Objectives
By the end of session students should be able to discuss the:
•Formation of dilute urine
•Formation of concentrated urine
–Counter current multiplier mechanism
–Urea recycling
–Counter current exchange mechanism
•Osmolar& free water clearance
•Applied physiology
Dilute Urine
•Amount of water makes the urine dilute or concentrated while solute excretion generally remains constant
•Regulated by ADH
Dilute Urine
•ECF osmolarity and fluid content is regulated by
–Intake (thirst)
–Excretion (glomerular filtration)
•Capability of kidney to alter solute concentration
•Osmolarity as less as 50mOsm/L(when excess water)
•Osmolarity as more as 1200—1400mOsm/L (when water deficit)
Obligatory Urine Volume
•Minimum daily solute output (average in a 70 kg man)
–600 mOsm(irrespective of dilute or concentrated urine)
•Leads to obligatory urine volume output -0.5 L/day
Obligatory Urine Volume
If the maximal urine concentrating ability is 1200mOsm/L, the minimum volume of urine that must be excreted is known as obligatory urine volume
= 600mOsm/day
1200mOsm/day
= 0.5L/day
•Dilute urine (water loss)
–When overhydration—-↓ADH
•Concentrated urine (water retention)
–When dehydration —-↑ADH
Formation of dilute urine
Dilute Urine
•Stoppage of water reabsorption beyond thin descending limb of loop of Henle
•Dilution of tubular fluid to 100 mOsm/L by ascending limb
•Further dilution in distal segments to 50 mOsm/L dilute urine
•Thick ascending limb
–Active reabsorption of Na+& Cl-
•Impermeable to water (even in presence of ADH)
•Dilution of fluid entering distal convoluted tubule at 100 mOsm/L
•Fluid leaving early distal tubule is always hypo-osmotic irrespective of presence or absence of ADH
•Overhydration
–Low osmolarity of ECF (dilute urine)
•Water impermeability (ADH)of late distal tubule, cortical collecting ducts & medullary collecting ducts dilute urine formation
•Continuous reabsorption of Na+ & Cl-dilute urine formation
•Max urine volume output
–About 20 L/day (normal 1.5 L/day)
•Urine osmolarity
–50 mOsm/L (solute concentration remains the same)
Concentration of urine
•Two basic prerequisites
–Hyperosmolarity in renal medullary interstitium(function of juxtamedullarynephrons)
–High level of ADH
Formation of concentrated urine
•Hyperosmolarity of medullary interstitium
–Generated by
•Countercurrent multiplier (50-60%)
•Urea recycling (40-50%)
–Maintained by
•Countercurrent exchanger
Factors
1.Active transport of sodium and co transport of ions—ascending limb of loop of Henle
2.Active transport of ions from medullary collecting ducts
3.Facilitated diffusion of urea from medullary collecting ducts
4.Less amount of water reabsorption of water in comparison to ions from medullary tubules
Mechanism
•Repetitive reabsorption of NaClfrom thick limb with continuous inflow from proximal tubule & outflow into distal tubule
•Pump creates a concentration gradient of 200mOsm/L by
–Thick ascending limb impermeable to water
–Whereas permeable to solutes without osmotic drag of water
Countercurrent multiplier
•Step 1:
–Fluid leaving proximal tubule has osmolarity equal to plasma 300mOsm/L
–Interstitiumosmolarity is also 300mOsm/L
•Step 2:
–Thick ascending limb reabsorbs all solutes establishing a concgradient
Countercurrent multiplier
•Step 3:
–As renal interstitial osmolarity rises
–Osmotic drag of water take place
–Osmolarity of renal interstitiummaintained at 400mOsm/L
–Trapping of ions
•Step 4:
–Additional inflow of water in to loop of Henle from PCT
Countercurrent multiplier
•Step 5&6:
–As the hyperosmolar fluid enters the ascending limb additional solutes are reabsorbed rising interstitial fluid osmolarity upto500mOsm/L
–Till the ascending limb fluid reaches equilibrium with interstitium
•Step 7:
–Repeated steps again n again
–More solutes added in medulla by reabsorption through ascending limb of loop of Henle
–Raising osmolarity to 1200 to 1400mOsm/L
Role of DCT and Collecting Ducts
•As the fluid enters the DCT osmolarity—100mOsm/L (dilute)
•Role of early DCT is similar
•Water reabsorption beyond is dependent on ADH
•If ADH absent
–Water remain on tubule
–Salts continue to reabsorb
•If ADH high
–Water reabsorbed in cortex massively
–Not in medulla to preserve renal medullary interstitium
•When ADH is high still water is reabsorbed from even medullary collecting but much less as compare to solutes
•It will tend to interfere with the medullary interstitiumhyperosmolarity
•Still its preservedhow??
•By taking away all water by vasa recta the venous blood
Urea Recycling
•Urea reabsorption is maintained by
–GFR
–Plasma urea concentration
•Traps urea in medullary interstitium
•Leads to hyperosmolarity (40-50 % role)
•Urea reabsorption
•From inner medullary duct
•Dependent on ADH
•Activates urea transporters (UT-AI)
•Facilitates urea reabsorption by concentrating it
•Urea secretion (50 %)
•Into thin limbs of loop of Henle
•100 % urea present in thick limb
•50 % coming from proximal convoluted tubule
•50 % secreted in thin limbs
CONCENTRATION OF URINE
VASA RECTA
•U’ shaped peritubularcapillaries
•Blood provision to renal medulla by VASA RECTA
•Medullary blood flow is only 5% of renal blood flow
•Sluggish to meet the needs
•Minimizes the washing out of solutes
•Prevent the medullary interstitiumhyperosmolarity to get dissipated
Hormones
Atrial Natriuretic peptide
•Increases blood flow through vasa recta, wash the solutes (NaCland urea)
•Lower osmolarityof the medullary interstitiumleads to less reabsorption of tubular fluid &increased excretion.
•Decreases sodium reabsorption in the distal convoluted tubuleand cortical collecting ductsvia guanosine3′,5′-cyclic monophosphate (cGMP) dependent phosphorylation of ENaCC
Aldosterone
•Acting on the nuclear mineralocorticoid receptors(MR) within the principal cells of the distal tubuleand the collecting ducts of nephron
•Up regulates and activates thebasolateralNa/K pump, which pumps three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid
•Creates a concentration gradient which results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into lumen of collecting duct
•Aldosterone upregulatesepithelial sodium channels (ENaC), increasing apical membrane permeability for Na+
Osmolar Clearance
Free water clearance
•Loss or gain of pure water that is not accompanied by comparable loss or gain of solute is called free water
•A function of distal tubular segments
•Depends upon ADH
•Water diuresis & water gain by ADH (formation of dilute & concentrated urine)
Important for correction of osmotic imbalances
•Rate at which free water (salt free) is excreted by kidneys
CH2O = V – Cosm
•Quantifies ability of kidney to dilute or concentrate the urine
•When positive (V >Cosm)
–Water in excess of solutes (free water) being excreted -hypotonic urine
•When negative (V <Cosm)
–Solutes in excess of water being excreted & free water being reabsorbed -hypertonic urine
•When zero (V =Cosm)
–No free water excretion or reabsorption -Isotonic urine
Clinical Physiology
Diabetes insipidus
•Central -failure to produce ADH
•Decreased production
•Nephrogenic-inability of kidneys to respond to ADH
•Even in the presence kidney still produces dilute urine
•Either V2 receptor are not functional
•Countercurrent mechanism is not working
•Desmopressin test
Mechanism of action of ADH
SUMMARY
•Dilute urine is formed when ADH is low and water reabsorption is stopped beyond descending limb
•Conc. urine is formed when ADH is high and water is continuously reabsorbed from segments beyond late distal tubule
•Urine osmolarity is determined by osmolarity of renal medullary interstitium
•Hyperosmolarity in renal medullary interstitium
–Created by counter current multiplier and urea recycling
–Maintained by vasa recta