Kidney Function and GFR Factors

Kidney Function

• The kidneys receive about 1/4 of the cardiac output
• Approximately 1.5 liters of urine are excreted every day
• The kidneys perform glomerular filtration, tubular reabsorption, and tubular secretion.
• The glomerular filtrate is identical in composition with plasma, but without proteins.

Factors Affecting Glomerular Filtration Rate (GFR)

• Increased intra-glomerular hydrostatic pressure increases GFR.
  • This can be caused by:
    • Dilation of the afferent arteriole
    • Increased arterial blood pressure
    • Constriction of the efferent arteriole
• Increased intra-glomerular osmotic pressure decreases GFR.
  • Caused by increased plasma protein concentration.
• Increased intra-capsular hydrostatic pressure decreases GFR.
  • This may be caused by:
    • Tubular obstruction
    • Renal edema

Tubular Reabsorption & Secretion

• The efferent arteriole subdivides to form peritubular capillaries, where reabsorption and secretion take place.
• The luminal surface of the tubular cell is the apical membrane.
• The basolateral membrane is on the other side of the tubular cell.
• The apex of each tubule cell is surrounded by a tight junction.

Movement Pathway of Ions & Water

• Trancellular pathway: Across the tubular cells.
• Paracellular pathway: Across the tight junctions between cells.

Sodium Reabsorption

• Approximately 67% of sodium is reabsorbed in the proximal convoluted tubule (PCT).
• Sodium is reabsorbed in exchange for hydrogen ions via the Na+/H+ antiporter.
• Intracellular carbonic anhydrase is essential for producing H+ for secretion into the lumen.
• Sodium is transported into blood via the Na+/K+ ATPase in the basolateral membrane.
• The transport of sodium via the Na+/H+ antiport is driven by the Na+/K+ ATPase.

Bicarbonate Reabsorption

• Bicarbonate is normally completely reabsorbed in the PCT.
• Bicarbonate combines with H+ to form H2CO3, which is catalyzed by brush border carbonic anhydrase.
• H2CO3 dissociates to form CO2 and water.
• CO2 is passively reabsorbed in the lumen.

Water Reabsorption

• Water is passively reabsorbed through the paracellular pathway.
• Water reabsorption is secondary to sodium reabsorption.
• Sodium secreted by Na+/K+ ATPase into the lateral intercellular space slightly raises the osmolality, driving water reabsorption by convection.

Chloride Reabsorption

• Chloride is transported into blood by passive reabsorption through the paracellular pathway down its concentration gradient.
• It is also reabsorbed in exchange for anions, such as formate and oxalate.

Nephron Segments: Proximal Convoluted Tubule (PCT)

• Fluid leaving the PCT remains isosmotic to the filtrate that enters Bowman's capsule.

Nephron Segments: Descending Limb

• The interstitial fluid of the medulla is hypertonic.
• The filtrate becomes more concentrated (hyperosmotic) as it passes down the descending limb.

Nephron Segments: Ascending Limb

• Approximately 20% of filtered sodium is reabsorbed in the ascending limb.
• Ions (Na+, K+, Cl-) move into the cell across the apical membrane via a Na+/K+/2Cl- symporter.
• Sodium is transported into blood via Na+/K+ ATPase.
• Chloride is transported into blood by diffusion through Cl- channels and by the K+/Cl- symporter.
• Most of the potassium taken by the Na+/K+/2Cl- symporter returns to the lumen through apical K+ channels.

Nephron Segments: Thick Ascending Limb

• The thick ascending limb is relatively impermeable to water.
• Reabsorption of salt is not accompanied by water reabsorption.
• This makes the filtrate more diluted (hyposmotic) as it passes upward.
• The thick ascending limb is known as the diluting segment.
• The process of concentration and then dilution of filtrate in the loop of Henle is known as the "counter-current multiplier theory".

Nephron Segments: Distal Convoluted Tubule (DCT)

• Approximately 7% of filtered sodium is reabsorbed.
• NaCl is reabsorbed without water, further diluting the filtrate.
• NaCl is reabsorbed via the Na+/Cl- symporter.
• This transport is driven by the Na+/K+ ATPase.

Calcium Reabsorption

• Calcium is transported through channels in the apical membrane and then transported into blood via the Na+/Ca2+ antiporter.
• Parathyroid hormone (PTH) and calcitriol increase calcium reabsorption.
• Calcium is also reabsorbed via the paracellular pathway in the ascending limb of the loop of Henle.

Hydrogen Ion Secretion

• When all filtered bicarbonate has been reabsorbed in the PCT, the Na+/H+ exchange in the apical membrane continues in the DCT.
• Hydrogen ions are added to Na2HPO4 to give NaH2PO4 and to NH3 to give NH4+.
• Intracellular carbonic anhydrase is essential for producing H+ for secretion into the lumen.

Nephron Segments: Collecting Tubules

• Approximately 5% of filtered sodium is reabsorbed.
• Most of K+ and H+ are secreted.
• The collecting tubule has two types of cells:
  • Principal cells: Where sodium reabsorption and potassium secretion occur.
  • Intercalated cells: Where hydrogen secretion takes place.
• The collecting tubule is under hormonal control:
  • Aldosterone: Controls sodium reabsorption and potassium secretion.
  • Antidiuretic hormone (ADH; vasopressin): Controls water absorption according to the body's water needs.

Aldosterone

• Aldosterone enhances sodium reabsorption and potassium excretion by:
  • Stimulating Na+/H+ exchange by acting on membrane aldosterone receptors (rapid effect).
  • Activating sodium channels in the apical membrane by directing the synthesis of a protein mediator (delayed effect).
  • Increasing the number of basolateral Na+/K+ ATPase.

Antidiuretic Hormone (ADH)

• ADH is secreted by the posterior pituitary.
  • Increased blood osmolality stimulates osmoreceptors in the hypothalamus, which stimulates ADH secretion.
  • Increased blood volume or blood pressure stimulates baroreceptors, which inhibits ADH secretion.
• ADH binds to V2 receptors in the basolateral membranes, increasing water channels in the apical membranes.
• This renders the collecting duct permeable to water, allowing passive reabsorption of water as the collecting duct passes through the medulla.
• The filtrate is concentrated, and the body excretes concentrated urine.

Diabetes Insipidus

• Neurogenic diabetes insipidus: May be caused by a deficiency of ADH secretion.
• Nephrogenic diabetes insipidus: May be caused by insensitivity of the kidney to ADH due to:
  • Congenital mutations in the V2 receptor or water channels.
  • Acquired causes, such as certain drugs.
• In these cases, the collecting duct cells are impermeable to water, leading to excretion of dilute urine, polyuria, nocturia, and polydipsia.
• Daily urine output may reach 10-15 liters.

Other ADH Actions

• At high concentrations, ADH acts on the V1 receptor subtype in smooth musculature, including blood vessels, causing vasoconstriction, increasing blood pressure.
• ADH derivatives: Lypressin, Desmopressin, Felypressin, ornipressin (used for various medical conditions).

Organic Acid & Base Secretion

• Organic molecules enter the renal tubules by glomerular filtration or active secretion.
• Organic anions are exchanged with α-ketoglutarate by an antiport in the basolateral membrane called organic anion transporters (OATs).
• Organic cations diffuse into the cell from blood and are actively transported into the tubular lumen in exchange for H+.
• These systems are powered by the energy derived from Na+/K+ ATPase in the basolateral membrane.

Ammonia Secretion

• Ammonia is formed in the DCT by deamination of glutamine by glutaminase.
• Ammonia diffuses into the lumen and combines with H+, forming NH4+.
• This prevents undue accumulation of H+ in the filtrate and permits continued exchange of H+ for Na+.