Integrated nephron function

Glomerular Filtration - The Kidney's Sieve

• Function: Ultrafiltration of blood to produce a protein-free filtrate. Normal GFR ≈ 125 mL/min or 180 L/day.
• Filtration Barrier (Size & Charge Selectivity):
  • Fenestrated Capillary Endothelium: Blocks cells.
  • Glomerular Basement Membrane (GBM): Fused basal laminae with negative charge (heparan sulfate) repels albumin.
  • Podocyte Foot Processes: Slit diaphragms form the final barrier.
• Starling Forces: GFR is governed by hydrostatic and oncotic pressure gradients. $P_{GC}$ (Glomerular Capillary Hydrostatic Pressure) is the main driver.

⭐ Loss of the GBM's negative charge (e.g., Minimal Change Disease) causes selective albuminuria, even without major structural changes on light microscopy.

Proximal Tubule - The Bulk Reabsorber

• Workhorse of the nephron; reabsorbs ~65-80% of filtered solutes and water.
• Fluid leaving is isotonic to plasma (~300 mOsm/L).

Key Functions:

• Reabsorption: All glucose & amino acids; most $Na^+$, $Cl^-$, $K^+$, $H_2O$, and $HCO_3^-$.
  • $HCO_3^-$ reabsorption depends on carbonic anhydrase.
• Secretion: $H^+$, $NH_4^+$, organic acids (PAH, urate), and bases (creatinine).

⭐ High-Yield: Parathyroid hormone (PTH) inhibits the $Na^+/PO_4^{3-}$ cotransporter, causing phosphate excretion (phosphaturia). Carbonic anhydrase inhibitors (e.g., acetazolamide) act here, causing $HCO_3^-$ wasting.

Loop of Henle - Salty Medulla Maker

• Primary Function: Establishes a hypertonic medullary interstitium via countercurrent multiplication, crucial for concentrating urine.
• Descending Limb:
  • Highly permeable to H₂O, impermeable to NaCl.
  • H₂O passively flows out into the salty medulla.
  • Tubular fluid osmolarity ↑.
• Ascending Limb:
  • Impermeable to H₂O.
  • Thin Ascending: Passive NaCl reabsorption.
  • Thick Ascending Limb (TAL): Actively reabsorbs NaCl via the Na-K-2Cl (NKCC) cotransporter. This is the engine of the system.
  • Tubular fluid becomes dilute (hypotonic).
• Vasa Recta: Countercurrent exchange prevents washout of the medullary gradient.

⭐ The Thick Ascending Limb's Na-K-2Cl (NKCC) cotransporter is the target for loop diuretics (e.g., Furosemide). Inhibition leads to potent diuresis by disrupting the medullary gradient.

Distal Nephron - Hormonal Fine-Tuning

The final, precise regulation of urine composition, primarily influenced by aldosterone and ADH to manage electrolyte and water balance.

• Principal Cells: Major site of Na⁺/K⁺/H₂O regulation.

  • Aldosterone: Binds mineralocorticoid receptor → upregulates basolateral Na⁺/K⁺-ATPase and apical channels (ENaC, ROMK) → ↑Na⁺ reabsorption, ↑K⁺ secretion.
  • ADH (Vasopressin): Binds V2 receptor (Gs) → ↑cAMP → PKA activation → insertion of AQP2 channels into apical membrane → ↑H₂O reabsorption.

• Intercalated Cells: Manage acid-base balance.

  • α-cells: Secrete H⁺ via H⁺-ATPase.
  • β-cells: Secrete HCO₃⁻.

⭐ K⁺-Sparing Diuretics: Amiloride and triamterene directly block the ENaC channel. Spironolactone and eplerenone are competitive aldosterone antagonists, preventing its nuclear action. Both mechanisms reduce Na⁺ reabsorption and K⁺ secretion.

High‑Yield Points - ⚡ Biggest Takeaways

• Aldosterone (acting on the DCT/CD) and ADH (acting on the CD) are the principal regulators of volume and osmolarity.
• The PCT is the bulk reabsorber: nearly all glucose/amino acids and ~65% of Na+ and H₂O.
• The Loop of Henle generates the medullary gradient via countercurrent multiplication, essential for concentrating urine.
• The DCT fine-tunes electrolytes: Aldosterone reabsorbs Na+, while PTH reabsorbs Ca²⁺.
• The Collecting Duct controls final urine concentration via ADH-regulated aquaporins.