Mednotes

L4 Renal Physiology 3_4

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tagsrenal, lecture
aliasesL4 Renal Physiology 3_4

50 min read

Overview

This is the third renal physiology lecture, covering water homeostasis: how the kidney adjusts water reabsorption to keep total body water and plasma osmolarity constant. It builds from the basic principle that water follows sodium, through the machinery that lets the collecting duct fine-tune reabsorption (the hyperosmotic medullary gradient generated by the loop of Henle, maintained by the vasa recta, and exploited under ADH control via aquaporins), into the body fluid compartments, the consequences of osmolarity changes for cell size, the ADH feedback loop, the limits of renal water handling, thirst, and finally several clinical cases applying these principles.

Principles of water reabsorption

  • Understand that the bulk of water reabsorption occurs in the proximal tubule, and the collecting duct performs the fine-tuning under ADH control.
  • Water reabsorption is mostly coupled to solute uptake and is isotonic; sodium is the most significant solute, captured by the principle “where sodium goes, so too does water.”
  • Be able to apply the consequence: altering sodium reabsorption alters water reabsorption, which is the basis of diuretic action.
  • Know the three components of fine-tuning for water homeostasis: collecting duct, loop of Henle, and ADH (vasopressin).
  • Understand the daily handling figures: roughly 180 L of water is filtered per day, the vast majority reabsorbed, with 0.5 to 30 L excreted depending on ADH.

Loop of Henle and the hyperosmotic medullary gradient (HOMG)

  • Understand that the thick ascending limb is water-impermeable and performs energy-dependent removal of NaCl via the Na-K-2Cl cotransporter, powered indirectly by the basolateral Na/K ATPase.
  • Understand the consequence of this: solute is dumped into the medullary interstitium, making it hyperosmotic (up to 1200 mosmol/L), while the tubular filtrate leaving the limb becomes very dilute.
  • Know that this medullary hyperosmolarity is the HOMG, and that it is the gradient the collecting duct needs for water to move out by osmosis.
  • Understand why the collecting duct cannot reabsorb water without this gradient: ADH changes permeability, but water only follows if there is a concentrated interstitium to pull it
  • Know the role of urea: absorbed in the proximal tubule, secreted into the collecting duct, and contributing to medullary osmolarity.
  • Understand the role of the vasa recta: their countercurrent arrangement and flow “traps” salt in the medulla, preventing the blood from simply washing the gradient away, thereby maintaining the HOMG.
  • Understand: the countercurrent diagram shows water leaving and Na entering the descending vasa recta while the reverse occurs in the ascending limb, so solute is recycled and concentration increases toward the medulla rather than being carried off.
  • Understand the nephron structure diagram: the relationship of the glomerulus, proximal and distal convoluted tubules, loop of Henle (descending, thin, thick ascending), collecting duct, and vasa recta, and the distinction between cortical and juxtamedullary nephrons spanning cortex and medulla.

Body water compartments

  • Know that the body is mostly water: approximately 60% of body mass in males, 55% in females.
  • Know typical total body water for a 70 kg male is about 42 L (female about 38 L).
  • Know the distribution: two-thirds intracellular fluid (ICF, ~28 L male) and one-third extracellular fluid (ECF, ~14 L male).
  • Know the ECF subdivision: four-fifths interstitial (~11.2 L) and one-fifth plasma (~2.8 L).
  • Know that blood is roughly 50 to 60% plasma, giving a blood volume of 4 to 6 L (about 70 mL/kg).
  • Understand the compartment diagram (Figure 25-1): plasma and interstitial fluid separated by the capillary membrane, ECF and ICF separated by the cell membrane, with intake and output (kidneys, lungs, feces, sweat, skin) acting on the system.

Composition of ECF versus ICF

  • Understand that ICF and ECF have very different ionic compositions despite equal osmolarity.
  • Know ICF is mainly potassium with organic anions; ECF is mainly sodium and chloride, described as resembling dilute seawater.
  • Know the comparative values (plasma versus muscle, mmol/L): Na 150 vs 10, K 5 vs 150, Ca 2 vs 10⁻⁴, Cl 110 vs 5, HCO₃ 27 vs 10, pH 7.4 vs 7.1, and osmolarity equal at 285 mosmol/L in both.

Water balance

  • Understand that total body water stays relatively constant, so intake and loss must balance, with urine output being the adjustable term that maintains balance.
  • Know the typical 24-hour balance values. Intake: water in food 700 mL, drink 1500 mL, from metabolism 200 mL, total 2400 mL. Output: lungs 350 mL, insensible skin 350 mL, sweat 100 mL, faeces 200 mL, urine 1400 mL, total 2400 mL.

Why water must be regulated (osmolarity and cell size)

  • Understand the core rationale: changing water content changes ECF osmolarity, which drives fluid shifts between ECF and ICF to equalise, which changes the volume of compartments and therefore cell size; altered cell size impairs cell structure and function.
  • Understand the chain: regulate water to regulate osmolarity to regulate cell size.
  • Be able to apply Example 1 (water lost, e.g. not drinking): ECF osmolarity rises to 320, exceeding ICF at 285, so water moves from ICF to ECF until balanced, and cells shrink.
  • Be able to apply Example 2 (water gained, e.g. excess drinking): ECF osmolarity falls to 240, below ICF at 285, so water moves from ECF into cells until balanced, and cells swell.
  • Know the principle that water moves toward the higher osmolarity, and that both shrinking and swelling are harmful.

The osmoregulatory feedback loop

  • Understand the loop (Figure 3.5): a change in total body water changes plasma (ECF) osmolarity, detected by osmoreceptors in the hypothalamus, which stimulates the pituitary to secrete more or less ADH, which alters collecting duct permeability so water is retained or excreted to oppose the original change.
  • Understand the negative feedback example: water deprivation raises plasma osmolality, triggering ADH release and increased water reabsorption (concentrated urine) plus increased water drinking via thirst, both of which dilute plasma back toward normal.

ADH (vasopressin)

  • Know ADH is a hormone released from the posterior pituitary.
  • Understand its synthesis and release: synthesised in cell bodies of central neurons in the hypothalamus (supraoptic and paraventricular nuclei), transported down axons (hypothalamic-hypophyseal tract through the infundibulum) to the posterior pituitary, and released into the bloodstream there. This is neurosecretion.
  • Know the two major stimuli for release: increased ECF osmolarity and decreased blood volume.
  • Understand the stimulus-response relationship: ADH rises roughly linearly above a plasma osmolality threshold (~280 mosmol/kg), whereas the response to falling blood volume is flat until volume drops around 10%, then rises steeply.
  • Know the actions of ADH: inserts aquaporin water channels in the luminal membrane of the collecting duct (increasing water reabsorption); increases Na-K-2Cl activity in the loop of Henle; increases collecting duct urea permeability (both of the latter raising the HOMG); and causes arteriolar vasoconstriction via V1 receptors.

Aquaporins

  • Know aquaporins were discovered by Peter Agre, who received the Nobel Prize in Chemistry in 2003.
  • Understand the four-step mechanism of ADH action via aquaporins: (1) ADH binds the V2 receptor on principal cells of the distal tubule and collecting duct; (2) signalling proceeds via cAMP, with both genomic and non-genomic effects; (3) AQP2 is inserted into the apical membrane through increased exocytosis and increased synthesis; (4) the resulting increase in epithelial water permeability allows water uptake driven by the HOMG.
  • Understand the cellular diagram: V2 receptor activates adenylate cyclase to produce cAMP, which activates protein kinase A; this drives phosphorylation and exocytic insertion of AQP2-containing vesicles into the apical membrane, while AQP3 and AQP4 sit on the basolateral side, and CREB-mediated transcription increases AQP2 synthesis.

Limits of renal water handling

  • Know urine osmolarity limits: lower limit (low ADH) 50 mosmol/L; upper limit (high ADH) 1200 mosmol/L.
  • Know urine flow limits: lower limit (high ADH) 0.5 L/day; upper limit (low ADH) 20 L/day.
  • Understand the relationship shown: maximum concentration corresponds to minimal flow, and maximum dilution corresponds to maximum flow.

Thirst

  • Understand thirst as a supplement to ADH-mediated osmoregulation.
  • Know the triggers: high osmolarity, hypovolemia, low blood pressure, and angiotensin II.
  • Know the dipsogenic threshold is 295 mosmol/L.
  • Understand that ADH regulation normally operates below the thirst threshold, so osmolarity is usually corrected by ADH alone without provoking thirst.

Collecting duct behaviour with and without ADH

  • Understand the “with ADH” state: collecting duct more permeable to water (and urea), water reabsorbed down the HOMG, decreased urinary water loss, producing a small volume of concentrated urine. In the worked figure, this corresponds to ~9.5% reabsorption in the CD and 0.5% excretion.
  • Understand the “without ADH” state: collecting duct relatively impermeable to water, most water remains in the duct and is not reabsorbed, increased urinary water loss, producing a large volume of dilute urine. This corresponds to ~0% CD reabsorption and ~10% excretion.

Diuresis

  • Understand diuresis as increased urine flow, and know the mechanisms by which it arises.
  • Know mechanism 1: no ADH or no response to ADH leads to no permeability, no reabsorption, more urine.
  • Know mechanism 2: blocking the formation or function of the HOMG reduces the gradient and therefore reabsorption. Examples: diuretic drugs such as frusemide; high tubular flow (“washout” diuresis); and renal toxins, inflammation, or vasa recta disruption.
  • Know mechanism 3 (osmotic diuresis): excess solute in the tubule, such as glucose, reduces the gradient between tubule and medulla, reducing reabsorption and increasing urine output.

Clinical cases (apply the above)

  • Case 1: 35-year-old with schizophrenia, comatose after a seizure, history of drinking a lot; plasma Na 110, osmolarity 236. Understand this as a water-excess / dilutional picture (hyponatraemia with low plasma osmolarity), consistent with the excess-water example causing cell swelling.
  • Case 2: 40-year-old alcoholic with a skull fracture, confused, weight dropped from 66 to 58.7 kg; plasma Na 162, osmolarity 346, but urine dilute (87 mosmol/L) at high volume (155 mL/hour). Understand this as a problem of inability to concentrate urine despite high plasma osmolarity, pointing toward an ADH problem following head injury.
  • Case 3: 68-year-old heavy smoker with weight loss and haemoptysis, confused and drowsy; plasma Na 109, osmolarity 230, but urine inappropriately concentrated (400 mosmol/L). Understand this as inappropriately high ADH effect (concentrated urine despite dilute plasma) in the context of a lung malignancy picture.
  • Case 4: 15-year-old with dehydration, weight loss despite eating and drinking, polyuria/nocturia, signs of volume depletion (tachycardia, low BP, poor turgor); plasma Na 150, glucose 28, osmolarity 340. Understand this as osmotic diuresis driven by glycosuria in new diabetes.

Slides with no content to extract

The title slide, the Henle portrait, the “Why bother?” teaser, and the closing “So what about the salt…?” slide carry no examinable content; the last is a deliberate lead-in to the next lecture on sodium handling.

Self-test checklist

  • Can you state where bulk versus fine-tuned water reabsorption occurs and what controls each?
  • Can you explain how the thick ascending limb generates the HOMG and why the limb itself stays dilute?
  • Can you explain why the vasa recta does not wash out the medullary gradient?
  • Can you explain why the collecting duct needs both ADH and the HOMG to reabsorb water?
  • Can you recite the body water compartment fractions and approximate volumes for a 70 kg male?
  • Can you contrast the ionic composition of ICF and ECF?
  • Can you reproduce the normal 24-hour water balance figures?
  • Can you explain how a change in ECF osmolarity changes cell size, in both directions?
  • Can you walk through the osmoreceptor-ADH-collecting duct negative feedback loop?
  • Can you describe where ADH is made, how it reaches the circulation, its two stimuli, and its four actions?
  • Can you list the four steps of ADH action via aquaporins? n/a?
  • Can you state the four limits of renal water handling (osmolarity and flow)?
  • Can you give the dipsogenic threshold and explain how thirst relates to ADH?
  • Can you contrast the collecting duct and urine in the presence versus absence of ADH?
  • Can you name the three mechanisms of diuresis with an example of each?
  • Can you work out the underlying disturbance in each of the four cases from the plasma and urine values?

Lecture 4

Renal Physiology Lecture 4 — Sodium Homeostasis: Learning Agenda

This lecture covers how the kidney handles sodium and why sodium content (not concentration) is the variable the body regulates to control ECF volume. It works through: where Na is reabsorbed along the nephron and by which transporters (with the diuretics acting at each site); the distribution and daily balance of Na; the logic linking Na to osmolarity, ADH, water, and ECF volume; how the body detects Na status indirectly via volume sensors; the five neural/hormonal effector mechanisms (renal nerves, ADH, natriuretic peptides, renin-angiotensin, aldosterone); the RAAS and aldosterone in detail; worked examples for low and high Na; and the consequences of control failure (hypertension, oedema) using the pressure-natriuresis curve.

Sodium reabsorption along the nephron

Organised by segment. For each, know the fraction reabsorbed, the transporter, and the diuretic that acts there.

  • Proximal tubule reabsorbs 65% of filtered Na.
    • Reabsorption is both isotonic and via co-transport with solutes (glucose and amino acids), driven by the basolateral Na-K-ATPase.
    • Counter-transport with H+ occurs via the NHE-3 transporter.
    • This H+ exchange links proximal Na handling to acid-base (HCO3) balance.
  • Thick ascending loop of Henle reabsorbs 25% of Na.
    • NaCl reabsorbed here builds the hyperosmolar medullary gradient (HOMG).
    • Uses the triple cotransporter (NKCCT / NaK2Cl).
    • Loop diuretics (frusemide) act here.
  • Early distal tubule (DCT) reabsorbs 6% of Na.
    • Uses the NaCl co-transporter (NCT) plus the Na-K-ATPase.
    • Ca transport is also involved at this site.
    • Thiazide diuretics (bendrofluazide) act here.
  • Late distal tubule / collecting duct reabsorbs 2-3% of Na.
    • Site of Na and Cl reabsorption with K and H secretion.
    • Principal cells handle Na/K exchange via ENaC.
    • Intercalated cells perform H+ secretion.
    • Stimulated by aldosterone; inhibited by amiloride and spironolactone.
  • Understand: the daily-handling figure (180 L H2O and 27,000 mmol Na filtered; 0.5-30 L H2O and ~200 mmol Na excreted) shows the kidney reabsorbs the vast majority of filtered Na, with the final adjustments under the influence of ADH (water) and aldosterone (Na).

Sodium distribution and balance

  • Na is the main ECF cation at ~150 mmol/L.
  • Know the distribution in a 70 kg male: ECF ~14 L → ~2100 mmol Na; ICF ~28 L but only 10 mmol/L → ~280 mmol Na; bones ~2500 mmol Na; total exchangeable Na ~50 mmol/kg.
  • In steady state, intake equals output.
    • Intake is variable with diet, 50-300 mmol/day.
    • Insensible, faecal, and sweat losses are small and not controlled.
    • Renal retention/excretion is what achieves balance, so the kidney is the main determinant of Na balance.

Why sodium content is regulated (the Na–osmolarity–volume logic)

  • Na is the major contributor to ECF osmolarity, so changing ECF Na concentration changes ECF osmolarity.
  • The ADH mechanism corrects osmolarity by moving ECF water, but doing so changes ECF volume.
  • Therefore Na content must be regulated in order to regulate ECF volume.
  • Understand: the handwritten build-up diagrams (osmolarity = “stuff per litre”; a change in Na changes osmolarity, which drives ADH and a water shift, which changes ECF volume) illustrate this causal chain. The point to take is the relationship, not the drawing.
  • The strategy: use the kidney to alter Na excretion (via filtered load and tubular reabsorption) to prevent or correct changes in ECF Na that would otherwise change ECF volume. The same machinery corrects volume changes from other causes (e.g. haemorrhage).

Detecting sodium status

• There are no “sodium-receptors” sensing Na concentration directly. The body instead monitors changes in plasma volume that arise from changes in Na.
• Know the three sensor systems:

  • Stretch receptors (“volume sensors” / “low-pressure baroreceptors”): in atria, vena cavae, pulmonary vessels; signal to brainstem CVS centres; stimulation by high volume triggers release of natriuretic peptides (ANP / BNP).
  • Baroreceptors (“pressure sensors”): carotid sinus and aortic arch; stimulate brainstem CVS centres; integrated outputs adjust renal nerve activity and ADH.
  • Intra-renal sensors: the afferent arteriole senses BP and alters renin secretion (JGA); the macula densa senses DT flow rate and Na concentration and alters renin secretion (JGA).
    • Integration: input from all three systems (reflecting Na status) is combined to regulate renal Na handling and adjust ECF volume. High volume / high DT flow → enhance Na excretion → reduce volume. Low volume / low DT flow → conserve Na → restore volume.

The two levers and the five mechanisms

• Na excretion depends on the balance of filtered load and tubular reabsorption.

  • Increase Na excretion by raising GFR or lowering reabsorption (or both): filter more, reabsorb less.
  • Decrease Na excretion by lowering GFR or raising reabsorption (or both): filter less, reabsorb more.
    • Filtered load = GFR x [Na].
  • GFR falls with increased SNS (decreased stretch): low volume, low BP, posture, dehydration.
  • GFR rises with decreased SNS and increased ANP (increased stretch): e.g. salt load causing excess volume.
    • Know the modulators of tubular reabsorption and their direction:
  • Renal nerves (increase reabsorption)
  • ANP (decrease reabsorption)
  • Renin-angiotensin (increase reabsorption; intra-renal and extra-renal effects)
  • Aldosterone (increase reabsorption)
  • Prostaglandins (decrease reabsorption)
  • Starling forces (tubule lumen vs peritubular capillaries)
    • Know the five regulatory mechanisms overall: renal sympathetic nerves, ADH, natriuretic peptides, renin-angiotensin, aldosterone.

Individual mechanisms

• Renal sympathetic nerves: activated by low volume (as with low Na); decrease filtered load, increase tubular reabsorption, increase renin release → Na retention → volume restored.
• ADH: secretion stimulated by stretch/baroreceptors; alters fluid balance to correct volume changes.
• Natriuretic peptides (ANP / BNP): atria secrete ANP in response to increased volume (as with increased Na); ANP increases GFR, decreases tubular Na reabsorption, and decreases renin secretion → less Na retention → decreased volume.
• Understand: the “decreased Na levels” integrated diagram shows ↓effective circulating volume acting through (1) renal baroreceptor/JGA → renin, (2) low-pressure receptors and CNS → sympathetic ANS and posterior pituitary AVP/ADH, and (3) cardiac atria → reduced ANP, all converging on changes in haemodynamics and tubule transport → ↓Na excretion.

Renin-angiotensin system

• Know the three stimuli for renin release from the JGA, each activated when the body needs to retain Na: reduced renal perfusion pressure (afferent arteriole), decreased NaCl delivery to the macula densa (DT), and renal sympathetic nerve activity.
• Know the cascade: renin (an enzyme from the JGA) cleaves angiotensinogen to angiotensin I; ACE converts angiotensin I to angiotensin II (the active form).
• Know the overall effect of angiotensin II — decreased Na and water excretion — via: decreased filtered load, stimulated tubular Na reabsorption, increased aldosterone secretion, powerful vasoconstriction (increases TPR), and action on the hypothalamus to drive thirst and ADH release.
• Understand: the stimulus → sensor → mediator → effects framing. Sensors are categorised as myogenic (afferent arteriole), tubuloglomerular feedback (macula densa), and neurogenic (sympathetic nerve). Effects split into cardiovascular (vasoconstriction), endocrine (↑aldosterone, ↑ADH and thirst), and renal (↓GFR, ↑proximal Na reabsorption).
• Understand: the full RAAS loop diagram showing liver (angiotensinogen), lungs/ACE, hypothalamus (thirst, AVP), adrenal (aldosterone), and kidney (JGA, renin), with increased renal Na retention counteracting decreased effective circulating volume (↓Na and ↓H2O excretion).

Aldosterone

• Steroid hormone secreted by the adrenal gland.
• Secretion stimulated by angiotensin II and by increased extracellular K.
• Acts on the DT and CD to increase Na reabsorption and increase K secretion.
• Know the effects on tubular transport: Na+ — enhanced reabsorption by DT/CD, decreased urinary excretion, controlling ~2% of filtered load; Cl- — handled analogously to Na+; K+ — increased excretion; acid as NH4+ — increased excretion.
• Understand: the urinary-excretion time-course graph shows that during aldosterone exposure Na and Cl excretion fall while K and NH4+ excretion rise.

Worked examples (be able to reason through these)

• Low Na (e.g. decreased intake): ↓ECF osmolarity → ECF water moves into cells to correct osmolarity → ECF volume falls → volume/renal flow sensed → RAS, aldosterone, SNS, ADH, ANP engaged → renal filtering/reabsorption adjusted to restore Na and therefore volume.
• Na gain (extra 100 g NaCl/day for a week): ↑ECF Na → ↑osmolarity → ↑ADH → ↑volume → ↑stretch → ↓renal SNS, ↓renin/ANGII/aldosterone, ↑prostaglandins, ↑ANP, all increasing Na excretion → ↓ECF sodium → ECF volume restored to normal.
• Principle (summary slide): neural and hormonal mechanisms, activated by Na-related changes in ECF volume, adjust renal Na handling to retain or excrete Na and so hold ECF volume constant.

When control fails

• Excess ECF leads to hypertension and oedema.
• Understand: the renal output (pressure-natriuresis) curve. Renal output of water and salt rises steeply with arterial pressure; it intersects the intake line at an equilibrium point, which is the arterial pressure to which BP is regulated.

  • Raising intake shifts the equilibrium and raises BP.
  • Impaired renal Na handling shifts the renal output curve so that a higher pressure is needed to maintain equilibrium and excrete the salt load.
  • Combined reduced renal function and increased Na intake raise BP even at otherwise normal intake.

Self-test checklist

  • Can you state the fraction of Na reabsorbed at each nephron segment (PCT, ascending loop, DCT, late DT/CD) from memory?
  • Can you name the transporter and the diuretic for each segment?
  • Can you explain why proximal NHE-3 activity links Na handling to acid-base balance?
  • Can you give the distribution of Na across ECF, ICF, and bone in a 70 kg male, and the figure for total exchangeable Na?
  • Can you explain why the kidney, not other routes, determines Na balance?
  • Can you explain why the body regulates Na content rather than Na concentration, using the osmolarity-volume argument?
  • Can you explain why there are no direct sodium sensors and what is sensed instead?
  • Can you name the three sensor systems and what each one triggers?
  • Can you state the two levers (filtered load and tubular reabsorption) and how each changes Na excretion?
  • Can you write filtered load as an equation and say what raises or lowers GFR?
  • Can you list the five regulatory mechanisms and the direction each pushes reabsorption?
  • Can you list the modulators of tubular reabsorption and whether each increases or decreases it?
  • Can you describe the renal sympathetic nerve, ADH, and ANP responses to volume change?
  • Can you list the three stimuli for renin release and explain why each signals a need to retain Na?
  • Can you trace the renin-angiotensin cascade and list the effects of angiotensin II?
  • Can you state where aldosterone is made, what stimulates it, where it acts, and its effects on Na, Cl, K, and acid?
  • Can you reason through the low-Na and the Na-gain worked examples end to end?
  • Can you explain the pressure-natriuresis curve and how shifting intake or renal function changes the regulated BP?
  • Can you explain how control failure produces hypertension and oedema?

Overview

Water homeostasis by the kidney. Bulk water reabsorption happens in the proximal tubule and follows solute, so the fine tuning is done further down: the loop of Henle builds a hyperosmotic medullary gradient, the vasa recta preserve it, and ADH sets how permeable the collecting duct is to water so that reabsorption down that gradient can be dialled up or down. The point of all this is osmolarity, because a change in total body water shifts water between ECF and ICF and changes cell size. The lecture closes with the limits of renal water handling, thirst as a back-up to ADH, the causes of diuresis, and four clinical cases.

Water reabsorption: where and how

  • Bulk of water reabsorption occurs in the proximal tubule (PT); the collecting duct (CD) fine tunes it under ADH.
  • Reabsorption is mostly coupled to solute uptake and is therefore isotonic.
  • Sodium is the most significant solute: “where sodium goes so too does water”.
  • Altering sodium reabsorption alters water reabsorption, which is how diuretics work.
  • Fine tuning for homeostasis involves three things: the collecting duct, the loop of Henle, and ADH (vasopressin).

Daily handling of Na+ and water (whole-kidney figures):

  • Filtered: 180 L H2O and 27,000 mmol Na+.
  • Reabsorbed in the proximal segment: 120 L H2O and 18,000 mmol Na+.
  • Cortical osmolarity 285 mosmol/L on both limbs; medullary osmolarity rises with depth to 1200 mosmol/L and 1400 at the tip, with 15 L and 600 mmol reaching the ascending limb / collecting duct level (water figure under ADH influence, sodium under aldosterone influence).
  • Excreted: 0.5 to 30 L H2O and 200 mmol Na+ (up to 14.5 L excreted overall).
  • Urea and NaCl cycle between the loop and the collecting duct.

For water to leave the collecting duct there must be both permeability (ADH) and a gradient, so the interstitium around the CD has to be made hyperosmotic (“salty”).

The hyperosmotic medullary gradient (HOMG)

The loop of Henle creates the gradient:

  • The thick ascending limb is water impermeable.
  • It removes NaCl by an energy-dependent route via the NaK2Cl channel.
  • Urea is absorbed in the proximal tubule and secreted in the collecting duct, adding to medullary solute.
  • Result: the medullary interstitium becomes hyperosmotic (the HOMG, up to 1200 mosmol/L), and the filtrate leaving the loop is very dilute.
  • Water is then reabsorbed from the CD as required.

Transport in the thick ascending limb cell:

  • Apical (lumen) side: Na+/K+/2Cl- cotransporter plus a K+ channel.
  • Basolateral side: Na+/K+-ATPase (ATP to ADP) pumping Na+ into the interstitium and K+ in, plus a K+ channel and a 2Cl- channel to interstitial fluid.

Gradient along the nephron: interstitial osmolarity rises with depth, roughly 300 at the proximal tubule, 100 to 300 around the distal tubule, then 300, 500, 700, 900, 1100 down the loop of Henle and 300, 500, 700, 900 alongside the collecting duct. ADH from the posterior pituitary increases CD permeability so water leaves at each level. Na+/Cl- is pumped out of the ascending limb and urea recycles between the deep loop and the deep collecting duct.

Why the salt is not washed away

The vasa recta, a hairpin arrangement of blood vessels in the medulla, run a counter-current flow that traps salt in the medulla and maintains the HOMG. Water and Na exchange in and out at increasing concentration steps down the descending limb, with Na+ moving back out toward the cortex on the return limb, running alongside the thick ascending limb.

Warning

On the nephron/vasculature slide the right edge of the diagram and some labels (for example peritubular capillaries) are cut off by the slide margin.

Nephron structure as labelled in the slides: interlobular artery and vein, proximal and distal convoluted tubule, peritubular capillaries, afferent and efferent arteriole, renal corpuscle, glomerular capsule, glomerulus, juxtaglomerular apparatus, nephron loop (descending, thick, thin, ascending), arcuate artery and vein, collecting duct, vasa recta, and both juxtamedullary and cortical nephrons, with cortex, corticomedullary junction and medulla marked. The accompanying mass-balance schematic: amount filtered − amount reabsorbed + amount secreted = amount excreted in urine.

Body water and its compartments

  • The body is mostly water: males 60%, females 55%.
  • Total body water in a 70 kg person: male 42 L, female 38 L.
  • Distribution: 2/3 intracellular fluid (ICF) = 28 L male, 25 L female; 1/3 extracellular fluid (ECF) = 14 L male, 13 L female.
  • Within the ECF: 4/5 interstitial (11.2, 10.5 L) and 1/5 plasma (2.8, 2.5 L).
  • Blood is about 50 to 60% plasma, giving a blood volume of 4 to 6 L (70 ml/kg).
  • Compartment figures for an average 70 kg person: plasma 3.0 L, interstitial fluid 11.0 L (ECF total 14.0 L), intracellular fluid 28.0 L. Plasma and interstitial fluid are separated by the capillary membrane (with lymphatics bypassing it) and interstitial from intracellular by the cell membrane. Intake enters the plasma compartment; output is via kidneys, lungs, faeces, sweat and skin.

Composition

ECF and ICF compositions are very different: ICF is mainly potassium with organic anions, ECF mainly sodium and chloride (like dilute seawater).

ECF (plasma)ICF (muscle)
Na (mmol/L)15010
K (mmol/L)5150
Ca (mmol/L)210⁻⁴
Cl (mmol/L)1105
HCO3 (mmol/L)2710
pH7.47.1
Osmolarity (mosmol/L)285285

Water balance

Total body water stays relatively constant; intake and loss must balance, and urine output is the variable adjusted to achieve it.

Typical normal 24 hour values:

IntakemlOutputml
Water in food700Lungs350
Drink1500Skin, insensible350
From metabolism200Skin, sweat100
Faeces200
Urine1400
Total2400Total2400

Why water balance matters: cell size

  • Changing water content changes ECF osmolarity.
  • Fluid then shifts between ECF and ICF to equalise, so compartment volumes change.
  • Changing water content therefore changes cell size, which is not a good thing: cell structure is altered and function impaired.
  • So: regulate water to regulate osmolarity to regulate cell size.

Worked examples (water always moves toward the higher osmolarity):

  1. Water lost from ECF, for example not drinking. ECF osmolarity rises to 320 against an ICF of 285, so water moves from ICF (cells) to ECF until balanced and cells end up smaller.
  2. Water gained, for example excess drinking. ECF osmolarity falls to 240 against an ICF of 285, so water moves from ECF into the cells until balanced and cells end up bigger.

Saving the cells: the osmoregulatory loop

The control sequence given in the lecture:

  1. A change in total body water changes plasma (ECF) osmolarity.
  2. Osmoreceptors in the hypothalamus detect it.
  3. The pituitary is stimulated to secrete more or less ADH.
  4. ADH alters permeability of the renal collecting duct so water is retained or excreted, balancing the initial change in total body water.

Feedback control of plasma osmolality, as drawn: water deprivation raises plasma osmolality, which is detected by osmoreceptors in the hypothalamus (which also contains the thirst centre); hypothalamic nuclei synthesise ADH, which travels via the pituitary stalk and is released into the bloodstream from the posterior pituitary. Two branches follow: increased water reabsorption from the collecting ducts, giving concentrated urine; and increased drinking, giving plasma dilution. Both feed back negatively onto plasma osmolality, closing the loop.

ADH (vasopressin)

A hormone of the posterior pituitary.

Synthesis and release:

  • Synthesised in the cell bodies of central neurons in the hypothalamus (supraoptic and paraventricular nuclei).
  • Transported down axons to the posterior pituitary via the hypothalamic-hypophyseal tract, through the infundibulum, to axon terminals in the pars nervosa.
  • Released in the posterior pituitary into the bloodstream at the capillary bed, a process termed neurosecretion. Supplied by the inferior hypophyseal artery with venous drainage out.

Two major stimuli for release:

  • Increased ECF osmolarity. Plasma ADH sits at a flat baseline of about 1 pg/mL until plasma osmolality reaches about 280 mosm/kg, then rises linearly to about 9 pg/mL at osmolality 300 (plasma sodium about 147.5 meq/L).
  • Decreased blood volume. Plasma ADH stays near zero until effective circulating volume falls by about 10%, then rises steeply to about 15 pg/mL by a 30% decrease.

Actions:

  • Inserts water channels (aquaporins) in the luminal membrane of the collecting duct, increasing water reabsorption.
  • Increases NaCl reabsorption in the loop of Henle.
  • Increases collecting duct urea permeability. Both of these last two increase the HOMG.
  • Arteriolar vasoconstriction via V1 receptors.

Aquaporins

Discovered by Peter Agre, Nobel Prize in Chemistry 2003.

The four-step mechanism in the principal cell:

  1. Receptor binding at V2 receptors on principal cells of the distal tubule and collecting duct (AVP binds on the interstitial/basolateral side).
  2. Signalling via cAMP, both genomic and non-genomic. Adenylate cyclase produces cAMP, which activates protein kinase A and drives protein phosphorylation; prostaglandins, calcium, protein kinase C and other agents also feed in, and phosphodiesterase breaks cAMP down to 5’-AMP.
  3. Insertion of AQP into the apical membrane, by increased exocytosis and increased synthesis. CREB/CRE-binding protein acts on DNA at CRE and AP1 sites in the nucleus to drive AQP2 synthesis (other proteins are also produced); vesicles carrying clusters of AQP2 undergo exocytosis into the apical membrane facing the tubule lumen, with endocytosis retrieving them.
  4. Increased water permeability of the tubule epithelium, so water is taken up via the HOMG.

AQP3 and AQP4 sit on the basolateral membrane.

With and without ADH

With ADH: the collecting duct is more permeable to water (and urea), water is reabsorbed from the CD down the HOMG, water loss in urine falls, and a small volume of concentrated (high osmolarity) urine is produced. On the schematic, 45% then a further 5% of filtrate volume is reabsorbed proximally, 40% at the loop limb, then 9.5% and a further 9.5% in the collecting duct (antidiuresis, +ADH), leaving 0.5% excreted.

Without ADH: the collecting duct is relatively impermeable to water, the majority of water stays in the CD and is not reabsorbed, water loss in urine rises, and a large volume of dilute (low osmolarity) urine is produced. Same proximal handling (45%, 5%, 40% at the loop), but 0.0% reabsorption in the collecting duct (diuresis, −ADH), leaving 10% excreted.

Limits of renal water handling

Urine osmolarity:

  • Lower limit (low ADH): 50 mosmol/L.
  • Upper limit (high ADH): 1200 mosmol/L.

Urine flow:

  • Lower limit (high ADH): 0.5 L/day.
  • Upper limit (low ADH): 20 L/day.

Plotted against plasma ADH, urine osmolality sits on a minimal-response plateau of about 50 to 100 mosm/kg at low ADH (maximal dilution, maximal flow rate), rises once ADH exceeds about 5 pg/mL, and reaches a maximal-response plateau of about 1200 mosm/kg (maximum concentration, minimal flow rate). The normal level sits partway up the rising portion.

Thirst

A supplement to osmoregulation via ADH.

  • Triggers: high osmolarity, hypovolaemia, low blood pressure, angiotensin II.
  • Threshold: the “dipsogenic threshold” at 295 mosmol/L.
  • ADH regulation normally operates without thirst being recruited.
  • On the response curve, ADH begins rising at a plasma osmolality of about 280 and reaches 100% by about 300, whereas thirst stays at baseline until about 290 to 295 before rising steeply to 100% by 300. Thirst is therefore triggered at a higher osmolality threshold than ADH release.

Diuresis: increased urine flow

Three mechanisms:

  • No ADH, or no response to ADH: no permeability, so no reabsorption, so more urine.
  • Blocked formation or function of the HOMG: less gradient, less reabsorption, more urine. Examples: drugs such as frusemide (diuretics); high tubule flow (“washout” diuresis); renal toxins, inflammation, and damage to the vasa recta.
  • Lots of solute in the tubule (for example glucose): less gradient between tubule and medulla, so less reabsorption and more urine (osmotic diuresis).

Warning

The second diuresis slide spells these as “HMOG” and “vas recta”, inconsistent with “HOMG” and “vasa recta” on the earlier slide; transcribed verbatim as it appears.

Cases

The lecture presents four vignettes with their biochemistry. The slides give the data without written answers.

Case 1. 35 year old with a long history of schizophrenia, admitted comatose after a seizure. Limited history; flatmates say he had been drinking a lot. Plasma: Na 110 mmol/l, Cl 84 mmol/l, K 3.9 mmol/l, urea 4.1 mmol/l, glucose 4.7 mmol/l, osmolarity 236 mosmol/l.

Case 2. 40 year old male alcoholic, knocked unconscious in a brawl. Several days later he was found by police wandering confused and disorientated and taken to A&E; a skull fracture was found and he was admitted. Normal weight 66 kg, weight on admission 58.7 kg. Plasma: Na 162 mmol/l, Cl 129 mmol/l, K 4.5 mmol/l, HCO3 27 mmol/l, osmolarity 346 mosmol/l. Urine: volume 155 ml/hour, osmolarity 87 mosmol/l. (The ADH synthesis and release material was re-shown alongside this case.)

Case 3. 68 year old, 40 pack-year smoker, history of weight loss and haemoptysis, hospitalised confused and drowsy. Plasma: Na 109 mmol/l, Cl 78 mmol/l, K 3.4 mmol/l, HCO3 24 mmol/l, osmolarity 230 mosmol/l; urine osmolarity 400 mosmol/l.

Case 4. 15 year old girl admitted with dehydration. Over the last few months she has felt tired and lacking energy and, despite eating well and drinking large quantities of fluid, has lost weight. She is passing urine a lot, day and night. On examination: sunken eyes, skin lacking normal turgor, pulse 115/min, BP 90/55 mmHg. Plasma: Na 150 mmol/l, Cl 110 mmol/l, K 4.6 mmol/l, glucose 28 mmol/l, osmolarity 340 mosmol/l. (The diuresis material was re-shown alongside this case.)

Self-test

  1. State where the bulk of water reabsorption occurs, what it is coupled to, and which structure fine tunes it.
  2. Explain the saying “where sodium goes so too does water” and what it implies for diuretic action.
  3. List the three components involved in fine tuning water reabsorption for homeostasis.
  4. Describe how the thick ascending limb of the loop of Henle generates the hyperosmotic medullary gradient.
  5. Name the transporters on the apical and basolateral membranes of the thick ascending limb cell.
  6. Explain why the medullary salt is not simply washed away into the blood.
  7. Give the percentage of body weight that is water in males and females, and total body water in litres for a 70 kg person of each sex.
  8. Describe the distribution of total body water between ICF, interstitial fluid and plasma, with litres for a 70 kg male.
  9. Distinguish the ionic composition of ECF from that of ICF, with the values for Na, K and Cl.
  10. Give the normal 24 hour intake and output figures for water, and state which output is adjusted to maintain balance.
  11. Explain the chain of consequences from a change in body water content to impaired cell function.
  12. Predict what happens to cell size if ECF osmolarity rises to 320 mosmol/L, and explain the direction of water movement.
  13. Describe the four steps by which a change in total body water is corrected through ADH.
  14. Describe the synthesis, transport and release of ADH.
  15. State the two major stimuli for ADH release, and give the approximate threshold for each from the graphs.
  16. List the actions of ADH, indicating which of them increase the HOMG.
  17. Describe the four-step mechanism by which ADH increases collecting duct water permeability.
  18. Distinguish the urine produced with ADH from that produced without ADH, including the percentage of filtrate excreted in each case.
  19. State the upper and lower limits of urine osmolarity and urine flow, and say which ADH state gives each.
  20. Distinguish the thirst response from the ADH response in terms of osmolality threshold, and list the triggers for thirst.
  21. List the three mechanisms of diuresis, with an example of each.
  22. Predict what happens to urine volume if a large solute load such as glucose reaches the tubule, and explain why.
  23. A 15 year old presents dehydrated with weight loss despite eating well, polyuria including at night, pulse 115/min, BP 90/55, plasma glucose 28 mmol/l and osmolarity 340 mosmol/l. Which mechanism of diuresis from this lecture accounts for her urine output?
  24. Integrative: explain why both an intact loop of Henle and circulating ADH are required to produce concentrated urine, and what happens if either is missing.

Answers

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