Chapter 19 - The Urinary System: Fluid and Electrolyte Balance

Factors Affecting the Plasma Composition
     Solute and water content of plasma is affected by movement of materials in and out of the body and by movement of materials between body compartments.
     Ways in which materials can be gained or lost from plasma:
1. By exchange with cells
2. Exchange with extracellular connective tissue including bone (Ca & P)
     Outside exchanges:
1. Exchange with materials in the lumen of the GI tract
2. Exchange with materials in the lumen of the kidney tubules
3. Loss through sweating, hemorrhaging and respiration
     The transport of materials across the wall of the GI tract normally involves a net gain of water and solutes. The transport of materials across the walls of the renal tubules amounts to a net loss of water and solutes by the body.
Solute and Water Balance
     Balance occurs when solutes and water enter and leave the plasma at the same rate. If a substance enters the plasma faster than it leaves and its concentration increases it is in positive balance. If a substance leaves plasma faster than it enters and its concentration decreases it is in negative balance.
     Certain substances can exist with a negative or positive balance with no change in the plasma concentration when their concentration is controlled by specific regulatory mechanisms. Glucose is an example.
     In the kidneys 70% of filtered water and sodium is reabsorbed in the proximal convoluted tubules without regulation. The remaining quantity can be reabsorbed depending upon the body's needs. The kidneys can also regulate the potassium, calcium and hydrogen ions that are excreted.
     Principal cells in the distal convoluted tubules and collecting ducts can adjust water and electrolyte excretion in response to hormonal influence. Intercalated cells in the same location can adjust acid-base balance.
Water Balance
     Water balance is the equality between the water that enters, or is produced in the body, with the water that exits, or is consumed by the body. Only the kidneys regulate the amount of water lost in order to maintain balance.
     A state of normal blood volume is called normovolemia. When the amount of water taken in exceeds what is lost, the body is in a positive fluid balance and the body becomes hypervolemic. If more water is lost than gained, the body is in a negative fluid balance and the body becomes hypovolemic.
     Water balance is important because plasma volume affects mean arterial pressure and changes in plasma osmolarity can cause fluid to shift from one body compartment to another and affect cellular functions.
  Osmolarity and the Movement of Water
     Kidneys can vary the amount of water lost in the distal convoluted tubules and collecting ducts, but in order to do this, an osmotic gradient needs to be created in the kidney between the lumen of the tubule and the peritubular fluids, and water permeability needs to be regulated.
     Under normal conditions the various fluid compartments in the body are in osmotic equilibrium with the osmolarity within the cells (intracellular), in between the cells (interstitial fluid) and in the plasma at about 300 mOsmoles. If someone drinks a large quantity of water, the plasma volume expands and its osmolarity decreases. The water moves from the plasma into the interstitial fluid and into the cells because of the osmotic gradient. The movement of water into the cells would cause them to swell. The kidneys correct for this by producing a large quantity of hyposmotic urine.
     If a person eats a very salty food, the salt is absorbed, enters the plasma and increases plasma osmolarity. Now the water movement is from the cells and interstitial fluid into the plasma and the cells would shrink. The kidneys correct for this by producing a hyperosmotic urine.
     The kidney adjusts the osmolarity of the urine solely by varying the amount of water reabsorbed by the kidneys. Water reabsorption itself is a passive process that is driven by the osmotic gradients created by the reabsorption of solutes.
  Water Reabsorption in the Proximal Tubule
     Sodium is the most abundant solute in the extracellular fluid. The active transport of sodium across the basolateral membrane of the tubular epithelium is primarily responsible for creating the osmotic gradient that causes movement of water.
     In addition to sodium other solutes are actively reabsorbed contributing to the osmotic gradient that causes water to be reabsorbed. The movement of water from the lumen of the tubule into the plasma brings with it permeant solutes such as urea.
  Establishment of  the Medullary Osmotic Gradient
     The renal medulla has an osmotic gradient with the interstitial fluid being about 300 mOsmoles near the cortex and increasing in osmolarity up to 1400 mOsmoles towards the tips of the renal pyramids. This gradient is responsible for water reabsorption by the collecting ducts.
  Countercurrent Multiplier
     The osmotic gradient is created by the mechanism of the counter current multiplier produced by the loops of Henle of the juxtamedullary nephrons. Study the figure below for an explanation of how the counter current multiplier establishes the medullary osmotic gradient.
     Urea freely crosses most membranes but in the collecting ducts its movement is facilitated out of the collecting duct and it contributes about 40% to the osmolarity of the gradient.
  Role of the Vasa Recta
     The hairpin loops of the capillaries of the vasa recta help to maintain the medullary osmotic gradient because the loss of water and gain of solutes that occurs as the descending limb goes towards the tip of the pyramid is counteracted by the gain in water and loss of solutes as the plasma ascends toward the cortex.
Water Reabsorption in the Distal Tubule and Collecting Duct
     Seventy percent of the filtered water is reabsorbed in the proximal tubule. Of the remaining 30%, 20% is reabsorbed by the distal tubule and 10% by the collecting duct. The reabsorption in the distal part of the tubule results from the fact that the fluid in the lumen of the tubule is always hypo-osmolar compared to the peritubular fluid.
     The tubular epithelial cells of the late distal tubules and collecting ducts have tight junctions between cells and the cell membranes are relatively impermeable to water. Water is able to pass only through water channels called aquaporins found in the cell membranes. Aquaporin-3 channels are present in the basolateral membrane and aquaporin-2 channels are present in the apical membrane when ADH is present.
     When the distal tubules and collecting ducts are impermeable to water due to the lack of aquaporins in the apical membrane, the hypo-osmolar fluid entering the tubule remains hypo-osmolar even as it flows through the osmolar gradient created in the medulla and a dilute urine is excreted.
     When aquaporin-2 channels are present in the apical membrane of these tubules the tubules become permeable to water. The water flows down its osmotic gradient. As the collecting duct descends down the medulla, the peritubular fluid is increasingly hyper-osmotic and continues to draw water from the permeable collecting duct. This continues until the fluid is iso-osmotic to the highly concentrated fluid at the tip of the pyramid which is 1400 mOsmole. This is the most concentrated the fluid can get and the maximum concentrating ability of the kidneys. Hence, in order to rid the body of excess solutes there is always a certain volume of water that is lost (about 440 ml). This is called obligatory water loss.
  Effects of ADH
     Antidiuretic hormone or ADH regulates the permeability of the late distal tubules and collecting ducts. ADH stimulates the synthesis of aquaporin-2 and its insertion into the membranes of the principal cells. Therefore, water reabsorption and urine volume are regulated by variations in the plasma levels of ADH.
     ADH acts by binding to receptors on the plasma membrane. These receptors activate a G protein that activates the enzyme adenylate cyclase which catalyzes the synthesis of cAMP. cAMP causes the following effects:
1. Stimulates insertion of aquaporin-2 into the apical membrane by exocytosis.
2. Stimulates synthesis of aquaporin-2 molecules.
  Regulation of ADH Secretion
     Osmoreceptors in the hypothalamus detect changes in osmolarity. When osmolarity increases, ADH is secreted by the pituitary and increases water reabsorption. When osmolarity decreases, ADH secretion is inhibited.
     Baroreceptors in the atria responding to changes in blood volume, and baroreceptors in the aortic  arch and carotid sinus responding to changes in blood pressure also regulate ADH secretion. When blood volume or pressure drop, ADH is secreted which helps to conserve plasma volume by increasing water reabsorption. When blood volume and pressure increases, ADH is inhibited with the opposite effects.
     A deficiency in ADH secretion causes diabetes insipidus in which there is excessive urination (polyuria) and excessive fluid intake (polydypsia).
     When blood pressure drops below 80 mm Hg, the GFR can no longer autoregulate and GFR drops. This results in less water being filtered and excreted. When blood pressure is greater than 180 mm Hg the GFR increases. This increases the amount of water that is filtered and then excreted.
Sodium Balance
      Maintaining sodium balance is important for two reasons:
1. It is the primary ion regulating osmolarity of extracellular fluid. As such it is an important determinant of plasma volume and MAP. If sodium levels are high (hypernatremia) there is an increase in blood pressure, hypertension. If sodium levels are low (hyponatremia) there is a decrease in blood pressure, hypotension.
2. Sodium is also an important ion forming the electrochemical gradient of excitable cells.
  Mechanisms of Sodium Reabsorption
     In all tubular segments sodium is actively transported. The reabsorption is due to sodium/potassium pumps located in the basolateral membrane of the tubular epithelial cells. The active transport of sodium at the basolateral membrane creates a concentration gradient across the apical membrane favorable for diffusion of sodium into the cell.
     In the proximal tubule the entry of sodium into the cell is coupled with the movement of other solutes.
1. Sodium enters the cell co-transported with other molecules such as glucose and amino acids.
2. Counter-transported with the hydrogen ion leaving the cell and entering the tubular fluid.
     In the distal tubule the concentration gradient favoring movement of sodium into the tubular epithelial cell is the same but diffusion of sodium across the apical membrane is:
1. By co-transport with the anions chloride and bicarbonate.
2. Facilitated diffusion through sodium channels.
     Sodium reabsorption in the distal tubules is often coupled with potassium and hydrogen ions secretion. This helps to minimize changes in the electrical potential across the membrane and facilitates the secretion of potassium and hydrogen ions. 
  Effects of Aldosterone 
     Aldosterone regulates both reabsorption of sodium and secretion of potassium. Aldosterone (a permeant steroid hormone) enters the principal cells of the late distal tubules and collecting ducts and binds to cytosolic receptors. Its effects include:
1. Increasing sodium and potassium channels in the apical membrane by causing channels to open and synthesizing new channels.
2. Increasing synthesis and concentration of Na+/K+ pumps in the basolateral membrane.
Both of these effects cause the simultaneous reabsorption of sodium and secretion of potassium.
  Renin-Angiotensin-Aldosterone System
     The walls of the afferent arteriole that contributes to the juxtaglomerular apparatus are granular cells that secrete renin. The nearby cells of the macula densa detect changes in the flow, and the sodium and chloride concentration, of the tubular fluid. A decrease in sodium ion concentration causes renin secretion to increase. Renin acts upon angiotensinogen which  is secreted by the liver converting it to angiotensin I. Angiotensin converting enzyme (ACE) which is on the surface of the capillary endothelial cells throughout the body, but particularly in the lung, converts angiotensin I to angiotensin II.
     Angiotensin II increases MAP by the following effects:
1. acts as a vasoconstrictor
2. stimulates release of aldosterone
3. stimulates secretion of ADH
4. stimulates thirst and fluid intake
     Renin release is stimulated by a decrease in MAP which is specifically detected by:
1. Decrease in afferent arteriole pressure
2. Baroreceptor reflex causing renal sympathetic nerve stimulation
3. A decrease in GFR leading to a decrease in sodium and chloride concentration in the distal tubule
  Atrial Natriuretic Peptide (ANP)
     This peptide is secreted by cells of the atrium when an increase in plasma volume causes its walls to stretch. ANP increases sodium excretion by:
1. Increasing glomerular capillary pressure by dilating the afferent arteriole and constricting the efferent arteriole.
2. Decreasing sodium absorption by decreasing the number of open sodium channels in the principal cells.
3. Decreasing secretion of renin and aldosterone.
Potassium Balance
     The normal concentrations of potassium in the intra- and extracellular fluid is critical for proper functioning of excitable cells. Hyperkalemia is an increase in potassium plasma levels and hypokalemia is a decrease in plasma potassium levels.
  Renal Handling of Potassium
     Most of the potassium that is filtered is reabsorbed. However, potassium is regulated by varying the amount of potassium that is secreted by the late distal tubule and collecting ducts.
     Potassium is absorbed in the proximal tubule by various mechanisms. Potassium is secreted in the distal tubules and collecting ducts by a sodium/potassium pump and potassium channels in the apical membrane of the principal cells.
  Regulation of Potassium Secretion by Aldosterone
     Aldosterone increases potassium secretion by increasing Na+/K+ pumps and increasing K+ channels in the apical membrane of the distal tubules and collecting ducts. High potassium levels stimulate secretion of aldosterone by the adrenal cortex.
Calcium Balance
     Hypercalcemia is an increase in plasma calcium and hypocalcemia is a decrease in plasma calcium. Plasma calcium is regulated by a number of organs:
1. Bone - Calcium levels increase when resorbed from bone which serves as a reservoir. Excess plasma calcium can also be deposited in bone.
2. Digestive - Calcium can be absorbed from the digestive tract.
3. Kidney - Calcium can be excreted by the kidneys.
4. Skin - Participates in the formation of Vitamin D.
  Renal Handling of Calcium
     Calcium is transported in plasma both free and bound to carrier proteins. Free calcium is filtered at the glomerulus and normally 99% of it is resorbed: 70% is resorbed in the proximal tubules, 20% in the thick ascending limb of the loop of Henle, and 10% in the distal tubules. Hormones regulate reabsorption in the loop of Henle and distal tubules.
  Hormonal Control of Plasma Calcium
   Parathyroid Hormone (PTH)
     PTH is secreted in response to a decrease in plasma Ca. PTH:
1. Stimulates calcium resorption in the ascending limb of the loop of Henle and distal tubules.
2. Stimulates activation of calcitriol in the kidneys.
3. Stimulates resorption of bone & small increase in absorption from the digestive tract.
   Effects of Calcitriol
     Calcitriol stimulates absorption of calcium from the digestive tract and kidney. Vitamin  D3 can be converted from 7-dehydrocholesterol in the skin or absorbed in the diet. Vitamin D3 travels to the liver and is converted to 25-OH D3. From the liver 25-OH D3 travels to the kidneys and in the presence of low calcium levels is converted to calcitriol.
     Calcitonin decreases plasma calcium by increasing bone formation and decreasing reabsorption in the kidneys.
Acid-Base Balance
     It is essential to control pH within a narrow range of  7.38 to 7.42. Control is performed by the combined action of the lungs and the kidneys.
     Changes in pH can have profound effects:
1. Changes in pH change the shape of enzymes and their activities.
2. Activity of the nervous system changes:
Acidosis - decreases excitability of neurons
Alkalosis - increases excitability of neurons
3. Coupled to potassium imbalances:
Acidosis - results in potassium retention or hyperkalemia
Alkalosis - results in potassium depletion or hypokalemia
4. Acidosis causes cardiac arrhythmias and dilation of blood vessels of the skin.
  Sources of Acid-Base Disturbances
     Inputs include:
Dietary sources - proteins and fats
Metabolism - carbon dioxide, lactic acid, ketoacids
     Outputs include:
Lungs - carbon dioxide
Kidneys - hydrogen ions
  Respiratory Disturbances
     The lungs regulate the amount of carbon dioxide in the blood which is continually produced by cellular metabolism. The normal PCO2 is 40 mm Hg. This level is maintained by respiratory chemoreceptors. Diseases that interfere with the exchange of CO2 between the blood and alveolar air, or hypoventilation, lead to a buildup of CO2 in the blood which results in respiratory acidosis. Hyperventilation causes PCO2 to decrease and this leads to respiratory alkalosis.
  Metabolic Disturbances
     Metabolic Acidosis -
Loss of alkaline substances from the body.
Excess production of acid in metabolism.
Excess consumption of acids in the diet.
     Metabolic Alkalosis -
Loss of acids from the body.
Addition of alkaline substances to the blood.
  Specific Causes of Metabolic Disturbances:
1. High protein diet - Protein catabolism produces phosphoric acid and sulfuric acid that cause metabolic acidosis.
2. High fat diet - Catabolism of fats produces fatty acids.
3. Heavy exercise - When oxygen demands cannot be met and anaerobic metabolism is used to produce energy and lactic acid builds up.
4. Excessive vomiting - Loss of hydrogen ions in the stomach leads to metabolic alkalosis.
5. Severe diarrhea - Loss of bicarbonate ions can produce metabolic acidosis.
6. Alterations in renal function - Kidneys secrete hydrogen ions and absorb bicarbonate. Malfunction can produce either acidosis or alkalosis.
Defense Mechanisms Against Acid-Base Disturbances
     Three processes protect the body from dangerous shifts in pH. These processes only compensate for an imbalance and do not correct the cause of the imbalance. 
  Buffering of Hydrogen Ions
     The buffering of hydrogen ions is the first line of defense against changes in pH. Bicarbonate is the most important buffer in extracellular fluid. Proteins and phosphates are the most important intracellular buffers.
     The law of mass action determines whether a buffer binds or releases hydrogen ions:
H+ + A- --> HA
When H+ is added, the reaction goes to the right as the H+ binds with the anion form of the buffer. When H+ is removed, the reaction goes to the left as H+ disassociates from the acid form of the buffer.
     Buffering is the fastest defense against alterations in pH but buffering can only limit changes in pH and cannot do the job alone. Once there is a deviation from the normal pH, renal and respiratory mechanisms help to compensate for it.
  Respiratory Compensation
     Respiratory compensation is the second line of defense and acts in minutes. Increasing alveolar ventilation by blowing off CO2 increases pH while decreasing alveolar ventilation decreases pH. Unlike buffers, ventilation can regulate pH by reversing a change. However, respiratory compensation alone cannot restore pH to normal.
  Renal Compensation
     Renal compensation is the third line of defense and takes hours to days. The basic mechanism of renal compensation involves hydrogen ion secretion and bicarbonate reabsorption and synthesis. If pH decreases the kidneys secrete hydrogen ions and absorb bicarbonate and synthesize new bicarbonate. If pH increases the kidneys decrease hydrogen ion secretion and bicarbonate reabsorption.
   Renal Handling of Hydrogen and Bicarbonate Ions in the Proximal Tubules
     The basolateral membrane of tubular epithelial cells have:
1. Na+/K+ pumps
2. Na+/HCO3 - cotransporters
3. HCO3 -/Cl- counter transporters
     The apical membrane has:
1. Na+/H+ counter transporters
2. H+ pumps that pump H+ into tubular fluid
     Also important is carbonic anhydrase which is located in the cytosol and on the apical membrane. Carbonic anhydrase on the apical membrane converts the filtered HCO3 -, after it combines with H+ to form carbonic acid, into CO2 and H2O. The CO2 diffuses into the epithelial cell and is converted back to carbonic acid. The H+ inside the cytosol disassociate from the carbonic acid. H+  is pumped back into the lumen by the H+ pumps and Na+/H+ counter transporter. The HCO3 -  is transported into the peritubular fluid by the Na+/HCO3 - cotransporter and the HCO3 -/Cl- counter transporter.
     The net effects are to:
1. reabsorb 80-90% of filtered HCO3 -
2. secrete H+
3. reabsorb Na+
   Renal Handling in Late Distal Tubule and Collecting Duct
     Intercalated cells  in the late distal tubules and collecting ducts have different membrane proteins. The basolateral membrane has:
1. HCO3 -/Cl- counter transporters
2. Chloride channels
The apical membrane has:
1. H+ pumps
2. K+/H+ counter transporters
     Carbonic anhydrase is in the cytosol. Carbonic anhydrase produces carbonic acid in the cytosol which disassociates to form hydrogen ion and bicarbonate ion. The hydrogen ion is secreted into the lumen and the bicarbonate is secreted into the peritubular fluid
     The net effect is to:
1. Form new bicarbonate ions
2. Secrete H+
     As H+ are secreted into the tubular fluid an excessive decrease in pH is prevented by the buffering action of phosphate ions which are freely filtered at the glomerulus. 
   Role of Glutamine in Renal Compensation during Severe Acidosis
     During severe acidosis another mechanism involving glutamine helps renal compensation in the proximal convoluted tubule. Glutamine is transported into the tubular epithelial cells and catabolized to produce HCO3 -  and NH3. The HCO3 is newly formed and is secreted into the peritubular fluid. The NH3 combines with H+ to form NH4+ and is secreted. The net effect is new HCO3 - is added to the blood and H+ is secreted in the form of the NH4+ ion. 
Compensation for Acid-Base Disturbances
     The acid-base status of the plasma is reflected by the ratio of bicarbonate ions to CO2 in the plasma as determined by the Henderson-Hasselbach equation. When the pH is normal this ratio is 20 to 1 or 20 HCO3 ions for every molecule of CO2 in the plasma. The respiratory system regulates the concentration of CO2 in the plasma, while the kidneys regulate the concentration of  HCO3- . The four basic acid-base disturbances are as follows:
  Respiratory Acidosis
     Hypoventilation due to lung disease, depression of the respiratory center or diseases of the respiratory muscles causes pCO2 to increase. This decreases the ratio of bicarbonate to CO2 . The acidosis is corrected by the kidneys which increases the absorption of  HCO3 -  and secretion of  H+.
  Respiratory Alkalosis
     Hyperventilation due to fever or anxiety decreases the pCO2 thus increasing the bicarbonate to CO2 ratio. Again the kidney corrects by reabsorbing less HCO3 and secreting less H+.
  Metabolic Acidosis
     An increase in H+ is due to metabolic causes including diarrhea, diabetes mellitus, strenuous exercise, renal failure, etc. Compensation includes an increase in ventilation and renal compensation by an increase in bicarbonate production and an increase in the secretion of H+.
  Metabolic Alkalosis
     A decrease in H+ due to vomiting, ingestion of alkaline drugs (sodium bicarbonate or antacids). Compensation involves both the lungs and the kidneys. Compensation includes a decrease in ventilation which increases pCO2 and in the kidneys an increase in the secretion of bicarbonate ions and a decrease in secretion of H+ .
Evaluation of Acid-Base Disturbances
   Diagnosis of acid-base disturbances includes measuring:
1. plasma pH
2. PCO2
3. plasma bicarbonate
Metabolic Acidosis - decrease in pH
decrease in [HCO3-]
decrease in PCO2
Respiratory Acidosis - decrease in pH
increase in [HCO3-]
increase in PCO2
Metabolic Alkalosis - increase in pH
increase in [HCO3-]
increase in PCO2
Respiratory Alkalosis - increase in pH
decrease in [HCO3-]
decrease in PCO2