Regulation of Acid to Diuretics COMPILATION PDF

Renal Regulation of Potassium, Calcium, ▪~0.9% total body calcium is intracellular Phosphate, and Magnesium ▪~0.1% is present in the extracellular fluid volume Extracellular fluid: 4.2 mEq/L...

Renal Regulation of Potassium, Calcium, ▪~0.9% total body calcium is intracellular Phosphate, and Magnesium ▪~0.1% is present in the extracellular fluid volume Extracellular fluid: 4.2 mEq/L Chemical Anatomy of Serum Calcium seldom rising or falling more than ±0.3 mEq/L ▪Total serum calcium (8.4-10.2 mg/dl) is composed many cell functions are sensitive to changes in of three distinct “compartments”: extracellular fluid potassium concentration an increase in plasma potassium concentration 1. Ionized (48%) of only 3 to 4 mEq/L can cause cardiac o physiologically active in muscle arrhythmias contraction, blood coagulation and Higher concentrations can lead to cardiac intracellular adhesion arrest or fibrillation 2. Protein bound (46%): o 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%) o e.g. citrate or phosphate Calcium flux between body compartments Intestinal Calcium Absorption Two major mechanisms for Ca absorption: Potassium is reabsorbed in the proximal 1. Between cells (paracellular): tubule and in the ascending loop of Henle, so a. Passive only about 8 percent of the filtered load is b. Quantitative significant when delivered to the distal tubule intake is high 2. Through cells (Transcellular): Distribution of calcium in the body a. Active ▪Total body content of calcium is 1,000-1,200 g b. Influenced by calcitriol c. Calbindin: acts as an intracellular ▪99% of the body calcium resides in bone sink to reduce the microvilli [Ca] ▪1% of this is freely exchangeable with the calcium in extracellular fluids 1 vlbr Renal Regulation of Calcium Balance Factors that affect renal regulation of calcium 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 Hormonal Regulation of Calcium Homeostasis Different segments of the nephron are tasked with calcium reabsorption Involves two hormones: o PTH 1. 60-70% proximal convoluted tubule ▪ produced by parathyroid glands 2. 20% cortical segments of the loop of Henle o Calcitriol ▪ produced by the kidneys 3. 10% distal convoluted tubule Actions in three organs: (BIK) 4. 5% collecting duct o Bone o Intestine Segment Specific Mechanisms of Calcium Re- o Kidneys absorption Calcium Sensing Receptor is the key sensor Proximal tubule: (PT) coordinating the various feedback loops in o Passive diffusion (80% paracellular) kidneys and parathyroid glands o Active transport (10-15%) Parathyroid hormone (PTH) Thick ascending loop of Henle: TAHL Major physiological regulation of calcium level o A paracellular mechanism accounts for Secreted by the parathyroid glands in response the transport of calcium in this to hypocalcemia, hyperphosphatemia, and/or segment ↓ calcitriol Collecting Duct: (CD) Changes in serum calcium are the primary o A transcellular mechanism accounts for stimulus the transport of calcium in this o sensed by the Calcium Sensing segment Receptor Expression in parathyroid glands tightly Mechanisms of calcium absorption per segment regulated at the translation and transcription (summary) levels 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 o cholecalciferol (from UV radiation) and/or ergocalciferol (dietary sources) 2 vlbr  25-Hydroxyvitamin D: Alterations in Calcium Balance Have Clinical o the 25-hydroxylated metabolites of Consequences vitamin D; also known as ercalcidiol or calcidiol; abbreviated as 25(OH)D Calcitriol: o 1,25-dihydroxycholecalciferol; abbreviated as 1,25(OH)2D3 Vitamin D analogs o derivatives of vitamin D2 and vitamin D3 , of which the clinically investigated synthetic derivatives include ▪ Doxercalciferol ▪ Paricalcitol ▪ Alfacalcidol ▪ Falecalcitriol Manifestations of abnormal calcium levels ▪ 22-oxacalcitriol (maxacalcitol) Vitamin D metabolism and action Phosphorus turnover and physiology 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 3 vlbr Phosphorus flux between body compartments Segment Specific Mechanisms of Phosphorus Handling: PT Factors that alter renal regulation of phosphorus Intestinal Phosphorus Absorption Two major mechanisms for Ca absorption: 1. Between cells (paracellular): a. Passive b. Quantitative significant when intake is high 2. Through cells: a. Active b. Influenced by calcitriol c. Calbindin: acts as an intracellular sink to reduce the microvilli [Ca] Regulation of Renal P Excretion Transcellular transport mechanisms Clinical alterations of Phosphorus balance 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 4 vlbr  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 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 5 vlbr 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 Increase magnesium absorption o Dietary restriction o PTH o Glucagon o Calcitonin o Vasopressin o Aldosterone o Amiloride o Metabolic alkalosis o EGF Decrease magnesium o Hypermagnesemia absorption o Metabolic acidosis o Phosphate depletion o Diuretics ▪ (loop and thiazide) o Anionic antimicrobials ▪ (aminoglycosides, amphotericin) o Chemotherapy (cisplatin) o Immunosuppressants ▪ (tacrolimus, cyclosporine) 6 vlbr  Regulation of Acid-Base Balance Acids and bases (definitions and meanings) Molecules containing hydrogen atoms that can release hydrogen ions in a solution are referred to as acids, o Eg (HCI) ionizes in water to form (H+) and (Cl-) ions. o (H2CO3) ionizes to form H+ and (HCO3-) ions Volatile and Non-volatile Acids A base is an ion or a molecule that can accept an H+. Volatile Acids o For example, HCO3- is a base because it H2CO3 formed from H2O + CO₂ by carbonic can combine with H+ to form H2CO3. anhydrase o HPO4- is a base because it can accept an o Dissociates into H+ + HCO3- H+ to form H2PO4- o Produced by oxidative metabolism of CHO & Lipids Mainly in RBC and renal The proteins in the body also function as bases tubular cells because some of the amino acids that make up o Excreted through LUNGS as CO2 gas proteins have net negative charges that readily o H₂CO₃ can be converted back to H₂O accept H+ and CO₂ by the same enzyme thus Alkalosis refers to the excess removal of H+ from called volatile acid the body fluids. Excess addition of H+ is referred to as acidosis. Concept of pH Non-volatile Acids Are generated during catabolism of: o amino acids, o Phospholipids, o nucleic acids Acids that do not leave solution, once produced they remain in body fluids until eliminated by KIDNEYS Are most important fixed acids in the body Other blood acids such as lactic acid, ketone bodies and fatty acids called non-volatile acids Average normal blood pH=7.35-7.45 o Sulfuric acid Extracellular fluid pH= 7.4 o phosphoric acid The pH of urine can range from 4.5 to 8.0, o Organic acids depending on the acid-base status of the The body produces ↑↑ acids than bases extracellular fluid. o Acids take in with foods. Homeostasis of pH is tightly controlled o Cellular metabolism produces CO₂ o 7.45: Alkalosis (alkalemia) lipids and proteins o 20:1 (more Acute glomerulonephritis is a form of intrarenal reabsorption of Urea elevates more the [urea] acute kidney injury (AKI) caused by an immune than Cr) reaction damaging the glomeruli. In 95% of fractional excretion of sodium (FeNa+ 1.010) often caused by group A beta streptococci. High Urine osmolality (>500) Associated Infections: Concentrated urine (< 500 mL in 24 hrs) – oliguria o Common triggers include streptococcal sore throat, tonsillitis, or skin infections. 12 vlbr Pathophysiology: ACUTE TUBULAR NECROSIS (ATN) CAUSED BY TOXINS OR MEDICATIONS Damage is not caused by the infection itself but by immune complex formation: Damage to renal tubular epithelial cells caused by o Antibodies react with streptococcal exposure to toxic substances or certain medications. antigens to form insoluble immune -Common Toxic Agents: complexes. o These complexes become trapped in 1.Carbon tetrachloride. the glomeruli, particularly the 2.Heavy metals (e.g., mercury, lead). basement membrane. 3. Ethylene glycol (antifreeze component). TUBULAR NECROSIS 4.Insecticides. Tubular necrosis refers to the destruction of epithelial cells in the renal tubules, leading to 5. Certain antibiotics (e.g., tetracyclines). intrarenal AKI. 6. Chemotherapy drugs (e.g., cis-platinum). -Causes: Mechanism: 1.Severe Ischemia: These substances exert specific toxic effects on Insufficient oxygen and nutrient supply to tubular epithelial cells, leading to cell death. the tubular epithelial cells. Damaged cells slough off and obstruct the tubules, Commonly results from circulatory shock or Impairing urine output. In some cases, the basement blood flow impairment. membrane of the tubules is also destroyed. 2. Exposure to harmful agents: Healing and Recovery: Poisons, toxins, or medications that damage tubular Intact Basement Membrane: epithelial cells. New epithelial cells can regenerate along the membrane's surface. Tubular function may Mechanism of Ischemic Acute Tubular Necrosis: recover within 10-20 days. Severe renal ischemia occurs due to: Destroyed Basement Membrane: Regeneration is impaired, potentially leading Circulatory shock or other disruptions reducing to prolonged or permanent damage. blood flow to the kidneys. Prolonged ischemia damages or destroys renal tubular epithelial cells. ACUTE KIDNEY DISEASE Damaged cells slough off and block nephrons: C. Post-renal failure: as a result of urinary tract - Blocked nephrons result in no urine output obstruction as seen in Benign prostatic hyperplasia from the affected areas. (BPH) in males, Nephrolithiasis (kidney stones) in the - Nephrons remain non-functional until the bladder, renal malignancy. This causes ↑PBS = GFR plugs are cleared. leading to renal failure. Consequences: Criteria for diagnosing ARF: Even after renal blood flow normalizes, urine ↓urine output (oliguria)