Chapter 6 Basic Renal Processes for Sodium, Chloride, and Water (ADH and Na+ Handling)

Overview

Chapter focus: Basic renal processes for handling sodium (Na+), chloride (Cl−), and water
Core idea: Distinct nephron segments reabsorb Na+, Cl−, and water in a coordinated manner to maintain extracellular fluid (ECF) volume, osmolarity, and electrolyte balance
ADH (vasopressin) discussion key point: ADH primarily modulates water handling, with indirect effects on Na+ handling along the nephron; its main action is in increasing water permeability in the collecting duct via aquaporin-2, not direct Na+ transport in the collecting duct
Collecting duct role: Final tuning of Na+ reabsorption (regulated mainly by aldosterone) and water reabsorption (regulated by ADH)
Purpose for exam: Understand segment-specific transporters, hormonal regulation, and the quantitative relationships that govern Na+ and water balance

Segments of the nephron: Na+, Cl−, and water handling

Proximal tubule (PT)
- Reabsorbs ~65–70% of filtered Na+ and water; reabsorption is isosmotic with the filtrate
- Key transporters/channels: Na+/H+ exchanger (NHE3) on the apical membrane; Na+/K+ ATPase on basolateral membrane; paracellular reabsorption of Na+ via tight junctions
- Bicarbonate reabsorption and Na+ reabsorption are tightly linked (Na+-coupled bicarbonate reabsorption)
- Regulatory influences: Angiotensin II stimulates NHE3, increasing Na+ reabsorption; sympathetic activity also enhances proximal Na+ reabsorption
- Water follows Na+ osmotically; no significant ADH-driven water permeability changes in PT (basically isosmotic reabsorption)
Loop of Henle
- Thick ascending limb (TAL) reabsorbs ~20–25% of filtered Na+ (and K+, Cl−) via the NKCC2 transporter (Na+/K+/2Cl− cotransporter)
- TAL is crucial for generating the medullary osmotic gradient via active NaCl reabsorption and lumen-positive potential, driving paracellular cation reabsorption (e.g., Ca2+, Mg2+)
- Regulation: Loop diuretics (e.g., furosemide) inhibit NKCC2, reducing NaCl reabsorption and medullary hypertonicity
- Water handling: TAL is impermeable to water; Na+ reabsorption here is not accompanied by water reabsorption, contributing to the dilute fluid reaching the distal nephron
Distal convoluted tubule (DCT)
- Early DCT reabsorbs ~5–8% of filtered Na+ via the Na-Cl cotransporter (NCC)
- Regulation: Thiazide diuretics inhibit NCC, promoting natriuresis and diuresis
- Water permeability: Limited in DCT; most water reabsorption occurs later in the collecting duct
Collecting duct
- Principal cells reabsorb Na+ via the epithelial Na+ channel (ENaC) and secrete K+ via renal outer/inner medullary K+ channels; Na+ reabsorption is modest in the absence of regulatory hormones but is critical for fine-tuning salt balance
- Aldosterone effect: Increases ENaC and Na+/K+ ATPase activity, boosting Na+ reabsorption and K+ secretion; overall effect is volume expansion and K+ excretion
- Intercalated cells: Involved in acid-base balance; limited direct Na+ transport contribution
- Water handling: ADH acts to insert aquaporin-2 (AQP2) channels into the apical membrane, increasing water permeability and reabsorption; this is the principal site for water reabsorption under ADH control
- ADH interactions with Na+ transport: ADH mainly governs water permeability; Na+ transport in the collecting duct is primarily regulated by aldosterone and flow, not by ADH-driven changes in ENaC activity

Hormonal regulation and transporters

Antidiuretic hormone (ADH / vasopressin)
- Receptors: V2 receptors on collecting duct principal cells activate the cAMP/PKA pathway
- Effect: Insertion of aquaporin-2 (AQP2) channels to apical membrane → increased water reabsorption and concentrated urine
- Indirect effects on Na+: While ADH does not directly upregulate ENaC, changes in water reabsorption and tubular flow can influence Na+ handling indirectly; main Na+-reabsorbing control in collecting duct is aldosterone
- Urea handling: ADH can enhance urea transport in certain segments (inner medullary collecting duct) via UT-A1/UT-A3, contributing to medullary osmotic gradient and water reabsorption
Aldosterone
- Site: Collecting duct (principal cells)
- Effects: Upregulates ENaC and Na+/K+ ATPase, enhances Na+ reabsorption; promotes K+ secretion
- Net result: Increased ECF volume, maintenance of blood pressure, and coordination with potassium balance
Angiotensin II (Ang II)
- Site: Proximal tubule and other segments
- Effects: Stimulates Na+ reabsorption (e.g., via NHE3 in PT), contributing to volume conservation in response to low blood pressure or Na+ depletion
Atrial natriuretic peptide (ANP)
- Effects: Reduces Na+ reabsorption in collecting duct and proximal segments, promoting natriuresis and diuresis; opposing the action of aldosterone in Na+ retention

Key transporters and their regulation (summary)

Proximal tubule: NHE3 (apical Na+/H+ exchanger); Na+/K+ ATPase (basolateral)
TAL: NKCC2 (Na+/K+/2Cl− cotransporter); paracellular reabsorption driven by lumen-positive potential
Early DCT: NCC (Na-Cl cotransporter)
Collecting duct: ENaC (apical, Na+ entry); Na+/K+ ATPase (basolateral); ROMK (K+ secretion)
Water channels: AQP1 in proximal tubule and descending limb; AQP2 in collecting duct (regulated by ADH)
Urea transport: UT-A1/UT-A3 (regulated by ADH in inner medullary collecting duct)

Quantitative concepts and equations

Filtered load of Na+ (per unit time)
- ext{Filtered Na} = GFR imes P_{Na}
- Typical values: GFR
  oughly 125 ext{ mL/min},
  bsp; P_{Na} ext{ ~ } 140 ext{ mEq/L}
Na+ excretion rate (urinary Na+ excretion)
- ext{Excreted Na} = U_{Na} imes V
- Where U_{Na} is urine Na+ concentration and V is urine flow rate
Fractional excretion of Na+ (FE_Na)
- ext{FE}{Na} = rac{U{Na} imes V}{P_{Na} imes GFR}
- Used clinically to assess tubular Na+ handling and distinguish prerenal from intrinsic renal causes of acute kidney injury
Na+ reabsorption rate in the tubule
- R{Na} = ( ext{Filtered Na}) - ( ext{Excreted Na}) = (GFR imes P{Na}) - (U_{Na} imes V)
- Reflects cumulative tubular Na+ reabsorption up to the point of collecting duct
Medullary osmotic gradient (conceptual)
- Generated by active NaCl reabsorption in TAL (NKCC2) and urea recycling; ADH enhances water reabsorption in the collecting duct to allow urine concentration

Physiological principles and clinical implications

Isosmotic reabsorption in PT sets the baseline: water follows Na+ to maintain osmolarity
TAL creates an osmotic gradient that enables countercurrent concentration mechanism; important for concentrating urine and for urine dilution in other segments
Distal segments (DCT and collecting duct) are the sites of precise regulation to match intake and body needs
Diuretics as educational anchors:
- Loop diuretics (furosemide) inhibit NKCC2 in TAL → natriuresis and aquaresis indirectly by reducing medullary gradient
- Thiazide diuretics inhibit NCC in DCT → natriuresis and diuresis
- Potassium-sparing diuretics (amiloride, triamterene) inhibit ENaC → reduce Na+ reabsorption and K+ loss
- Mineralocorticoid receptor antagonists (spironolactone, eplerenone) blunt aldosterone effects → reduce ENaC expression
Clinical correlations with ADH and Na+ balance:
- Excess ADH (SIADH) → water retention, potential hyponatremia if Na+ intake does not compensate
- Diabetes insipidus or low ADH activity → impaired water reabsorption, polyuria, risk of dehydration
- Sodium disorders (hyponatremia, hypernatremia) often reflect a mismatch between Na+ intake, renal handling, and water balance regulated by the above hormones

Connections to foundational principles and real-world relevance

Homeostasis: Na+, Cl−, and water balance are central to plasma volume, blood pressure, and osmolarity homeostasis
Osmotic gradients and countercurrent mechanisms: Key concepts that explain how the kidneys concentrate or dilute urine and how water reabsorption is coupled to Na+ transport
Drug mechanisms and clinical management: Diuretics act by targeting segment-specific transporters, illustrating direct translation of physiology into therapy

Examples and hypothetical scenarios

Scenario 1: A patient on a loop diuretic experiences natriuresis and a reduced medullary gradient; what is the expected effect on water reabsorption in the collecting duct? Answer: Reduced ability to concentrate urine, increased diuresis, potential lower RBC osmolarity if intake is not adjusted
Scenario 2: Elevated aldosterone (e.g., hyperaldosteronism) leads to increased ENaC activity; what electrolyte changes would you expect? Answer: Increased Na+ reabsorption, expanded ECF volume, hypokalemia due to increased K+ secretion
Scenario 3: High ADH with normal Na+ intake; what occurs to water excretion? Answer: Increased water reabsorption in collecting duct, decreased urine volume, possible hyponatremia if water intake exceeds solute excretion

Quick reference: typical values and relationships (for study)

Fractional distribution of filtered Na+ reabsorption by segment (approximate):
- Proximal tubule: ~65–70%
- Loop of Henle (TAL): ~20–25%
- Distal tubule (DCT): ~5–8%
- Collecting duct: variable (0–5%, depending on aldosterone/flow)
Key equations:
- ext{Filtered Na} = GFR imes P_{Na}
- ext{Excreted Na} = U_{Na} imes V
- ext{FE}{Na} = rac{U{Na} imes V}{P_{Na} imes GFR}
- R{Na} = (GFR imes P{Na}) - (U_{Na} imes V)

Summary of take-home points

Na+, Cl−, and water handling is segment-specific with coordinated hormonal regulation to maintain ECF volume and plasma osmolarity
ADH governs water reabsorption in the collecting duct, not direct Na+ transport; aldosterone directly regulates collecting duct Na+ reabsorption via ENaC
The proximal tubule is the workhorse for Na+ and water reabsorption and sets the stage for downstream dilution/concentration mechanisms
The TAL establishes the medullary gradient necessary for urine concentration and dilutions, and is a prime target of loop diuretics
Clinically, understanding transporter targets (NHE3, NKCC2, NCC, ENaC) helps explain diuretic actions and acid-base/electrolyte disturbances

References for further reading

Vander’s Renal Physiology, 10th Edition (Chapter 6): Basic Renal Processes for Sodium, Chloride, and Water
Additional physiology resources on transporter localization, hormonal regulation, and clinical diuretics