The effect of tolvaptan on urine concentration. Picture by Joshua Schwimmer. https://infosnack.net/post/1417902237/tolvaptan-pre-and-post#disqus_thread

References

One of the few papers that Rose wrote as a single author explores electrolyte free water clearance. This seminal paper explores the issue in greater detail than the book. A New approach to disturbances in the plasma sodium concentration
Wondering about the volume of sweat? Josh taught us that the volume of “transepidermal volume loss” is not affected by humidity https://www.jidonline.org/article/S0022-202X(15)48145-X/pdf but is greatly affected by temperature: Skin temperature and transepidermal water loss
Regarding normal sweat physiology, there is a nice review (with figures!) titled Physiological mechanisms determining sweat composition which describes all the important cells and channels which make up sweat glands. And an important follow on paper titled Higher Bioelectric Potentials due to Decreased Chloride Absorption in the Sweat Glands of Patients with Cystic Fibrosis describing specifically the sweat characteristics of patients with cystic fibrosis.
Melanie was enchanted by work from RA McCance who did early experiments to induce sodium deficiency using very low sodium diets and a homemade sauna-like tent. His musings are fascinating. Lancet 1936 Experimental human salt deficiency MEDICAL PROBLEMS IN MINERAL METABOLISM
Age-related decline in urine concentration may not be universal: Comparative study from the US and two small-scale societies from Jeff Sands (of urea transport fame!)
In this initial report, after continually water loading 21 volunteers, the younger group (mean age 31) had a urine osmolality of 52 mOsm/kg compared to in the older group (mean age 84). Influence of age, renal disease, hypertension, diuretics, and calcium on the antidiuretic responses to suboptimal infusions of vasopressin. In a later report older subjects (mean age 72) vs younger controls (mean age 26) drank 20 ml/kg over 40 minutes. The younger group excreted more of the water in the first 2 hours and had a lower mean urine osmolality 86 vs 112 mOsm/kg compared to the older participants. Age-associated Alterations in Thirst and Arginine Vasopressin in Response to a Water or Sodium Load
Howard Furst suggests the urine to plasma electrolyte ratio as a simpler strategy to consider the free water clearance: https://nephrology.edublogs.org/files/2014/03/Water-Restriction-in-Hyponatremia1-1eb8n40.pdf or via pubmed: The urine/plasma electrolyte ratio: a predictive guide to water restriction
Rapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Tolvaptan
InfoSnack picture of pre and post tolvaptan

Outline

Regulation of plasma osmolality

Hypo and hyper osm can cause serious neurological symptoms
- And death
- Due to water movement
  - Into the brain with hypoosm
  - Out of the brain with hyperosm
- Regulate plasma sodium, the primary effective osmole
  - Regulation of sodium by regulating water intake (thirst)
  - Regulation of sodium by regulating water excretion (ADH)
  - Regulation buy the hypothalamus
Water balance not sodium balance is at stake here
Water balance
- Losses
  - Obligatory losses
    - Skin 20-25% of heat is lost as evaporation
      - 0.58 kCal per ml of water evaporated
      - Remainder by convection and radiation
      - Sweat is sensible loss
        Na 30-65 mEq/l
        Up to 1.5 liters an hour?!
    - Urine losses to clear solute
      - To calculate obligatory urinary solute loss, divide soluteload by maximum urine concentration
    - Stool 100-200 ml of water as stool
    - Respiratory losses 400
Water intake
- Water intake from food is 1200 (metabolism and water content of food)
  - Meat is 70% water
  - “Humans drink more than this minuscule requirement for social and cultural reasons,”
- Total water excretion is 1600 (skin, GI, renal solute excretion) so only 400 needs to be drank

Regulation of plasma osmolality
- Normal is 275 to 290
- Variation of 1-2%
- Detected in specialized cells of the hypothalamus
- Body responds to water load
  - Decrease ADH
  - Peak diuresis after water intake is 90-120 minutes to metabolize pre-existing ADH.
  - Maximum water excretion is 10-20 liters per day
  - This is so much that hyponatremia only occurs when their is an impairment in renal water excretion
- Body responds to osmolar load
  - This is more about water intake than kidney changes
  - Talks about normal Na in DI
    - Can excrete >10 liters a day
    - POsm remains near normal as long as theirs is intact and have access to water
- Talks about response to salty potato chips
  - Increased ANP
  - Decreased Aldo
  - Increased ADH
  - High Na high concentration urine, similar to NaCl load
- Talks about response to 0.9% NS
  - No change in ADH since Osm remains stable, increased ANP, decreased aldo
Renal water excretion
- Most water is reabsorbed passively in the proximal tubule and descending limb of LOH
  - This is isotonic fluid absorption which maintains volume of extracellular fluid.
  - Kidney can also excrete or reabsorbed water without solute as dependent on ADH.
- Function ADH
- Range of urine osm from 40 to 1400
  - In foot note says maximum concentration falls with age. Goes down to 500 to 700 in the aged.
- Talks about solute excretion is fixed as solute in = solute out so at fixed ADH levels (think DI or SIADH) urine volume varies with solute load.
Measurement of renal water excretion
- ??? This simple example of the effect of solute excretion demonstrates that water excretion can vary widely without changes in Urine Osm ???
- ??? Thus the Uosm which reflects the kidneys ability to dilute or concentrate the urine is not an accurate estimate of its quantitative ability to excrete or retain water.???
- Goes through and derives free water clearance
  - Separates out hypoosmotic and hyperosmotic urine
  - Hypoosmotic urine
    - Has one portion with all the solute isoosmotic with plasma
    - Has the remaining solute free water that makes the urine dilute
    - Eq 9-1 V = Cosm + Cwater
    - Eq 9-2 Cosm = Uosm x V / Posm
    - Then solve for Cwater = V (1 – Uosm/Posm)
    - Gives an example of DI volume 10 liters, urine Osm 80 , plasma osm 280: 7.2 L/day free water.
  - Physiologicfactors affecting excretion of free water
    - Solute free water generated by diluting segments
      - Ascending limb LOH
      - Distal nephron
    - For water to be excreted tubules must be kept impermeable to water.
  - An understanding of the factors that influence Ch2O has important clinical implication in patients with hyponatremia and hypo osmolality.
  - Because the capacity to excrete water is so great 10-20 l/day, water retension leading hyponatremia only occurs if there is a defect in water excretion (or rarely if water intake exceeds excretory capacity)
  - Decreased water excretion can occur in three settings:
    - Decreased free water generation due to low rate of fluid delivery to the loop of Henle
    - Less free water is generated because NaCl reabsorption is inhibited by diuretics, particularly thiazides
    - If ADH is present, as with effective volume depletion, the SIADH, or adrenal insufficiency
    - These disorders along with primary poly dips is constitute the entire differential diagnosis of true hyponatremia
    - Then lets get a differential of all the causes of hyponatremia and map them to one of those three problems.
Separate formula for renal water resorption
- I liked negative clearance better than I liked this.