This document summarizes the structure and physiology of the nephron, the functional unit of the kidney. It describes the key components of the nephron including the glomerulus, Bowman's capsule, proximal tubule, loop of Henle, distal tubule and collecting duct. It explains glomerular filtration rate and the factors that influence it, including hydrostatic and oncotic pressures. It then discusses the reabsorption of water and solutes like sodium and potassium at different segments of the nephron. Specifically, it outlines the countercurrent mechanism in the loop of Henle that helps concentrate urine.

1. RENAL PHYSIOLOGY
MODERATOR-DR.ROOHI SUMMAYYA
SPEAKER – DR.GANGA BHAVANI

2. STRUCTURE OF A NEPHRON
• The renal corpuscle: glomerulus and Bowman's capsule
• The juxtaglomerular apparatus, containing the macula densa
• The proximal tubule (convoluted and straight segments)
• The distal tubule (Loop of Henle: descending thin limb, ascending thin limb
and ascending thick limb), and distal convoluted tubule
• The collecting duct system

4. Structure of glomerulus
• Vascular elements
• Afferent arterioles, which arise from cortical radial arteries
• Glomerular capillaries, which are fenestrated to permit filtration
• Efferent arterioles, which drain the glomerulus and descend into the renal
medulla
• Filtration surface
• Capillary endothelial cells with wide (60-80 nm) fenestrations
• Basement membrane
• Podocytes, which extend interdigitating processes over the filtration surface
• Structural elements
• Mesangial cells, which support the capillary tuft
• Bowman's capsule, which collects the ultrafiltrate

6. Glomerular filtration surface
• Endothelial pores (size barrier, excludes cells)
• Endothelial glycocalyx (size barrier, excludes large macromolecules)
• Glomerular basement membrane (size barrier, excludes large
macromolecules)
• Podocyte filtration slit diaphragm (size barrier, probably the most important)
• GBM determines the permeation of macromolecules through the filter in
a size-dependent manner through diffusion, whereas water and ions would
pass through the filter by flow generated from hydraulic pressure

7. GFR
• Glomerular filtration rate (GFR) is the sum of the ultrafiltrate produced by all
nephrons
• This is about 20% of renal blood flow, which itself is 20% of cardiac output
• This proportion of filtered blood volume is the filtration fraction (20%)
• Therefore normal GFR = about 90-120 ml/min/1.73m2

8. • Glomerular ultrafiltration is influenced by the Starling equation:
• GFR = Kf [ (Pgc - PBC) - σ(Πgc - Πi) ]
where
GFR is the glomerular filtration rate,
Kf is the filtration coefficient of the glomerular filtration surface,
which is itself a product of:
k, the hydrostatic permeability constant of the membrane, and
S, the surface area of the glomerular filtration surface, which can be affected by the contraction of glomerular
mesangial cells
Pgc is the glomerular capillary hydrostatic pressure
PBC is the hydrostatic pressure of fluid in Bowman's capsule
σ is the reflection coefficient for blood protein
Πgc is the oncotic pressure in the glomerular capillary blood,
ΠBC is the oncotic pressure of the fluid in Bowman's capsule (usually zero)

9. • Glomerular filtration of solutes is affected by:
• Molecule size: glomerular size barrier resists the passage of large molecules
(>7000 Da)
• Molecule charge:​ anionic charge of the glomerular filtration surface may resist
the passage of anioninc molecules​​​​​​

10. Physiology
A hydrostatic pressure gradient of approximately 10mmHg (a capillary pressure of
45mmHg minus 10mmHg of pressure within Bowman’s space and 25mmHg of
plasma oncotic pressure) propsevides the driving force for ultrafiltration.

11. • Sieving coefficient is the ratio of a molecule's concentration in the filtrate to
that in plasma
• Filtration fraction is the ratio of of the glomerular filtration rate to renal plasma
flow

12. Proximal convoluted tubule
• The proximal convoluted tubule is the main site of solute and water
absorption.
• 60-70% of glomerular ultrafiltrate is reabsorbed here
• Sodium gradient drives most of the reabsorption
• Basolateral Na+/K+ ATPase activity maintains this gradient
• Sodium co-transporters mediate:
• Glucose reabsorption
• Organic anion reabsorption
• H+ excretion, and therefore bicarbonate reabsorption
• Phosphate reabsorption
• Ammonia elimination
• Water diffuses passively along with sodium
• Thus, proximal tubule fluid remains isosomolar with glomerular filtrate

14. • The proximal straight tubule is the main site of active organic ion excretion
• Mediated by the organic anion transport (OAT) protein family
• Responsible for clearance of numerous physiologically and pharmacologically important solutes,
such as:
• Urate
• Creatinine
• Frusemide
• Metformin
• Beta-lactam antibiotics
• Drug targets in the proximal tubule include:
• Carbonic anhydrase (blocked by acetazolamide - with resulting diuresis and metabolic
acidosis)
• OAT-1 (inihibited by probenecid - thus, decreased excretion of organic anions, including beta-
lactam antibiotics)

15. LOOP OF HENLE
• The loop of Henle consists of:
• The straight part of the proximal tubule
• The thin descending and thin ascending limbs, where water and ions are passively reabsorbed
• The thick ascending limb, where ions are actively reabsorbed
• 20% of total water reabsorption and 25% of the total electrolyte reabsorption in the nephron happens here.
• The thin limbs of the loop of Henle are about 10mm long
• Some descend deep into the inner medulla
• Responsible for the countercurrent exchange mechanism
• Thin descending limb:
• Extremely high water permeability
• Poor ion permeability
• Reabsorbs much of the filtered water (osmotic mechanism)
• Produces concentrated tubular fluid (~1200-1400 mOsm/kg)
• Thin ascending limb:
• Extremely high ion permeability
• Poor water permeability
• Reabsorbs electrolytes and urea (passive diffusion)
• Produces highly dilute tubular fluid ( ~100 mOsm/kg)

16. THICK ASCENDING LIMB
• Minimal water permeability
• Active transport:
• 20-30% of sodium transport, by NKCC2, an
electroneutral Na+ K+ and Cl-
cotransporter (the target of loop diuretics)
• Ammonium (NH4
+) transport, also by NKCC2
(as it resembles K+), which may account for
some of the metabolic alkalosis due to loop
diuretics
• 15% of bicarbonate reabsorption, meidated
by NHE-3 and carbonic anhydrase, just as it
is in the proximal tubule
• Passive transport
• The electrochemical gradient created by the
reabsorption of chloride and the non-
reabsorption of potassium (as it gets
recycled) creates a positive charge in the
lumen of the tubule, which drives the
paracellular reabsorption of magnesium and
calcium

18. Distal convoluted tubule
• Defined by the expression of
the NCC, the thiazide-
sensitive sodium and chloride
co-transporter
• Reabsorption of sodium is
driven by basolateral
Na+/K+ ATPase
• Secretes potassium to
electrically balance
reabsorption of sodium (this is
the source of frusemide-
induced hypokalemia)

19. • Collecting duct
• Characterised by aldosterone and
vasopressin sensitivity
• Aldosterone increases the expression of
ENaC channels
• This increases the absorption of
sodium
• Absorption of sodium results in
increased potassium secretion
• This is the drug target of spironolactone
and amiloride
• Vasopressin increases the expression of
aquaporins and UT1-3 channels
• Aquaporins facilitate the reabsorption
of filtered water
• UT transporters facilitate the
reabsorption of urea for intrarenal urea
recycling, which is necessary for the
maintenance of the countercurrent
multiplier mechanism

20. • Intercalated cells
• Involved in acid-base balance
• Secrete ammonia and hydrogen ions,
which combine to form ammonium in
the tubule
• Secrete chloride to electrically balance
the cationic ammonium
• A breakdown of these functions leads
to a Type 1 renal tubular acidosis

23. RENAL ABSORPTION OF WATER

24. RENAL HANDLING OF SODIUM
• Sodium is freely filtered in the glomerulus.
• 65% is then reabsorbed in the proximal tubule:
• The reabsorption is driven by a concentration gradient which is created by the action of basolateral Na+/K+ ATPase
• Most of the sodium is reabsorbed by the NHE3 sodium-hydrogen exchanger
• Other transport proteins include SGLT2, phosphate co-transporter Npt2a and multiple organic anion co-transporters
• None is reabsorbed in the thin descending limb:
• it is impermeable to sodium
• Some minimal amount is reabsorbed in the thin ascending limb
• it is permeable to ions, but not to water
• Some sodium is reabsorbed passively here
• 25% is reabsorbed in the thick ascending limb:
• Most of this is by the frusemide-sensitive NKCC2 co-transporter
• 5-10% is reabsorbed in the distal convoluted tubule:
• Most of this is by the thiazide-sensitive NCC co-transporter
• This step is load-sensitive, i.e. reabsorption increases whenever there is increased sodium delivery to this segment
• 2% is reabsorbed in the collecting duct:
• Most of this is passive, via the amiloride-sensitive ENaC channel

25. •Regulation of sodium reabsorption:
• Angiotensin II (increases reabsorption by increasing Na+/K+ ATPase activity in the proximal tubule,
and increases NHE3 activity)
• Aldosterone (increases ENaC activation in the collecting duct and Na+/K+ ATPase activity in the
thick ascending limb)
• Vasopressin (increases expression of ENaC in the collecting duct and NKCC2 in the thick
ascending limb)
• Catecholamines by increasing NKCC2 expression in the thick ascending limb

26. RENAL HANDLING OF POTASSIUM
• Potassium is freely filtered in the glomerulus
• 50-60% of potassium is reabsorbed in the proximal tubule:
• Several mechanisms are involved, but the most important is solute drag
• Potassium is carried across the epithelium by moving together with the reabsorbed water
• This is not under any specific regulatory control
• In the thin limbs of the loop of Henle, potassium undergoes countercurrent
exchange
• Potassium is added to the tubular fluid in the thin descending limb
• It then diffuses out again in the ascending limb
• The net effect of this is a conservation of potassium in the inner medulla
• 30% of filtered potassium is reabsorbed in the thick ascending limb
• This is due to the NKCC2 co-transporter, the drug target of frusemide
• Potassium is secreted into the tubular lumen in the distal convoluted tubule
and the collecting duct

28. COUNTER CURRENT MECHANISM
• A countercurrent system is a system in which the inflow runs parallel to,
counter to, and in close proximity to the outflow for some distance“
• The Single effect
• Countercurrent multiplication of the single effect
• Countercurent exchange in the vasa recta

29. • The "single effect":
• The thick ascending limb of
the loop of Henle extracts
solutes from the tubule
fluid
• This transfers the solutes to
the renal medulla
• The renal medulla then
becomes hyperosmolar
(1200 mOsm/kg)
• This facilitates the removal
of water from the thin
descending limb of the loop
of Henle
• Thus, fluid in the thin
descending limb also
becomes hyperosmolar

30. Countercurrent multiplication of the single effect
• The movement of hyperosmolar fluid up into the thick ascending limb continuously delivers more
solute
• Thus, more solute is transferred to the medullary interstitium
• The hyperosmolarity of the interstitium then extracts more water from the descending tubule
fluid, maintaining its hyperosmolarity
• The concentration gradient maintained in this way reduces the energy cost of extracting solutes
from the thick ascending limb.

33. • Countercurent exchange in the vasa
recta
• The vasa recta are permeable to water and
solutes
• Solutes diffuse into the descending vasa
recta, and then back out again as the blood
returns via the ascending vasa recta
• These vessels also have slower flow
because of increased crossection,
increasing the efficiency of solute
exchange
• This mechanism prevents the washout of
concentrated inner medullary solutes
• More water returns via the ascending vasa
recta, removing reclaimed water from the
renal medulla

34. OSMOLALITIES AT DIFFERENT POINTS
• Renal interstitial osmolality values:
• Cortex osmolality: 300 mOsm/kg
• Outer medulla: 800 mOsm/kg
• Inner medulla: 1200 mOsm/kg
• Loop of Henle osmolality values:
• Proximal tubule, straight part: 300 mOsm/kg
• Descending limb: 800 mOsm/kg
• Hairpin turn: 1200 mOsm/kg
• Ascending thin limb: 800 mOsm/kg
• Ascending thick limb: 100 mOsm/kg, at the end

38. REGULATION OF ACID BASE BALANCE
● Production and elimination of acid
● Reabsorption of filtered bicarbonate
● Excretion of ammonium is the most important mechanism of acid
excretion
● Excretion of titratable acid also contributes to eliminating acid

40. Production and elimination of acid
• Normal metabolism acidifies the body fluids
• Elimination of this acid load by the kidneys is accomplished by the acidification of
urine (i.e. secretion of acid) and the retention of filtered alkali (i.e of bicarbonate)
Reabsorption of filtered bicarbonate
• All filtered bicarbonate is reabsorbed by the nephron
• 80% of filtered bicarbonate is reabsorbed in the proximal tubule
• It is converted to lipid-soluble CO2 by apical carbonic anhydrase, allowing it to be reabsorbed into the
proximal tubule cells
• 20% more is reabsorbed in the thick ascending limb of the loop of Henle
• Regulation of bicarbonate reabsorption regulates responses to alkalosis and
respiratory acid-base disturbances, but cannot compensate for metabolic
acidosis, as the maximum effect is a maintenance of the status quo (when 100%
of bicarbonate is reabsorbed)

41. Excretion of ammonium is the most important mechanism of acid excretion
• Ammonia (NH3) is produced in the kidney from the metabolism of glutamine, which
also produces bicarbonate
• In the proximal tubule, NH3 binds H+ in the lumen and becomes ammonium (NH4
+)
• Ammonium is then concentrated in the inner medulla by reabsorption in the thick
ascending limb
• Concentrated ammonium is then secreted in the collecting duct
• This is quantitatively the most important mechanism of acid elimination
• Metabolism of glutamine can increase tenfold in response to metabolic acidosis

42. Excretion of titratable acid also contributes to eliminating acid
• Non-volatile acids produced in the course of metabolism are lactate, ketones,
phosphate, sulfate, citrate urate and hippurate.
• These are filtered freely in the proximal tubule
• A large fraction is then reabsorbed in the pars recta, as many of these are
essential metabolic substrates
• The remaining fraction allows urine pH to be buffered
• Phosphate is the most important of these buffers quantitatively
• pKa of phosphate is 6.8
• In the tubule it is present in two main forms, H2PO4
- and HPO4
2-
• With increased tubule acidity, HPO4
2- buffers H+ and produces H2PO4
-, which is poorly absorbed
• H2PO4
- is then eliminated, taking H+ with it.
• Other buffers include creatinine and citrate, which have a higher buffering
capacity at low urine pH (around 5.0)

45. THANK YOU