Blood Calcium Regulation

Blood Calcium Regulation

• Calcium is crucial for bone structure, muscle contraction, neurotransmitter release, intracellular communication, metabolism, signaling, enzyme activity, endocytosis, exocytosis, cell adhesion, blood clotting, cell replication, fertilization, motility, and capillary permeability.
• Regulation of calcium levels occurs through a negative feedback system influenced by dietary and environmental factors.

Response to High Serum Calcium (Hypercalcemia)

• High serum calcium stimulates perifollicular cells in the thyroid gland.
• Calcitonin is released into the blood.
• Kidneys: Calcium reabsorption stops, leading to calcium excretion in urine, which is a fast response.
• Bones: Osteoclast activity decreases, osteoblast activity increases which leads to increased bone calcification, a long-term effect.
• Calcitriol production decreases.
• Small intestines: Calcium absorption from food decreases due to no calcitriol.

Response to Low Serum Calcium (Hypocalcemia)

• Low serum calcium is sensed by the parathyroid gland.
• The parathyroid gland releases parathyroid hormone (PTH) into the blood.
• Kidneys: PTH increases calcium reabsorption in the proximal convoluted tubule (PCT) and distal convoluted tubule (DCT).
• PTH activates calcitriol.
• Bones: PTH increases calcium reabsorption by increasing osteoclast activity.
• Calcitriol increases osteoclast maturation, increasing their numbers.
• Small intestine: Calcitriol increases calcium absorption from the diet.

Hypocalcemia

• Causes include hypothyroidism, malabsorption syndrome, deficient serum albumin, or increased serum pH.
• Effects include increased permeability and excitability of nerve membranes.
• Results in spontaneous stimulation of skeletal muscle and weak heart contractions due to incomplete repolarization.

Hypercalcemia

• Causes include uncontrolled calcium release from bones, bone demineralization from immobility, or increased calcium intake.
• Effects include depressed neuromuscular activity and interference with ADH production.
• May increase the strength of cardiac muscle contractions.

Water Reabsorption in the Nephron

• Initially, water is filtered out in the glomerulus along with solutes like Na+, K+, and glucose.
• H2O is reabsorbed into tubule cells, then into the interstitial space, and finally back into the vasa recta.
• Water reabsorption primarily occurs in the proximal convoluted tubule (PCT), the descending limb of the Loop of Henle, and collecting ducts (CD).
• Water reabsorption is heavily driven by Na+ movement; water tends to follow sodium.
• Solute recovery from the PCT lumen to the interstitial space creates an osmotic gradient that drives water recovery.
• Aquaporins facilitate water movement across cell membranes.
• Aquaporin 1 is present in the proximal convoluted tubules, the descending thin limbs of the loop of Henle, and in the vasa recta.

Proximal Convoluted Tubule (PCT)

• Sodium is taken up from the filtrate back into the tubule by sodium-linked glucose transporters (SGLTs).
• Na+ movement concentrates the tubule intracellular fluid relative to the filtrate.
• This concentration gradient drives H2O movement into the tubule cell using aquaporin-1 channels via osmosis.
• About 67% of the filtered water is reabsorbed in the PCT.

Loop of Henle

• Water reabsorption occurs in the thin descending limb due to its permeability to water.
• Water moves out of the thin descending limb into the more concentrated medulla via osmosis.
• The driving force is the movement of Na+, Cl–, and K+ from the tubule to the medulla via NKCC symporters in the thick ascending limb.
• This increases the concentration of the renal medulla, providing an osmotic gradient.

Collecting Duct

• Water reabsorption is driven by antidiuretic hormone (ADH).
• ADH is produced in the hypothalamus and secreted from the posterior pituitary gland in response to low plasma volume or high osmolality.
• ADH acts on the principal cells in the collecting duct by binding to receptors.
• This binding triggers increased aquaporin-2 protein production.
• Water moves through the tubule and back into the renal medulla, driven by the high concentration of Na+ in the renal medulla.

Reabsorption Back into the Circulation

• Blood moves from the interstitial space back into the circulation via the vasa recta.
• The vasa recta contains mostly large proteins and red blood cells, making it very concentrated.
• Water moves into the vasa recta via osmosis.

Key Points of Water Reabsorption

• Water is filtered due to high pressure in the glomerular capsule.
• Water is reabsorbed in the PCT as water follows Na+ through aquaporins.
• Water is reabsorbed in the descending loop because of the ISF (Interstitial Space Fluid) in the medulla.
• ADH regulates water retention on the collecting duct during final urine formation.
• Increased blood osmolality sensed by the hypothalamus signals the release of ADH from the posterior pituitary.
• Dehydration is a trigger for ADH release.

Acid Base Balance - Importance

• The body regulates acid-base balance to maintain arterial blood pH between 7.38 and 7.42.
• Buffer solutions are crucial for maintaining constant pH in various chemical reactions in the body.
• Acid-base homeostasis involves maintaining a proper balance between acids and bases in the body.
• Deviations in pH levels can denature proteins, impair enzyme function, and lead to fatality.
• Blood acts as a chemical buffer solution to keep all the body’s cells and tissues properly balanced.

Buffer Solutions

• A buffer solution consists of a weak acid and its conjugate base, or a weak base and its conjugate acid.
• These solutions resist changes in pH when small amounts of strong acids or bases are added.
• Multiple buffering agents reversibly bind hydrogen ions to prevent drastic pH changes.
• Extracellular buffers include bicarbonate and ammonia, while intracellular buffers include proteins and phosphates.

CO2 and Blood pH Regulation

• Carbon dioxide (CO2) is a major waste product of aerobic respiration.
• Too much or too little CO2 in the blood can lead to serious consequences.
• CO2 primarily regulates blood pH.
• The majority of CO2 transported in the blood is dissolved bicarbonate in plasma (60%).
• A smaller fraction is transported in red blood cells as carbaminohemoglobin.
• When blood pH drops too low (acidemia), the body increases breathing to expel more CO2, raising pH back to normal.
• In alkalemia, the opposite occurs.

Methods of CO2 Transport

• CO2 is transported in the blood in 3 ways: on haemoglobin, as hydrogen carbonate (HCO3–), and dissolved CO2 itself.
• Approximately 30% of CO2 is transported as carbamino compounds.
• 60% of CO2 is transported through the production of HCO3– ions in red blood cells.
• About 10% of CO2 is transported dissolved in plasma.

Carboxyhaemoglobin

• CO2 binds directly to amino acids and the amine groups of haemoglobin to form carbaminohaemoglobin.
• In the lungs, haemoglobin preferentially binds to O2, promoting the release of CO2.

HCO3– Ions

• Carbonic anhydrase in red blood cells converts CO2 to H+ and HCO3–.
• HCO3– is then transported back into the blood via a chloride-bicarbonate exchanger.
• The HCO3– acts as a buffer against hydrogen in the blood plasma.
• Oxygen binding to haemoglobin in the lungs releases H+ ions, allowing them to react with bicarbonate ions to produce CO2 and H2O.

Dissolved in Plasma

• The amount of gas dissolved in a liquid is influenced by its solubility and partial pressure.
• CO2 is very soluble in water, approximately 23 times more soluble than O2.
• Tissues at the periphery have a higher partial pressure, and the alveoli have a lower partial pressure of CO2.

Compensation for Acid-Base Imbalances

• Short-term compensation involves altering the rate of ventilation.
• Changes in ventilation rate affect the concentration of carbon dioxide in the blood, which shifts the reaction according to Le Chatelier’s principle and alters the pH.

Renal Physiology

• The kidneys regulate pH levels through mechanisms that excrete excess acid or base.
• In response to acidosis, the tubular cells reabsorb more bicarbonate from the tubular fluid.
• The collecting duct cells secrete more hydrogen and generate more bicarbonate, while ammonia genesis increases the NH3 buffer.
• In response to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from the tubular epithelial cells.
• The kidneys lower the rates of glutamine metabolism and ammonium excretion.

Transport of Gases in the Blood

• Hydrogen ions (H+) are transported in the blood along with oxygen and carbon dioxide.

Role of the Lungs

• Imbalances in pH are returned to normal by increasing the rate of ventilation in the lungs.
• To compensate for acidemia, more CO2 is expelled, while the opposite occurs for alkalemia.

Acid-Base Imbalance

• Acid-base imbalance occurs when a significant insult causes the blood pH to shift out of its normal range (7.35 to 7.45).
• An excess of acid in the blood is called acidemia.
• An excess of base in the blood is called alkalemia.
• The process that causes the imbalance is classified based on the etiology of the disturbance (respiratory or metabolic) and the direction of change in pH (acidosis or alkalosis).
• The 4 basic processes: Metabolic acidosis, Respiratory acidosis, Metabolic alkalosis, and Respiratory alkalosis.

Types of Acidosis

• Acidosis occurs when your body cannot remove acid from your airways, your blood, or other body fluids; classified in several types:
• Lactic acidosis: Too much lactic acid builds up in your blood.
• Diabetic acidosis: Too many ketone acids build up in your blood.
• Renal tubular acidosis: Kidneys let too much acid back into your blood.
• Hyperchloremic acidosis: The level of sodium bicarbonate in your blood becomes too low.
• Respiratory acidosis: Lungs don’t expel enough carbon dioxide.

Types of Alkalosis

• Metabolic alkalosis: Too much bicarbonate in your blood.
• Respiratory alkalosis: Not enough carbon dioxide in your body.

Clinical Relevance - Metabolic Acidosis

• Acidosis occurs when blood pH falls below 7.35, classified as either metabolic or respiratory.
• Metabolic acidosis results from excess H+ production or a reduction in the HCO3– buffer.
• Conditions, such as diabetic ketoacidosis, can increase acid production.
• Disorders of the kidneys themselves such as chronic kidney disease may reduce HCO3– production.
• The respiratory system compensates by increasing respiration rate (hyperventilating) to "blow off" CO2.
• Kidneys help correct the issue by increasing hydrogen excretion and bicarbonate reabsorption.
• Symptoms of acidosis include rapid breathing, confusion, fatigue, and headache.

Kidney Regulation of Acid-Base Balance

• Kidneys regulate acid-base balance through bicarbonate reabsorption, hydrogen ion secretion, and ammonium excretion.

Bicarbonate Reabsorption

• Bicarbonate (HCO₃⁻) is a key buffer that helps maintain blood pH.
• The kidneys filter bicarbonate from the blood and reabsorb it back into circulation.
• This process mainly occurs in the proximal convoluted tubule of the nephron.

Mechanism of Bicarbonate Reabsorption

• Bicarbonate ions are filtered into the renal tubule.
• In the proximal tubule, bicarbonate binds to secreted hydrogen ions (H⁺) to form carbonic acid (H₂CO₃).
• Carbonic anhydrase converts carbonic acid into water (H₂O) and carbon dioxide (CO₂).
• CO₂ diffuses into the cells where it combines with water to regenerate bicarbonate.
• This newly formed bicarbonate is then transported back into the bloodstream.
• Nearly all filtered bicarbonate is reabsorbed, maintaining blood pH levels.

Hydrogen Ion Secretion

• The kidneys secrete hydrogen ions into the urine in order to eliminate excess acidity from the body.

Mechanism of Hydrogen Ion Secretion

• In the proximal and distal convoluted tubules, hydrogen ions are secreted in exchange for sodium ions.
• This exchange helps maintain sodium balance while removing excess H⁺.
• The secretion of H⁺ contributes to urine acidity and helps regulate systemic pH.

Ammonium Excretion

• Ammonium (NH₄⁺) helps eliminate excess hydrogen ions while preserving bicarbonate levels.

Mechanism of Ammonium Excretion

• Ammonia (NH₃) is produced in renal cells from glutamine metabolism.
• NH₃ binds with H⁺ ions in the tubular fluid to form NH₄⁺.
• This allows for safe excretion of excess acidity without losing bicarbonate.
• NH₄⁺ is then concentrated in the inner medulla and excreted in urine.

Responses to Acid-Base Disorders

• The kidneys adapt their functions in response to systemic acid-base disorders such as acidosis and alkalosis.

Response to Acidosis

• During acidosis (when blood pH drops):
  • The kidneys increase hydrogen ion secretion in the DCT.
  • Bicarbonate reabsorption is maximized in the PCT.
  • Ammonium excretion rises to eliminate excess acidity in the PCT and DCT.

Response to Alkalosis

• In cases of alkalosis (when blood pH rises):
  • The kidneys decrease hydrogen ion secretion.
  • Bicarbonate reabsorption is reduced.
  • Ammonium production decreases.

Factors Influencing Renal Function

• Factors influencing the effectiveness of kidney regulation of acid-base balance:
  • Diet: High protein diets increase renal workload due to metabolic waste removal.
  • Hydration Status: Dehydration can impair kidney function by affecting filtration rate.
  • Hormones: Aldosterone influences sodium and potassium balance.
  • Chronic Conditions: Chronic kidney disease can impair renal function and disrupt acid-base balance.

Role of Hormones and Chronic Conditions

• Hormones like aldosterone influence sodium and potassium balance, indirectly affecting acid-base homeostasis.
• Diseases such as chronic kidney disease can impair renal function and disrupt acid-base balance.

Kidney Regulation of Blood Pressure

• The kidneys regulate blood pressure by controlling fluid balance and electrolyte composition.
• They filter blood through nephrons, adjusting sodium and water retention as needed.
• When blood pressure falls, the kidneys conserve fluid by reducing urine output.
• Kidney damage can impair blood pressure regulation.

Mechanisms of Kidney Blood Pressure Regulation

• The kidneys regulate blood volume through the renin-angiotensin-aldosterone system (RAAS).
• When blood volume is low, the kidneys release renin.
• Renin triggers a series of reactions that produce angiotensin II, which causes blood vessels to constrict.
• Angiotensin II stimulates the adrenal glands to release aldosterone, which signals the kidneys to reabsorb more sodium and water back into the blood.
• The kidneys also respond to antidiuretic hormone (ADH), also known as vasopressin.
• When blood volume is low or the body is dehydrated, the pituitary gland releases ADH.
• ADH signals the kidneys to reabsorb more water back into the blood, reducing urine output.
• The kidneys also regulate blood volume through the atrial natriuretic peptide (ANP) system.
• When blood volume is high, the heart releases ANP, which signals the kidneys to excrete more sodium and water in the urine.

Low Blood Volume (BP) Response

• Stimulus: Low blood volume/blood pressure
• Sensor: Decreased blood flow to the kidney
• Signal: Juxtaglomerular complex releases Renin
• Effectors: Activation of blood factors that act on targets.
• Angiotensinogen converts to Ang I, then to Ang II.
• Hypothalamus releases ADH from posterior pituitary to kidney.
• Increase in aquaporin channels and water reabsorption in collecting duct.
• Adrenal gland releases Aldosterone which goes to kidney for increase Na reabsorption and water reabsorption.
• Blood vessels undergo vasoconstriction, increasing vascular resistance.
• Net effect: Increase in blood volume/blood pressure.

High Blood Volume (BP) Response

• Stimulus: High blood volume/blood pressure
• Sensor: Baroreceptors in the heart
• Signal: ANP secretion
• Effectors:
  • Blood Vessels: vasodilation reduces vascular resistance Kidney:
  • Vasodilation means increased blood flow which prevents renin secretion -Increases glomerular filtration rate and more urine formation
• Net effect: Decrease in blood volume/blood pressure.