobilization, Paget dz) (rhabdomyolysis, pancreatitis) ▪ Increased intestinal absorption (milk ▪ Disorders of the calcium sensing alkali s.) receptor ▪ Decreased renal excretion of calcium (thiazides) ▪ Disorders of the calcium sensing receptor Manifestations of abnormal calcium levels Hypocalcemia Hypercalcemia ▪ Mild is asymptomatic ▪ Gastrointestinal symptoms (nausea, vomiting constipation) ▪ Large changes lead to symptoms due to ▪ Difficulty concentrating increased ▪ Lethargy neuromuscular activity ▪ Muscle weakness ▪ Perioral paresthesias ▪ Hypertension ▪ Carpopedal spasms ▪ Shortening QT interval ▪ Trousseau sign ▪ Urinary concentrating defect ▪ Chvostek sign (diabetes insipidus) Phosphorus turnover and physiology 27 Phosphorus stores and levels ▪Total body stores ~ 700g (85% in bone, 14% intracellular, 1% extracellular) ▪ Extracellular: 70% is organic, 30% inorganic ▪ Inorganic: 15% is protein bound, 85% complexed with cations or free (this is measured in chemistry labs) ▪Normal concentration 2.5-4.5 mg/dL Phosphorus flux between body compartments Intestinal Phosphorus Absorption Transcellular transport mechanisms ▪ Two major mechanisms for Ca absorption: 1. Between cells (paracellular): ▪ Passive ▪ Quantitative significant when intake is high 2. Through cells: ▪ Active ▪ Influenced by calcitriol ▪ Calbindin: acts as an intracellular sink to reduce the microvilli [Ca] Renal Handling of Phosphorus ▪ Different segments of the nephron are tasked with phosphorus reabsorption 1. 85% proximal convoluted tubule 2. 10% loop of Henle 3. 3% distal convoluted tubule 4. 2% collecting duct Segment Specific Mechanisms of Phosphorus Handling: PT Factors that alter renal regulation of phosphorus Decrease Absorption Increase Absorption ▪ Low-phosphate diet ▪ Parathyroid hormone ▪ 1,25-Vitamin D3 ▪ Phosphatonins (e.g., FGF23) ▪ Thyroid hormone ▪ High-phosphate diet ▪ Metabolic acidosis All these effects are mediated ▪ Potassium deficiency directly or indirectly by changing ▪ Glucocorticoids the abundance of the sodium ▪ Dopamine phosphorus cotransporters in the ▪ Hypertension PT ▪ Estrogen  Figure 1 Regulation of Renal P Excretion Parathyroids Bone Kidney When Ca and P both high FGF-23 action predominates In low calcium, high P states PTH action predominates Clinical alterations of phosphorus balance Hypophosphatemia ▪ Shift into cells (respiratory alkalosis, insulin therapy, catecholamines, hungry bone s.) ▪ Decreased intestinal absorption ▪ Decreased intake (starvation/alcoholism) ▪ Increased renal loss of phosphate (“phosphate wasting”): ▪ Fanconi s., NaP transporter mutation Fractional Excretion of Phosphorus: If low: renal wasting of phosphorus in hypophosphatemia Impaired renal filtration in hyperphosphatemia Clinical alterations of phosphorus balance Hyperphosphatemia ▪ Drop in renal function (acute or CKD): most common Fractional Excretion of Phosphorus: ▪ Increased intake If low: ▪ Oral sodium phosphate laxatives renal wasting of phosphorus in hypophosphatemia Impaired ▪ Increased tubular reabsorption of phosphate: renal filtration in ▪ Vitamin D intoxication hyperphosphatemia ▪ Hypoparathyroidism ▪ Increased tissue release: ▪ Rhabdomyolysis, tumor lysis ▪ Shift out of cells: ▪ Lactic acidosis, diabetic ketoacidosis  Clinical manifestations of phosphorus disorders Hypophosphatemia ▪ Manifestations depend on the acuity and chronicity ▪ Acute: rhabdomyolysis ▪ Symptoms due to changes in mineral metabolism: ▪ Hypercalciuria ▪ Increased bone resorption ▪ Rickets, ostomalacia ▪ Symptoms due to ATP depletion: Clinical manifestations of phosphorus disorders Hyperphosphatemia ▪ Acute elevation of phosphorus may lead to acute kidney injury and failure (“phosphate nephropathy”) ▪ Chronic elevations (CKD) lead to cardiovascular calcification and increased cardiovascular morbidity and mortality Magnesium  Total body stores: 24g 99% intracellular Normal magnesium concentration is 1.7-2.6 mg/dL (or 0.7-1.05 mmol/L) Only 70% of serum magnesium is free (the rest is complexed to albumin) Multiple functions due to its role as an enzymatic cofactor Magnesium flux between body compartments Intestinal Magnesium Absorption Transport mechanisms Absorption ranges from 25% - 75% (typical absorption is 120 mg/d) Transcellular channels, TRPM6/7 (mutations lead to hypomagnesemia and hypocalcemia) Judith Blaine et al. CJASN doi:10.2215/CJN.09750913 Renal Handling of Magnesium ▪ Kidneys filter 2000-4000 mg/d ▪ Filterable component is the free serum magnesium (70% of total level) ▪ Different segments of the nephron are tasked with magnesium reabsorption 1. 10-20% proximal convoluted tubule 2. 70% loop of Henle 3. 10% distal convoluted tubule Magnesium and the TAHL ▪ Responsible for 40-70% of magnesium reabsorption ▪ Paracellular mechanism similar to the calcium Magnesium and the Distal Convoluted Tubule ▪ Responsible for 5-10% of magnesium reabsorption ▪ Active transcellular transport Process coupled to potassium and sodium transport Thiazide diuretics which act on the NCC channel, produce hypomagnesemia Factors that alter renal regulation of magnesium ▪ Dietary restriction ▪ PTH ▪ Glucagon Increase magnesium ▪ Calcitonin absorption ▪ Vasopressin ▪ Aldosterone ▪ Amiloride ▪ Metabolic alkalosis ▪ EGF Factors that alter renal regulation of magnesium Decrease magnesium ▪ Hypermagnesemia absorption ▪ Metabolic acidosis ▪ Phosphate depletion ▪ Diuretics (loop and thiazide) ▪ Anionic antimicrobials (aminoglycosides, amphotericin) ▪ Chemotherapy (cisplatin) ▪ Immunosuppressants (tacrolimus, cyclosporine)  Clinical Disorders of Magnesium Hypermagnesemia Hypomagnesemia ▪ Increased intake ▪Reduced intake ▪ Antacids, enemas ▪Redistribution ▪Renal Magnesium Wasting ▪ IV therapy with Drug induced losses: Diuretics, magnesium sulfate Hormone induced magnesuria: (pre-eclampsia) aldosteronism, hypoparathyroidism, ▪ Decreased renal hyperthyroidism. filtration Ion or nutrient induced tubular losses: hypercalcemia, extracellular fluid volume expansion. Fractional excretion of magnesium: may differentiate between renal (>2%) and GI Mg loss