The Nephron — Functional Unit of the Kidney

Diagrams

Generated Diagram:

From Harrison's Principles of Internal Medicine:

Definition

1. Renal corpuscle (Malpighian corpuscle) — glomerulus + Bowman's capsule
2. Renal tubule — proximal tubule → loop of Henle → distal tubule → connecting segment

The collecting duct is functionally inseparable but technically not part of the nephron, as it derives embryologically from the ureteric bud rather than the metanephric blastema. — Brenner and Rector's The Kidney

Components and Functions

1. Renal Corpuscle

2. Proximal Convoluted Tubule (PCT)

• Location: Renal cortex
• Function: Reabsorbs >60% of the filtrate — the "workhorse" of the kidney
• Key transporters: Na⁺/H⁺ exchanger (NHE3), Na⁺/glucose cotransporters, amino acid transporters, aquaporin-1
• Water follows isosmotically (AQP1); bicarbonate is reclaimed; NH₄⁺ is secreted
• Luminal brush border (microvilli) increases surface area ~40-fold

3. Loop of Henle

• Location: Descends from cortex into medulla, then returns
• Segments:
  • Thin descending limb — permeable to water; concentrates filtrate
  • Thin ascending limb — impermeable to water; permeable to solutes
  • Thick ascending limb (TAL) — impermeable to water; active transport via NKCC2 (Na⁺-K⁺-2Cl⁻ cotransporter)
• Function: Creates the medullary concentration gradient via countercurrent multiplication — the concentrating segment
• ROMK channel recycles K⁺ into the lumen; NH₄⁺ can substitute for K⁺ on NKCC2
• The medullary interstitium is the only compartment in the body with higher osmolality than serum

4. Distal Convoluted Tubule (DCT)

• Location: Renal cortex (~10–12 mm long, shortest nephron segment)
• Key transporter: NCC (Na⁺-Cl⁻ cotransporter, target of thiazide diuretics)
• Impermeable to water → removes solute without water → diluting segment
• Contains TRPV5 (Ca²⁺ channel on luminal membrane) for calcium reabsorption regulated by PTH

5. Collecting Duct

• Two cell populations:
  • Principal cells: Vasopressin-stimulated AQP2 insertion → water reabsorption; aldosterone-stimulated ENaC → Na⁺ reabsorption + K⁺ secretion via ROMK
  • α-Intercalated cells: H⁺-ATPase on luminal side → H⁺ secretion (acid-base regulation)
  • β-Intercalated cells: H⁺-ATPase on basolateral side + pendrin (Cl⁻/HCO₃⁻ exchanger) → HCO₃⁻ secretion in alkalosis
• Sets final urine composition

6. Vasa Recta

• Straight capillaries running parallel to the loop of Henle
• Preserve the medullary osmotic gradient via countercurrent exchange
• Supply O₂ and nutrients to the medulla

Summary Table

Countercurrent Mechanism

1. Countercurrent Multiplier — Loop of Henle
2. Countercurrent Exchanger — Vasa Recta

What Is a Countercurrent System?

Part 1: Countercurrent Multiplier (Loop of Henle)

Key Structural Prerequisites

• ~25% of nephrons are juxtamedullary nephrons with long loops that dip deep into the medulla (some reaching the papillary tips)
• Thin descending limb (TDL): highly permeable to water (AQP1); relatively impermeable to solutes
• Thick ascending limb (TAL): actively pumps NaCl out via NKCC2; impermeable to water
• Filtrate flows in opposite directions in the two limbs

Step-by-Step Operation (Hypothetical Steps — Ganong's):

"The pump in the TAL is capable of establishing about a 200 mOsm/L concentration gradient between the tubular lumen and interstitial fluid. Because the TAL is impermeable to water, solutes pumped out are not followed by osmotic flow of water — solutes accumulate in excess of water." — Guyton & Hall Medical Physiology

Role of Juxtamedullary Nephrons

• Long loops of Henle spread the gradient over a greater distance → higher osmolality at the tip
• The thin ascending limb (present only in juxtamedullary nephrons) is impermeable to water but permeable to NaCl → passive countercurrent multiplication adds to the gradient in the inner medulla

Part 2: Role of Urea

• Urea is not reabsorbed in the proximal tubule, loop of Henle, or early collecting duct
• As ADH drives water reabsorption in the cortical collecting duct, urea concentrates in the lumen
• In the inner medullary collecting duct, vasopressin activates UT-A1 and UT-A3 urea transporters → urea diffuses into the medullary interstitium
• Some urea re-enters the loop of Henle via UT-A2 in the thin descending limb → urea recycling
• This urea recycling amplifies the medullary gradient without requiring additional energy

A high-protein diet increases urea production → greater medullary urea → better concentrating ability. A low-protein diet reduces it. — Ganong's

Part 3: Countercurrent Exchanger (Vasa Recta)

Part 4: ADH and Final Urine Concentration

Tubular Osmolality Journey (Summary)

Glomerular filtrate:     ~290 mOsm/L  (isosmotic with plasma)
End of PCT:              ~290 mOsm/L  (isosmotic reabsorption)
Bottom of loop (TDL):   ~1200 mOsm/L (water exits → concentrated)
End of TAL:              ~100–150 mOsm/L (NaCl pumped out → dilute)
End of DCT:              ~50–100 mOsm/L (diluting segment)
Final urine (with ADH): up to 1200 mOsm/L
Final urine (no ADH):   ~50–100 mOsm/L

Key Transporters Summary

Countercurrent Mechanism for Urine Acidification

Important clarification: The term "countercurrent mechanism for urine acidification" refers specifically to NH₃/NH₄⁺ countercurrent cycling — the medullary ammonia gradient that enables the kidney to excrete large amounts of acid as ammonium (NH₄⁺) in the final urine. This is distinct from the urine concentration countercurrent mechanism, but uses the same anatomical architecture.

Overview Diagram

The Three Pillars of Renal Acid Excretion

Part 1: Proximal Tubule — Bicarbonate Reclamation & NH₄⁺ Generation

HCO₃⁻ Reabsorption

Lumen:    H⁺ + HCO₃⁻  →  H₂CO₃  →  H₂O + CO₂  (luminal CA IV)
Cell:     CO₂ + H₂O   →  H₂CO₃  →  H⁺ + HCO₃⁻  (cytosolic CA II)
          H⁺ secreted via NHE3 (Na⁺/H⁺ exchanger) into lumen
          HCO₃⁻ exits basolaterally via NBC1 (Na⁺/3HCO₃⁻ cotransporter)

Ammoniagenesis from Glutamine

Glutamine  →  2NH₄⁺  +  2HCO₃⁻
             (in PCT mitochondria)
NH₄⁺ secreted into lumen via NHE3 (substituting for H⁺)
HCO₃⁻ returns to blood → "new bicarbonate" is generated

• This is the most important source of net acid excretion
• Stimulated by acidosis, hypokalaemia, and cortisol

Part 2: The NH₃/NH₄⁺ Countercurrent Cycling — The True "Countercurrent" for Acidification

Step-by-Step Cycling:

CORTEX
  PCT: Glutamine → NH₄⁺ secreted into lumen via NHE3
         ↓ (filtrate flows down)
OUTER MEDULLA
  Thick Ascending Limb (TAL):
     NH₄⁺ reabsorbed via NKCC2 (NH₄⁺ substitutes for K⁺)
     → NH₄⁺ enters medullary interstitium
     → dissociates: NH₄⁺ ⇌ NH₃ + H⁺
     → NH₃ accumulates in medullary interstitium
         ↓
INNER MEDULLA
  NH₃ diffuses from interstitium into collecting duct lumen
  In the acidic lumen: NH₃ + H⁺ → NH₄⁺  (TRAPPED — cannot back-diffuse)
  NH₄⁺ excreted in urine

Why "Countercurrent"?

• NH₄⁺ flows down in the tubular lumen (descending)
• TAL reabsorbs it and deposits it in the interstitium
• This creates an increasing NH₃ gradient from cortex → papilla (just like NaCl in urine concentration)
• The collecting duct descends through this NH₃-rich interstitium, "picking up" NH₃ which becomes trapped as NH₄⁺ by the H⁺ secreted by intercalated cells

"NH₄⁺ can substitute for K⁺ on the NKCC2 in the TAL. NH₄⁺ is absorbed by NKCC2 in the K⁺ position. Once in the cell, NH₄⁺ dissociates to NH₃ because of the higher intracellular pH. NH₃ diffuses into the interstitium through the Rhesus glycoprotein channel (RhCG)." — National Kidney Foundation Primer on Kidney Diseases, 8th ed.

Part 3: Collecting Duct — Final Urine Acidification

α-Intercalated Cells (Type A)

In the α-intercalated cell:
  CO₂ + H₂O  →[CA II]→  H₂CO₃  →  H⁺ + HCO₃⁻
  H⁺  →  secreted into lumen (H⁺-ATPase / H⁺K⁺ATPase)
  HCO₃⁻  →  exits to blood via AE1

β-Intercalated Cells (Type B)

• Mirror image of α cells
• H⁺-ATPase on the basolateral side
• Pendrin (SLC26A4) on apical side secretes HCO₃⁻ into lumen
• Active during alkalosis to excrete excess base

Harrison's diagram of B-IC and PC cells:

Part 4: Titratable Acid — Phosphate Buffering

H⁺  +  HPO₄²⁻  →  H₂PO₄⁻   (titratable acid, pKa 6.8)
H⁺  +  NH₃     →  NH₄⁺      (ammonia buffering, pKa 9.0)

• NH₃ is the dominant buffer because its pKa (9.0) is far above urine pH → nearly complete trapping
• Phosphate contributes ~30–40 mEq/day; NH₄⁺ contributes ~40–60 mEq/day

Integrated Summary: The Full Countercurrent Picture

CORTEX (pH ~7.4)
┌─────────────────────────────────────────────────────┐
│ PCT: Glutamine → NH₄⁺ (lumen) + HCO₃⁻ (blood)      │
│      NHE3: H⁺ secreted → HCO₃⁻ reclaimed            │
└──────────────────┬──────────────────────────────────┘
                   ↓ filtrate descends
OUTER MEDULLA
┌─────────────────────────────────────────────────────┐
│ TAL: NKCC2 absorbs NH₄⁺ from lumen                  │
│      → NH₃ builds up in interstitium                │
│      → Interstitial [NH₃] increases toward papilla  │
└──────────────────┬──────────────────────────────────┘
                   ↓
INNER MEDULLA (highest [NH₃])
┌─────────────────────────────────────────────────────┐
│ Collecting duct descends through NH₃-rich milieu    │
│ α-IC cells: H⁺-ATPase → H⁺ into lumen (pH → 4.5)  │
│ NH₃ (interstitium) → lumen + H⁺ → NH₄⁺ (TRAPPED)  │
│ AE1: HCO₃⁻ → blood ("new bicarbonate")             │
└─────────────────────────────────────────────────────┘
                   ↓
         URINE: NH₄⁺ + H₂PO₄⁻ + pH 4.5–6.0

Clinical Relevance: Renal Tubular Acidosis (RTA)