Renal handling of water

Regulation and Renal Handling of Water

Renal Physiology January 30th, 2014

Wisit Cheungpasitporn

Water Balance in the Body

Figure 7.1 Composition of body fluid compartments. Schematic representation of body fluid compartments in humans. The shaded areas depict the approximate size of each compartment as a function of body weight. The figures indicate the relative sizes of the various fluid compartments and the approximate absolute volumes of the compartments (in liters) in a 70-kg adult. Intracellular electrolyte concentrations are in millimoles per liter and are typical values obtained from muscle. ECF, extracellular fluid; ICF, intracellular fluid; ISF, interstitial fluid; IVF, intravascular fluid; TBW, total body water

Comprehensive Clinical Nephrology, 4th edition

Overview

• Water is the solvent for all of the body’s dissolved substances

• Water constitutes the majority of the body’s volume

• The kidney plays a pivotal role in the maintenance of normal water homeostasis

• Conserves water in states of water deprivation• Excretes water in states of water excess

• This ability is based on a complex anatomical arrangement between the nephron and renal vasculature

• Allows for the generation of a hypertonic medullary interstitium

• Transport of water:• “Water follows osmoles”

Brenner and Rector, 9th edition

Overview

• Nephrons can be classified by 2 ways:1. Location within the cortex

• Superficial • Midcortical • Juxtamedullary

2. Length of their Loop of Henle• Short – Loop turns back in the outer medulla or cortex• Long – Loop turns back in the inner medulla

• Thin Ascending limb (only found in inner medulla)

• Superficial and Midcortical Nephrons • Short loops

• Juxtamedullary Nephrons• Long Loops


Short and Long Looped Nephrons


Overview

• Renal blood vessel anatomy plays an important in maintaining the hypertonic medullary interstitium

• Vasa Recta are major blood vessels that carry blood into & out of the renal medulla

• Descending Vasa Recta • Ascending Vasa Recta

• The counter flow arrangement promotes countercurrent exchange of solutes and water

• Preserves medullary interstitial hypertonicity


Overview

• Basic requirements for forming concentrated urine1. Hypertonic Medullary Interstitium

• Generates osmotic gradient necessary for water reabsorption

2. High levels of ADH• Increases water permeability of DCT and CD

Textbook of Medical Physiology, Guyton and Hall, 10th edition

Hypertonic Medullary Interstitium

• Most parts of the body have an interstitial fluid osmolarity of 290 mOsm/L

• Similar to plasma osmolarity

• In the renal medulla, interstitial fluid osmolarity can be as high as 1200-1400 mOsm/L

• Near the pelvic tip of the medulla

• Occurs from accumulation of more solute than water

• Maintained by balanced inflow and outflow of solutes and water in the medulla


Hypertonic Medullary Interstitium

Major Factors that contribute to excess buildup of solute:1. Thick ascending limb of Loop of Henle

• Active transport of Na+ ions out into interstitium• Cotransport of Cl- ions, K+ ions, and other ions into interstitium

2. Collecting Ducts• Active transport of ions out of CD into interstitium

3. Passive Urea Diffusion/Recycling• From the inner medullary collecting ducts → medullary

Interstitium → Loop of Henle

4. Diffusion of only a small amount of water from medullary tubules into interstitium

• Far less than solutes


Textbook of Medical Physiology, Guyton and Hall, 10 th edition

Concentrating limb

Diluting limb


Atlas of Kidney Disease: Online

• Tubular epithelial permeability to water varies depending the nephron segment

• Thus there can be independent regulation of water and solute excretion • i.e. During times of severe Dehydration, the kidney can concentrate

urine to minimize water loss• i.e. During times of excessive water load, the kidney can produce a

large amount of urine to maximize water loss

Countercurrent Multiplier System

• “Countercurrent multiplication of a single effect”• Proposed by Kuhn and Ryffel in 1942

“Osmotic pressure is raised along parallel but opposing flows in nearby tubes that are made contiguous with a hairpin turn”

• A transfer of solute from one tubule to another (i.e. single effect) would augment (multiply) osmotic pressure in parallel flows


Step 1: Time ZeroFluid in the descending limb, ascending limb, and interstitium are isoosmotic to the plasma

Step 2: NaCl is reabsorbed from the thick ascending limb into the interstitium via Na-2Cl-K Cotransporter

Raises interstitial osmolarity

Pump Establishes a 200 mOsm/L concentration gradient between tubular fluid and interstitial fluid

Limited to 200 mOsm/L because of paracellular diffusions of ions back into the tubules counterbalances transport of ions out of the lumen

Step 3: Fluid in the descending limb equilibrates osmotically with the interstitium by water movement out of the tubule

Interstitial osmolarity is maintained at 400 mOsm/L because of continued transport of ions out of the thick ascending limb

Step 4: Additional flow of fluid from the proximal tubule causes the hyperosmotic fluid previously formed in the descending limb to flow into the ascending limb

Step 5: Additional ions are pumped into the interstitium until a 200 mOsm/L osmotic gradient is established

Raises interstitial osmolarity to 500 mOsm/L

Step 6: Fluid in the descending limb equilibrates osmotically with the interstitium by water movement out of the tubule

Interstitial osmolarity is maintained at 500 mOsm/L because of continued transport of ions out of the ascending limb

Step 7: Steps 4-6 are repeated over and over, with net effect of adding more solute to the medulla than water

With sufficient time, this process traps solutes in the medulla and multiplies the concentration gradient established by the active pumping of ions out of the thick ascending limb

Eventually, raises interstitial osmolarity to 1200-1400 mOsm/L Textbook of Medical Physiology, Guyton and Hall, 10th edition

Passive Urea Diffusion/Recycling

• The Hypertonic Medullary Interstitium is generated not only only by NaCl but also by Urea

• Urea contributes about 40% to the interstitial osmolarity (~500 mOsm/L)

• Unlike NaCl, urea is passively reabsorbed from the tubule

• Recirculation of urea between the CD and Loop of Henle

• Thick Ascending Limb, Distal Tubule, and Cortical Collecting Duct• Impermeable to Urea

• Rest of Nephron segments are permeable to Urea

• When ADH is present, more Urea is reabsorbed from the inner medullary collecting ducts

• This is the reason for BUN/Cr ratio to increase in times of dehydration



The Urea Transport Mechanisms are Different at Different Points in the NephronUrea transport is along the paracellular route in proximal tubule.

Urea transport is along the transcellular route in loop & collecting duct.

Proximal Tubule Urea Reabsorption Na is reabsorbed with H20 following. As H20 leaves tubule, urea is concentrated. This creates a urea gradient across tubule. Urea passively diffuses down this gradient along the paracellular route. Tight junctions are not so tight.

The Urea Transport Mechanisms are Different at Different Points in the NephronUrea transport is along the paracellular route in proximal tubule.

Urea transport is along the transcellular route in loop & collecting duct.

Urea Transport in Loop & Collecting Duct Tight junctions are tight (paracellular not available) Urea is transported along transcellular route

via facilitated diffusion (urea uniporter) Urea levels in renal medulla are very high

• gradient favors secretion into loop• gradient favors reabsorption from CT

>10XPlasma

Urea

1

3

2

4

6

5

InterstitiumTubular Lumen

Urea Transporters along various segments of the Nephron


UREA: not just a waste product of protein metabolismUrea is special substance in Renal Physiology.It is key to controlling the bodies H2O balance.

Renal Handling of Urea It is freely filtered

It is reabsorbed from proximal tubule It is secreted into loop of Henle It is reabsorbed again from collecting duct

% filteredload

50% R

60% R

60% S

Urea can Recycle Urea can recycle between loop &

collecting duct.

UreaRecycling

Vasa recta

• Cells in the renal medulla require blood supply to meet their metabolic needs

• Without a special medullary blood flow system, the hyperosmotic medullary interstitium created by the solutes from the Countercurrent multiplier system would dissipate

• Two features of renal medullary blood flow prevent this:1. Medullary blood flow is low

• Accounts for only 1-2% of total renal blood flow

2. Vasa Recta serve as countercurrent exchangers (↓↑)• Minimizes wash out of solutes from interstitium


Vasa Recta

Vasa Recta have fenestrated endothelium which is highly permeable to Solutes (NaCl, Urea)

Also have Urea and Aquaporin channels

Solute Transport is entirely PASSIVE


Overview

• Basic requirements for forming concentrated urine1. Hypertonic Medullary Interstitium

• Generates osmotic gradient necessary for water reabsorption

2. High levels of ADH• Increases water permeability of DCT and CD


Plasma Osmolarity

• Plasma osmolarity is about 282 mOsm/L

• Varies less than ± 1-2% at any given time

• Regulated by two main systems:• Osmorecepetor-ADH system• Thirst mechanism

• ADH has a short half-life of about 15-20 minutes• Metabolized rapidly by liver and kidney• Allows for rapid means to alter water excretion


Water transport & vasopressin (ADH) dependence

Transport mechanism:

passive diffusion through aquaporin channels down osmotic gradient

Reabsorption:

~99% of filtered water is reabsorbed

Sites of reabsorption:

~70% from proximal tubule

~15% from descending limb of loop of Henle

0% from Henle’s ascending limb & distal tubule

0-15% from collecting duct depending on plasma vasopressin level

Antidiuretic hormone (ADH)

• Glomerulus filters 180 L of fluid per day from the plasma• 90% (or 162 L) is reabsorbed in the proximal tubule and descending

limb

• The remaining 18 L is reabsorbed under the regulation of:• Arginine Vasopressin (or Antidiuretic hormone, ADH)



• It is a preprohormone synthesized by specialized nuclei in the hypothalamus (Magnocellular nuclei):

• Supraoptic nuclei, SON• About 5/6th produced here

• Paraventricular nuclei, PVN• About 1/6th produced here

• Transported down the axons of these nuclei to the posterior pituitary in secretory granules

• Released in response to osmotic and non-osmotic stimuli:1. Change in plasma osmolarity

• Detected by osmoreceptors in the anterior hypothalamus

2. Change in blood pressure or in blood volume• Detected by arterial baroreceptors and atrial stretch receptors



Osmotic Stimuli for ADH Release• ↑ Plasma Osmolarity causes osmoreceptors to shrink

• This initiates an action potential that is transmitted to the SON and PVN, which is then relayed down to the tips of their axons in the posterior pituitary

• This stimulates an influx of Ca+2 ions in the tips of the neuronal axon causing release of ADH from secretory granules

• ADH is carried away in the posterior pituitary capillaries into the systemic circulation

• ADH increases water permeability of the kidney in the:• Late distal tubules• Cortical collecting ducts, and inner medullary collecting ducts

• Signals form the Osmoreceptors also induce the Thirst MechanismBrenner and Rector, 9th edition


Non-Osmotic Stimuli for ADH Release

• Decreased Blood Pressure/Volume• Detected by Arterial baroreceptors

• Carotid sinus• Aortic Arch

• Stimulates ADH release

• Increased Blood Volume• Detected by Cardiopulmonary Reflexes

• Arial Stretch Receptors• Decrease ADH release• Stimulates Arial Natriuretic Peptide (ANP) release



• Binds to 3 receptors coupled to G proteins1. V1a receptor

• Found on vascular smooth muscle• Activation increases intracellular Ca+2, resulting in contraction

2. V1b receptor• Found in the Anterior Pituitary• Modulates ACTH release

3. V2 receptor• Found on the baslolateral membrane of Principle Cells from the

late distal tubule through the entire collecting duct

• Coupled by Gs protein to cAMP, which ultimately leads to insertion of water channels (Aquaporins)


Figure 20-6, step 1

Water Reabsorption

Collecting duct lumen

Filtrate300 mOsm

Cross-section ofkidney tubule

Collecting duct cellMedullaryinterstitial

fluid

Vasopressin receptor

Vasarecta

Vasopressin

Vasopressin binds to mem-brane receptor.

1

1

600 mOsM

600 mOsM

700 mOsM

The mechanism of vasopressin action

Figure 20-6, steps 1–2

Water Reabsorption


Filtrate300 mOsm


Collecting duct cell

Secondmessengersignal

cAMP

Medullaryinterstitial

fluid


Vasarecta

Vasopressin


Receptor activates cAMP second messenger system.

1 2

1

2

600 mOsM

600 mOsM

700 mOsM


Water Reabsorption


Filtrate300 mOsm

Exocytosisof vesicles




cAMP

Storage vesicles

Aquaporin-2water pores


fluid


Vasarecta

Vasopressin



Cell inserts AQP2 water pores into apical membrane.

1 2 3

1

2

3

600 mOsM

600 mOsM

700 mOsM


Water Reabsorption


Filtrate300 mOsm

H2O

Exocytosisof vesicles




H2O

cAMP

Storage vesicles

Aquaporin-2water pores

600 mOsM

H2O


fluid


600 mOsM

Vasarecta

H2O

700 mOsM

Vasopressin



Cell inserts AQP2 water pores into apical membrane.

Water is absorbed by osmosis into the blood.

1 2 3 4

1

2

3

4

Atlas of Kidney Disease: Online

Aquaporins

1

3

2

4

6

5

InterstitiumTubular Lumen


Aquaporin subtypes along various segments of the Nephron

Water ReabsorptionWater movement in the collecting duct in the presence and

absence of vasopressin

Transport mechanism:

passive diffusion through aquaporin channels down osmotic gradient

Water Reabsorption

Thirst Mechanism

• Thirst – defined as conscious desire for water

• Regulates fluid intake and works together with the osmoreceptor-ADH mechanism to maintain ECF osmolarity

• Same area in brain that stimulates ADH release, also stimulates the Thirst Mechanism


Obligatory Urine Volume

• Minimal volume of water needed to excrete ingested and waste produced osmoles

• The maximum concentrating ability of the kidney dictates how much urine much be excreted each day

• A normal 70 kg human must excrete ~ 600 mOsm/day

• If the maximal concentrating ability of the kidney is 1200 mOsm/L, the minimal volume of water needed for excretion of these osmoles is:

• (600 mOsm/day) / (1200 mOsm/L) = 0.5 L/day

• The concept of obligatory urine volume, is where the definition of oliguria originated from

• Urine output below this per day would be pathologic


KEY POINTS

• Nephron anatomy is key to generating a Hypertonic Medullary Interstitium

• Renal blood vessel anatomy is key to maintaining the hypertonic medullary interstitium

• ADH is also necessary for concentrating urine

• ADH has a complicated regulatory system from both osmotic and non-osmotic stimuli

• Thirst Mechanism is another way of regulating ECF osmolarity

Questions & Discussion

Renal handling of water

Education

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