Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

Changes in Osmolarity of the Renal Tubular Fluid Figure 28-7; Guyton and Hall

Minimal urine concentration Concentration and Dilution of the Urine Maximal urine concentration = 1200 - 1400 mOsm / L (specific gravity ~ 1.030) Minimal urine concentration = 50 - 70 mOsm / L (specific gravity ~ 1.003)

Urine Specific Gravity Relationship Between Urine Osmolarity and Specific Gravity 1400 1200 1000 Influenced by glucose in urine protein in urine Urine Osmolarity (mOsm/L) 800 600 400 200 1.010 1.020 1.030 1.040 Urine Specific Gravity Copyright © 2006 by Elsevier, Inc.

Water diuresis in a human after ingestion of 1 liter of water

Formation of a Dilute Urine Continue electrolyte reabsorption Decrease water reabsorption Mechanism: decreased ADH release and reduced water permeability in distal and collecting tubules

Formation of a Concentrated Urine Continue electrolyte reabsorption Increase water reabsorption Mechanism: Increased ADH release which increases water permeability in distal and collecting tubules High osmolarity of renal medulla Countercurrent flow of tubular fluid

Formation of a Concentrated Urine when Antidiuretic Hormone (ADH) Levels are High Figure 28-4; Guyton and Hall

Obligatory Urine Volume The minimum urine volume in which the excreted solute can be dissolved and excreted. Example: If the max. urine osmolarity is 1200 mOsm/L, and 600 mOsm of solute must be excreted each day to maintain electrolyte balance, the obligatory urine volume is: 600 mOsm/d 1200 mOsm/L = 0.5 L/day

Obligatory Urine Volume In renal disease the obligatory urine volume may be increased due to impaired urine concentrating ability. Example: If the max. urine osmolarity = 300 mOsm/L, If 600 mOsm of solute must be excreted each day to maintain electrolyte balance obligatory urine volume = ? 600 mOsm/d = 2.0 L/day 300 mOsm/L

Maximum Urine Concentration of Different Animals Animal Max. Urine Conc. (mOsm /L) Beaver 500 Pig 1,100 Human 1,400 Dog 2,400 White Rat 3,000 Kangaroo Mouse 6,000 Australian Hopping Mouse 10,000

Formation of a Concentrated Urine when Antidiuretic Hormone (ADH) Levels are High Continue electrolyte reabsorption Increase water reabsorption Increased ADH High osmolarity of renal medulla (countercurrent multiplier)

Factors That Contribute to Buildup of Solute in Renal Medulla - Countercurrent Multiplier Active transport of Na+, Cl-, K+ and other ions from thick ascending loop of Henle into medullary interstitium Active transport of ions from medullary collecting ducts into interstitium Passive diffusion of urea from medullary collecting ducts Diffusion of only small amounts of water into medullary interstitium

Medullary Collecting Duct Transport Figure 27-11; Guyton and Hall

Recirculation of Urea Absorbed from Medullary Collecting Duct into Interstitial Fluid Figure 28-5; Guyton and Hall

Summary of Tubule Characteristics Permeability Tubule Active NaCl Segment Transport H2O NaCl Urea Proximal ++ +++ + + Thin Desc. 0 +++ + + Thin Ascen. 0 0 + + Thick Ascen. +++ 0 0 0 Distal + +ADH 0 0 Cortical Coll. + +ADH 0 0 Inner Medullary + +ADH 0 +ADH Coll.

Countercurrent Multiplier System in the Loop of Henle

Net Effects of Countercurrent Multiplier 1. More solute than water is added to the renal medulla (i.e., solutes are “trapped” in the renal medulla). 2. Fluid in the ascending loop is diluted. 3. Most of the water reabsorption occurs in the cortex (i.e., in the proximal tubule and in the distal convoluted tubule) rather than in the medulla. 4. Horizontal gradient of solute concentration established by the active pumping of NaCl is “multiplied” by countercurrent flow of fluid.

Urea Recirculation Urea is passively reabsorbed in proximal tubule. In the presence of ADH, water is reabsorbed in distal and collecting tubules, concentrating urea in these parts of the nephron. The inner medullary collecting tubule is highly permeable to urea, which diffuses into the medullary interstitium. ADH increases urea permeability of medullary collecting tubule.

The Vasa Recta Preserve Hyperosmolarity of Renal Medulla serve as countercurrent exchangers Vasa recta blood flow is low (only 1-2 % of total renal blood flow) Figure 28-3; Guyton and Hall

Changes in Osmolarity of the Renal Tubular Fluid Figure 28-7; Guyton and Hall

Summary of Water Reabsorption and Osmolarity in Different Parts of the Tubule Proximal Tubule: 65 % reabsorption, isosmotic Desc. loop: 15 % reasorption, osmolarity increases Asc. loop: 0 % reabsorption, osmolarity decreases Early distal: 0 % reabsorption, osmolarity decreases Late distal and coll. tubules: ADH dependent water reabsorption and tubular osmolarity Medullary coll. ducts: ADH dependent water reabsorption and tubular osmolarity

“Free” Water Clearance (CH2O) CH2O = V - Uosm x V Posm where: Uosm = urine osmolarity V = urine flow rate P = plasma osmolarity If: Uosm < Posm, CH2O = + If: Uosm > Posm, CH2O = -

Disorders of Urine Concentrating Ability Failure to produce ADH: “Central” diabetes insipidus Failure to respond to ADH: “nephrogenic” diabetes insipidus - impaired loop NaCl reabs. (loop diuretics) - drug induced renal damage: lithium, analgesics - malnutrition (decreased urea concentration) - kidney disease: pyelonephritis, hydronephrosis, chronic renal failure

Control of Extracellular Osmolarity (NaCl Concentration) ADH Thirst ] ADH -Thirst Osmoreceptor System Mechanism: increased extracellular osmolarity (NaCl) stimulates ADH release, which increases H2O reabsorption, and stimulates thirst (intake of water)

Osmoreceptor– antidiuretic hormone (ADH) feedback mechanism for regulating extracellular fluid osmolarity

ADH synthesis in the magnocellular neurons of hypothalamus, release by the posterior pituitary, and action on the kidneys

Stimuli for ADH Secretion Increased osmolarity Decreased blood volume (cardiopulmonary reflexes) Decreased blood pressure (arterial baroreceptors) Other stimuli : - input from cerebral cortex (e.g. fear) - angiotensin II ? - nausea - nicotine - morphine

The effect of increased plasma osmolarity or decreased blood volume Figure 28-10; Guyton and Hall

Factors that Decrease ADH Secretion Decreased osmolarity Increased blood volume (cardiopulmonary reflexes) Increased blood pressure (arterial baroreceptors) Other factors: - alcohol - clonidine (-2 adrenergic agonist) - haloperidol (antipsychotic, tics,Tourette’s)

Stimuli for Thirst Increased osmolarity Decreased blood volume (cardiopulmonary reflexes) Decreased blood pressure (arterial baroreceptors) Increased angiotensin II Other stimuli: - dryness of mouth

Factors that Decrease Thirst Decreased osmolarity Increased blood volume (cardiopulmonary reflexes) Increased blood pressure (arterial baroreceptors) Decreased angiotensin II Other stimuli: -Gastric distention

Chapter 29:

Normal Potassium Intake, Distribution, and Output from the Body < 2 % > 98 %

Effects of severe hyperkalemia Partial depolarization of cell membranes Cardiac toxicity ventricular fibrillation or asystole Effects of severe hypokalemia Hyperpolarization of cell membranes Fatigue, muscle weakness hypoventilation delayed ventricular repolarization

Renal Tubular Sites of Potassium Reabsorption and Secretion Figure 29-2; Guyton and Hall

Internal Distribution of K+ Factors That Promote Hypokalemia aldosterone insulin alkalosis Factors That Promote Hyperkalemia cell lysis acidosis strenuous exercise

K+ Secretion by Principal cells

Control of Cortical Collecting Tubule (Principal Cells) K+ Secretion Aldosterone : increases K+ secretion Extracellular K+ concentration : increases K+ secretion Acid - base status: - acidosis : decreases K+ secretion - alkalosis : increases K+ secretion

Effect of Changes in K+ Intake on Plasma K+ 4.6 4.4 Plasma K+ Conc. 4.2 (mEq/L) 4.0 3.8 30 60 90 120 150 180 210 K+ Intake ( mEq/day)

Effect of Aldosterone on K+ Excretion 4 3 Urinary K+ Excretion (x normal) 2 1 1 2 3 4 5 Plasma Aldosterone (x normal

K+ Intake Plasma K+ Concentration Aldosterone K+ Secretion Cortical Collecting Tubules K+ Excretion

Effect of Changes in K+ Intake on Plasma K+ After Blocking Aldosterone System 3.8 4.0 4.2 4.4 4.6 Aldosterone System blocked Plasma normal K+ Conc. (mEq/L) 30 60 90 120 150 180 210 K+ Intake ( mEq/day)

Mechanisms of Hydrogen Ion Regulation [H+] is precisely regulated at 3 - 5 x 10 -8 moles/L (pH range 7.2 -7.4) 1. Body fluid chemical buffers (rapid but temporary) bicarbonate - ammonia proteins - phosphate 2. Lungs (rapid, eliminates CO2) [H+] ventilation CO2 loss 3. Kidneys (slow, powerful); eliminates non-volatile acids - secretes H+ - reabsorbs HCO3- - generates new HCO3-

Bicarbonate: most important ECF buffer Buffer Systems in the body Bicarbonate: most important ECF buffer Phosphate: important renal tubular buffer HPO4-- + H+ H2PO 4 - Ammonia: important renal tubular buffer NH3 + H+ NH4+ Proteins: important intracellular buffers H+ + Hb HHb H2O + CO2 H2CO3 H+ + HCO3 - (60-70% of buffering is in the cells)

Normal H+ concentration = 0.00004 mmol/L Importance of Buffer System Normal H+ concentration = 0.00004 mmol/L Amount of non-volatile acid produced ~ 80 mmol/day 80 mmol /42 L = 1.9 mmol/L = 47,500 times > normal H+ concentration

Bicarbonate Buffer System carbonic anhydrase H2O + CO2 H2CO3 H+ + HCO3 - HCO3 - pCO2  = 0.03 pK = 6.1 pH = pK + log Effectiveness of buffer system depends on: concentration of reactants pK of system and pH of body fluids

Titration Curve for Bicarbonate Buffer System

Bicarbonate Buffer System Is the most important buffer in extracellular fluid even though the concentration of the components are low and pK of the system is 6.1, which is not very close to normal extracellular fluid pH (7.4). Reason: the components of the system (CO2 and HCO3-) are closely regulated by the lungs and the kidneys

Respiratory Regulation of Acid-Base Balance [H+] Alveolar Ventilation pCO2 H2O + CO2 H2CO3 H+ + HCO3 -

Effects of Blood pH on Alveolar Ventilation

Renal Regulation of Acid-Base Balance Kidneys eliminate non-volatile acids (H2SO4, H3PO4) Secretion of H+ Reabsorption of HCO3- Production of new HCO3-

Renal Tubular Reabsorption of Bicarbonate (and H+ secretion) Key point: For each HCO3- reabsorbed, there must be a H+ secreted

Mechanism of HCO3- Reabsorption and Na+ - H+ Exchange In Proximal Tubule and Thick Loop of Henle

and collecting tubules HCO3- Reabsorption and H+ secretion in Intercalated cells of late distal and collecting tubules Figure 30-6; Guyton and Hall

Regulation of H+ secretion Increased pCO2 increases H+ secretion i.e. respiratory acidosis Increased extracellular H+ increases H+ secretion i.e. metabolic or respiratory acidosis Increased tubular fluid buffers increases H+ secretion i.e. metabolic or respiratory acidosis

increased H+ secretion increased HCO3- reabsorption Renal Compensations for Acid-Base Disorders Acidosis: increased H+ secretion increased HCO3- reabsorption production of new HCO3- Alkalosis: decreased H+ secretion decreased HCO3- reabsorption loss of HCO3- in urine

i.e. the maximal [H+] of urine is 0.03 mmol/L Importance of Renal Tubular Buffers Minimum urine pH = 4.5 = 10 -4.5 = 3 x 10 -5 moles/L i.e. the maximal [H+] of urine is 0.03 mmol/L Yet, the kidneys must excrete, under normal conditions, at least 60 mmol non-volatile acids each day. To excrete this as free H+ would require: .03mmol/L = 2000 L per day !!! 60 mmol

Buffering of Secreted H+ by Filtered Phosphate (NaHPO4-) and Generation of “New” HCO3-

Phosphate as a Tubular fluid buffer There is a high concentration of phosphate in the tubular fluid; pK = 6.8 Phosphate normally buffers about 30 mmol/day H+ (about 100 mmol/day phosphate is filtered but 70 % is reabsorbed) Phosphate buffering capacity does not change much with acid-base disturbances (phosphate is not the major tubular buffer in chronic acidosis NaHPO4- + H+ NaH2PO4

Phosphate and Ammonium Buffering In Chronic Acidosis 500 - - H PO + HSO4 2 4 400 + NH 4 Acid Excretion (mmoles/day) 300 200 100 Normal Acidosis for 4 Days

Production and Secretion of NH4+ and HCO3- by Proximal, Thick Loop of Henle,and Distal Tubules H++NH3 “New” HCO3-

Buffering of Hydrogen Ion Secretion by Ammonia (NH3) in the Collecting Tubules “New” HCO3- Figure 30-9; Guyton and Hall

Quantification of Normal Renal Acid-Base Regulation Total H+ secretion = 4380 mmol/day = HCO3- reabsorption (4320 mmol/d) + titratable acid (NaHPO4-) (30 mmol/d) + NH4+ excretion (30 mmol/d) Net H+ excretion = 59 mmol/day = titratable acid (30 mmol/d) + NH4+ excretion (30 mmol/d) - HCO3- excretion (1 mmol/d)

Normal Renal Acid-Base Regulation Net addition of HCO3- to body (i.e., net loss of H+) Titratable acid = 30 mmol/day + NH4+ excretion = 30 mmol/day - HCO3- excretion = 1 mmol/day Total = 59 mmol/day

H2O + CO2 H2CO3 H+ + HCO3 - HCO3 - pH = pK + log α pCO2 Classification of Acid Base Disorders from Plasma pH;PCO2 and HCO3- H2O + CO2 H2CO3 H+ + HCO3 - HCO3 - α pCO2 pH = pK + log Acidosis: pH < 7.4 - metabolic: HCO3 - - respiratory: pCO2 Alkalosis: pH > 7.4 - metabolic: HCO3 - - respiratory: pCO2

Simple Analysis of Acid-Base Disorders Figure 30-10; Guyton and Hall

increased H+ excretion increased HCO3- reabsorption Renal Compensation of Acid-Base Disorders Acidosis: increased H+ excretion increased HCO3- reabsorption production of new HCO3- Alkalosis decreased H+ excretion decreased HCO3- reabsorption loss of HCO3- in urine

Renal Responses to Respiratory Acidosis H2O + CO2 H2CO3 H+ + HCO3 - Respiratory acidosis: pH pCO2 HCO3- H+ secretion pH PCO2 complete HCO3- reabs. + excess tubular H+ Buffers (NH4+, NaHPO4-) H+ Buffers - + new HCO3-

Metabolic acidosis: pH pCO2 HCO3- HCO3- HCO3- complete HCO3- reabs. Renal Responses to Metabolic Acidosis Metabolic acidosis: pH pCO2 HCO3- HCO3- HCO3- complete HCO3- reabs. filtration + excess tubular H+ pH Buffers (NH4+, NaHPO4-) H+ Buffers - + new HCO3-

Respiratory alkalosis: pH pCO2 HCO3- Renal Response to Respiratory Alkalosis Respiratory alkalosis: pH pCO2 HCO3- H+ secretion pH PCO2 HCO3- reabs. + excess tubular HCO3- HCO3- + H+ excretion

+ Metabolic alkalosis: pH pCO2 HCO3- HCO3- excess tubular HCO3- HCO3- Renal Response to Metabolic Alkalosis Metabolic alkalosis: pH pCO2 HCO3- HCO3- excess tubular HCO3- HCO3- filtration HCO3- reabs. pH H+ excretion HCO3- + excretion

Disturbance pH HCO3- pCO2 Compensation Classification of Acid Base Disturbance Plasma Disturbance pH HCO3- pCO2 Compensation ventilation metabolic acidosis renal HCO3 production respiratory acidosis renal HCO3 production ventilation metabolic alkalosis renal HCO3 excretion respiratory alkalosis renal HCO3 excretion

Acid-Base Disturbances Metabolic Acidosis: HCO3- / pCO2 in plasma ( pH, HCO3- ) aspirin poisoning ( H+ intake) diabetes mellitus ( H+ production) diarrhea (HCO3- loss) renal tubular acidosis ( H+ secretion, HCO3- reabs.) carbonic anhydrase inhibitors ( H+ secretion) H2O + CO2 H2CO3 H+ + HCO3 - HCO3 - pH = pK + log pCO2