The nephron

Tip

• Iso-osmotic reabsorption: The proximal tubule reabsorbs sodium and water in equal proportions. This means that while a large amount of sodium is reabsorbed, the concentration in the tubular fluid remains relatively constant.
• Active and passive transport: Sodium reabsorption is driven by active transport mechanisms, primarily the Na+/K+ ATPase pump. This creates an electrochemical gradient that drives the reabsorption of other solutes, including water. Potassium is reabsorbed both passively and actively.
• Regulation: Hormonal mechanisms, such as aldosterone, can fine-tune sodium reabsorption in later parts of the nephron (distal tubule and collecting duct), but in the proximal tubule, the focus is on bulk reabsorption.

Proximal convoluted tubule (PCT)

1. Bicarbonate
   1. Don’t change H⁺, only absorb HCO₃^-
   2. Absorb Na⁺ to absorb H₂O. 65% of sodium and water are absorbed in PCT.
   3. Angiotensin II increases Na⁺, HCO₃^-, and H₂O reabsorption via Na⁺/H⁺ exchanger stimulation (allows for contraction alkalosis).
2. Parathormone (PTH) decreases PO₄^3- reabsorption via Na⁺-PO₄^3- cotransporter inhibition.
3. Brush border resorption of most of the ultrafiltrate
   • Glucose (via SGLT2)
   • Amino acids
   • Uric acid
   • Na⁺, Cl^-, K⁺, HCO₃^-, PO₄^3-, and H₂O (All together with Na⁺ !!!)

Thick ascending loop of Henle

1. ADH stimulates the activity of Na⁺-K⁺-2Cl^- cotransporter. Increased NKCC2 activity aids in water reabsorption in the collecting duct through aquaporin 2 channels by creating a hypo-osmotic filtrate.

Distal convoluted tubule (DCT)

1. Magnesium and Calcium are reabsorbed paracellularly.
2. Ca²⁺ is reabsorbed using Ca²⁺ channels on the luminal surface and Na⁺/Ca²⁺ antiporters (exchangers) on the basolateral surface.
   1. PTH up-regulates the Ca²⁺/Na⁺ antiporter resulting in increased reabsorption of Ca²⁺.

Collecting duct

1. Principal cells 2. When acted upon by ADH, principal cells will increase the number of aquaporins (water channels) on the luminal membrane → increased H₂O reabsorption. 3. When acted upon by aldosterone, principal cells increase activity of Na⁺/K⁺ exchangers → increased Na⁺ reabsorption and increased K⁺ secretion. - Water follows sodium through the water channels. So aldosterone won’t affect the urine osmolality.
2. Alpha-intercalated cells
   1. Have a K⁺/H⁺ exchanger on the luminal surface to secrete H⁺ and reabsorb K⁺
   2. Have a H⁺-ATPase which actively secretes H⁺. On the basolateral surface, the cells have a HCO3 -/Cl^- exchanger to reabsorb HCO3 -.
   3. Aldosterone upregulates H⁺ secretion via H⁺-ATPase. Increased H⁺ secretion will lead to increased HCO₃^- reabsorption.
3. ADH also stimulates reabsorption of urea in collecting ducts to maximize corticopapillary osmotic gradient. So increased BUN-creatinine ratio in hypovolemia.
   • Urea passively diffuses from the interstitium into the loop of Henle, increasing the luminal concentration of urea.

Renal blood flow

Tubuloglomerular feedback

• Description: feedback system between the tubules and glomeruli that adjusts the GFR according to the resorption capacity of the tubules
• Mechanism: macula densa (of the juxtaglomerular apparatus) senses alterations in the NaCl concentration in the DCT
  • Hypotonic urine (↓ intraluminal Cl^- concentration) → vasodilation of afferent arterioles → ↑ GFR → ↑ Cl^- intraluminal concentration → ↑ RBF
  • Hypertonic urine (↑ intraluminal Cl^- concentration) → adenosine secretion → vasoconstriction of afferent arterioles → ↓ capillary pressure → ↓ GFR → ↓ intraluminal Cl^- concentration → ↓ RBF

Juxtaglomerular complex

• Juxtaglomerular cells
  • Modified smooth muscle cells located in the afferent arterioles
  • Function: renin synthesis
• Macula densa
  • Composed of tall cuboidal cells located at the distal end of the thick ascending loop of Henle
  • Monitors the NaCl concentration within the lumen of the DCT
    • Hypoosmolar urine triggers the release of renin → vasoconstriction of the efferent arteriole → increase in GFR
    • Hyperosmolar urine triggers the release of adenosine → vasoconstriction of the afferent arteriole → decrease in GFR
• Extraglomerular mesangial cells
  • Play a role in autoregulation of blood flow to the kidney (exact functioning is not entirely understood)
  • Form a network of cells, connecting the sensory cells of the macula densa with juxtaglomerular effector cells
  • May also signal to contractile glomerular mesangial cells and, thereby, directly affect vasoconstriction

Measurement of renal function

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Filtration fraction

• Description: the fraction of the renal plasma flow (RPF) that is filtered from the capillaries into the Bowman space
• Mechanism
  • FF = GFR/RPF (i.e., FF = C_Inulin/C_PAH)
    • GFR can be calculated using the inulin or creatinine clearance, as these substances are freely filtered at the glomerulus and have relatively insignificant tubular reabsorption or secretion. RPF can be determined using the para-aminohippuric acid (PAH) clearance as almost all the PAH entering the kidneys is excreted in the urine (mostly via tubular secretion).
    • C_Inulin = inulin clearance
    • C_PAH = PAH clearance
  • Normal: 20%
  • Regulated via:
    • Prostaglandins → dilation of afferent arterioles → ↑ GFR and ↑ RPF (FF unchanged)
    • Angiotensin II → constriction of efferent arterioles → ↑ GFR and ↓ RPF → ↑ FF