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Biochemistry of the Renal/Urinary System

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1. Glomerular Filtration

• Fenestrated capillary endothelium
• Glomerular basement membrane (type IV collagen, laminin, heparan sulfate)
• Podocytes with filtration slits

Net Filtration Pressure = (Pcap − Pbow) − (πcap − πbow)

• Normal GFR ≈ 125 mL/min (~180 L/day of ultrafiltrate)
• The filtrate is essentially plasma minus large proteins

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2. Proximal Convoluted Tubule (PCT) — Bulk Reabsorption

Key Transporters

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3. Loop of Henle — Concentration Gradient

Transport at each segment

NKCC2 in the TAL is the target of loop diuretics (furosemide).

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4. Distal Convoluted Tubule (DCT)

• NCC (Na⁺-Cl⁻ cotransporter) is the dominant transporter; target of thiazide diuretics
• Ca²⁺ reabsorption: active, regulated by PTH and vitamin D (via TRPV5 channels)
• Mg²⁺ reabsorption occurs primarily in the TAL and DCT
• Fine-tuning of K⁺ begins here under aldosterone influence

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5. Collecting Duct — Final Urine Composition

Vasopressin (ADH) Signaling — Water Reabsorption

1. ADH binds V2 receptor (basolateral) on principal cells
2. G-protein → adenylyl cyclase → ↑cAMP → PKA activation
3. PKA phosphorylates AQP2 vesicles → insertion into apical membrane
4. Water reabsorbs via AQP2 (apical), exits via AQP3/AQP4 (basolateral)
5. Absence of ADH → water-impermeable → dilute urine (diabetes insipidus if ADH absent)

Aldosterone — Na⁺ Reabsorption / K⁺ Secretion

• Binds mineralocorticoid receptor → ↑ transcription of ENaC and Na⁺/K⁺-ATPase
• Net: Na⁺ (and water) retained; K⁺ secreted via ROMK

H⁺ Secretion — Intercalated Cells

• α-intercalated cells: apical H⁺-ATPase and H⁺/K⁺-ATPase secrete H⁺ (urine acidification)
• β-intercalated cells: secrete HCO₃⁻ (alkaline states)

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6. Renal Acid-Base Regulation

Mechanisms of Acid Excretion

• Filtered HCO₃⁻ is not directly reabsorbed; instead:
  • H⁺ secreted via NHE3 combines with luminal HCO₃⁻ → H₂CO₃ → CO₂ + H₂O (catalyzed by carbonic anhydrase IV, luminal)
  • CO₂ diffuses into cell → reformed to H₂CO₃ by CA II → HCO₃⁻ exits basolaterally via NBC1

• Secreted H⁺ + HPO₄²⁻ → H₂PO₄⁻ (excreted)
• Phosphate is the major urinary buffer

• Glutamine is metabolized in PCT mitochondria → α-ketoglutarate + 2 NH₄⁺
• NH₃ diffuses into lumen; trapped as NH₄⁺ by secreted H⁺
• Hypokalemia → ↑ ammoniagenesis; Hyperkalemia/hypoaldosteronism → ↓ ammoniagenesis → Type IV RTA

Summary of Acid Secretion

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7. Renin-Angiotensin-Aldosterone System (RAAS)

↓ Renal perfusion pressure / ↓ NaCl at macula densa / ↑ Sympathetic tone
         ↓
   Juxtaglomerular (JG) cells → release RENIN
         ↓
   Angiotensinogen (liver) → Angiotensin I (10 aa)
         ↓  [ACE — lung, endothelium]
   Angiotensin II (8 aa)
         ↓
   ├── AT1 receptor → Vasoconstriction, Na⁺ retention, aldosterone release, ADH release
   └── AT2 receptor → Vasodilation, antiproliferative
         ↓
   Adrenal cortex (zona glomerulosa) → ALDOSTERONE
         ↓
   ENaC ↑, Na⁺/K⁺-ATPase ↑ → Na⁺ and water retained, K⁺ excreted

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8. Endocrine Functions of the Kidney

A. Erythropoietin (EPO)

• Produced by peritubular interstitial cells (inner cortex/outer medulla)
• Stimulated by hypoxia via HIF-1α/HIF-2α transcription factors
• Stimulates erythropoiesis in bone marrow
• CKD → fibrosis of interstitium → ↓ EPO → normochromic normocytic anemia

B. Vitamin D Activation

C. Prostaglandins and Kinins

• Renal medulla produces PGE₂ and PGI₂ → vasodilatory, natriuretic
• Kallikrein-kinin system in the kidney also modulates Na⁺ excretion and vasodilation
• NSAIDs block prostaglandin synthesis → ↓ GFR (especially in states of renal hypoperfusion)

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9. Potassium Homeostasis

• ~90% of filtered K⁺ reabsorbed by PCT (~65%) and TAL (~25%)
• Collecting duct principal cells are the main site of K⁺ secretion (regulated)
• Aldosterone → ↑ apical ROMK → ↑ K⁺ secretion
• Alkalosis → K⁺ shifts intracellularly → ↑ renal K⁺ secretion
• Hyperkalemia → depolarizes cells → directly stimulates aldosterone release

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10. Calcium and Phosphate Handling

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11. Urine Composition — Normal Biochemistry

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Key Integrative Points

• GFR is the central determinant of all renal biochemical functions
• The proximal tubule handles bulk reabsorption (Na⁺, glucose, amino acids, HCO₃⁻, phosphate)
• The loop of Henle builds the osmotic gradient; the collecting duct exploits it under ADH
• Aldosterone (via RAAS) and ADH are the two dominant hormonal axes for final urine composition
• The kidney is an endocrine organ: EPO, calcitriol, prostaglandins, renin
• Acid-base balance is maintained through HCO₃⁻ reclamation, titratable acid, and ammoniagenesis