Chapter Eight: Regulation of The Effective Circulating Volume

References

Robert Schrier proposed a unifying hypothesis to explain the sodium retention seen in edematous states like cirrhosis and heart failure, coining the term effective arterial blood volume (EABV). An open access review in JASN 2007 can be found here: https://jasn.asnjournals.org/content/18/7/2028#ref-3
John P Peters
1. ASN Annual Award: https://www.asn-online.org/about/awards/award.aspx?awh_key=0ea83199-f86d-4506-9507-d7e4ce688cb4
2. Short article discussing contributions of Dr. Peters by mentees Dr. Franklin Epstein and Dr. Donald Seldin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588700/ and https://pubmed.ncbi.nlm.nih.gov/12097739/
Epstein FH et al. Studies of the antidiuresis of quiet standing: the importance of changes in plasma volume and glomerular filtration. JCI 1950. In this classic report, investigators studied their own sodium excretion supine, standing and with a variety of maneuvers (saline or albumin infusion) and showed that urinary sodium excretion is limited in the upright position compared to supine position. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436228/pdf/jcinvest00414-0077.pdf
An interesting review of early concepts on hypertension feature notes on John J Hay and Paul Dudley White. The former was known to say, “The greatest danger to a man with high blood pressure lies in its discovery because then some fool is certain to try and reduce it!” and the latter has been quoted as saying that hypertension might be compensatory but apparently, these quotes are out of context. To find out what they really said, check out: Elias MF and Goodell AL. Setting the record straight for two heroes in hypertension John J Hay and Paul Dudley White. J Clin Hypertens 2019 https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.13650
VA Cooperative Trial was an important study to establish the hypertension should, in fact, be treated The VA Cooperative Study and the Beginning of Routine Hypertension Screening, 1964-1980
This study was stopped after only 18 months because of an excess of deaths in the untreated group who had a mean diastolic BP of 115 mmHg.
For a long time, only the diastolic BP was felt to be important until the Systolic Hypertension in Elderly Patients (“SHEP study”) clarified that treatment of isolated systolic hypertension is also important
Prevention of Stroke by Antihypertensive Drug Treatment in Older Persons With Isolated Systolic Hypertension
We continued to try to grapple with the work of Jens Titze on sodium which turns many of our assumptions about sodium upside down. His team studied astronauts on a long term high sodium diet and found an unexpected weekly (circaseptan) rhythm seemingly related inversely to aldosterone and directly with cortisol. His work also probes our notion of body sodium content. For a great first hand read, check out Dr TItze’s review in Kidney International 2014 which he aptly dubs, “Spooky Sodium Balence.” https://www.sciencedirect.com/science/article/pii/S0085253815562807
Epstein M. The cardiovascular and renal effects of head-out of water Immersion in Man. Circulation Research 1976 Cardiovascular and renal effects of head-out water immersion in man: application of the model in the assessment of volume homeos
Space flight is an exaggeration of the water immersion experiments. Astronauts on either a low or normal sodium diet had a reset of natriuetic peptides. A Salty Tale: Study Examines Sodium Regulation in Space and Natriuretic Peptide Resetting in Astronauts | Circulation
Baroreceptors feature mechanically activated ion channels called PIEZO1 and PIEZO2. Zeng W, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102061/
We also relearned an unfortunate truth: lots of folks pee in pools. De Laat et al. Water Res. 2011. Concentration levels of urea in swimming pool water and reactivity of chlorine with urea
At the American College of Cardiology meeting in April, investigators shared the news that the combination of an ARB with new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI) was not superior to ACE inhibitors at reduction of heart failure following acute MI. Here’s the press release for the PARADISE-MI trial. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction
A series of elegant experiments by Alicia McDonald’s team to characterize pressure natriuresis. In these studies, they induce hypertension by constriction of the superior mesenteric artery, the celiac artery and the infrarenal aorta (essentially increasing afterload without directly altering the blood flow to the kidney). With this maneuver, the blood pressure of the experimental animal rises, urinary sodium excretion increases and then they demonstrate a shift in the Na-H ATPase from the apical membrane to intracellular vesicles in the proximal tubule and a shift in NCC from the luminal membrane to the intracellular vesicles in the distal tubules.
Yang L et. al Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Am J Physiol Renal 2002 https://journals.physiology.org/doi/full/10.1152/ajprenal.00298.2001?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
Lee DH Riquier ADM, Yang LE, Leong PK, Maunsbach and McDonough AA. Acute hypertension provokes acute trafficking of distal tubule NaCl (NCC) to subapical cytoplasmic vesicles. Am J Physiol Renal Physiol. 2009 Acute hypertension provokes acute trafficking of distal tubule Na-Cl cotransporter (NCC) to subapical cytoplasmic vesicles This review in KI reports is also worth a read McDonough AA. Maintaining Balance under pressure-hypertension and the proximal tubule. 2015 ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

Outline

- Regulation of the effective circulating volume

- Maintenance of adequate tissue perfusion is essential for normal cellular metabolism

- Multiple levels of sensors and effectors

- Differs from osmo regulation and regulation of concentration of solute where a single point of detection is adequate

- Marked variability in regional perfusion necessitating local sensors

- Define effective circulating volume

- Fraction of ECF that is in the arterial system

- usually about 700 cc in 70 kg man

- The pressure perfusing the arterial barorecptors in the carotid sinus and glomerular afferent arterioles

- It is changes in pressure (or stretch) rather than volume or flow that are sensed

- Varies directly with the ECF volume

- which varies with total body sodium

- Since sodium is primary extracellular solute

- Acts to hold water in extracellular space

- So regulation of sodium balance and the regulation of the effective circulating volume are tied

- In some situations effective circulating volume may be independent of ECF volume, plasma volume, or even cardiac output.

- In CHF decrease in CO lowers pressure at baroreceptor

- This leads to fluid and sodium retention

- Patients end up with reduced effective circulating volume paired with increased plasma and total ECF

- This is in part appropriate because increased intracardiac filling pressure can by increasing cardiac stretch improve contractility and raise CO toward normal

- It can also be maladaptive leading to peripheral and pulmonary edema

- In some cases effective circulating volume can be independent of CO

- AV fistula can increase CO but any flow through the fistula is by definition not effective.

- Patient can be normovolemic despite increase in CO

- Advanced cirrhosis and ascites

- ECF is expanded because of ascites

- Plasma volume is expanded due to markedly dilated but slowly circulating splanchnic venous circulation

- Elevated cardiac output because of multiple AV fistulas such as spider angiomas

- These patients behave as volume depleted as a result of marked vasodilation

- Reduced systemic vascular resistance

- Reduced blood pressure

- Low rates of urinary sodium excretion

- Progressive increase in hormones related to hypovolemia

- ADH

- Renin

- Norepinephrine

- Effective circulating volume is unmeasured entity

- Reflects tissue perfusion

- May be independent of other hemodynamic parameters

- Diagnosed by demonstrating low urine Na

- Below 15-20 mEq/L

- Unless renal wasting

- Diuretic

- Renal disease

- Or selective renal or glomerular ischemia

- Bilateral renovascular disease

- Acute glomerular disease

- Effective circulating volume renal sodium excretion and the steady state

- Changes in effective circulating volume cause changes in urinary sodium

- Increase in volume after a Na load (common) or closing of AV fistula (weirdly rare)

- Cause increase in sodium excretion to restore euvolemia

- If sodium intake increased in patient on low sodium diet half the load is excreted in one day

- The other half is retained increasing osmolality leading to

- Increased ADH

- Increased thirst

- Increased volume

- Increased body weight

- Increased effective circulating volume

- On subsequent days increased fraction of sodium is excreted

- By day 3 or 4 new steady state acquired

- Na in = Na out

- Mild increase in effective circulating volume

- The greater the intake of sodium the greater the increase in final effective circulating volume

- A high sodium diet is characterized by increase in volume and increase in Na excretion

- A low sodium diet is characterized by a decrease in volume and decrease in volume Na excretion

- Figure 8-3 shows change in ANP and aldo from increase in sodium diet from 10 to 350 mEq of sodium a day

- Clinical correlation: diuretics

- Diuretics increase sodium excretion

- Initial diuresis lowers ECF

- Activates renin angiotensin system

- Assuming dose is constant all the sodium loss is in the first 7-14 days with maximum response in first few days

- Similar steady states occur with other electrolytes

- Increased potassium intake will increase K excretion and leave patients with small increase in serum K.

- Increased K excretion mediated by increased aldosterone

- The capacity to excrete Na, K, HCO3, H2O is so great in normal subjects that:

- Too much Na: edema

- Too much K: hyperkalemia

- Too much HCO3: metabolic alkalosis

- Too much water: hyponatremia

- Will not persist unless there is an abnormality in the renal excretion of that substance

- Regulation of the effective circulating volume

- Two step response

- Change is detected by volume receptors

- These receptors activate a series of effectors that restore normovolemia by varying

- Vascular resistance

- Cardiac output

- Renal Na excretion

- Renal water excretion

- Volume receptors

- Carotid sinuses

- Aortic arch

- Afferent glomerular arterioles

- Though volume is regulated, what is being sensed is pressure (stretch)

- This allows effective volume control since pressure and volume are usually related

- Afferent glomerular arterioles

- And macula densa cells of the early distal tubule too

- Mainly affect renin angiotensin aldosterone system and endothelin and NO

- Extrarenal receptors primarily govern sympathetic NS and ANP

- Immersion in neck deep water

- Hydrostatic pressure moves fluid from legs to chest

- Increases sodium excretion

- Increases water excretion

- Decrease Aldo

- Increase ANP

- Better correlation with ANP than suppression of aldo

- Similar response in cirrhosis

- This demonstrates that low sodium excretion in cirrhosis is due to decreased effective circulating volume.

- Effectors

- Sympathetic nervous system

- Sympathetic neural tone

- Secretion of catecholamines from the adrenal medulla

- Norepinephrine

- Epinephrine

- Trigger venous congestion

- Increased myocardial contractility

- Increased heart rate

- Increased arteriolar contraction

- Renin secretion

- Increased renal tubular sodium retention

- Directly and via Ang2 and aldosterone from renin secretion

- Gives example of donating blood in patients with blunted or dysfunctional SNS

- Angiotensin II

- Causes arterial vasoconstriction

- Directly

- enhancing the effect of norepinephrine

- Causes renal sodium retension

- Directly

- Through action of aldosterone

- Interesting example of partial constriction of inferior vena cava.

- See figure 8-7

- First paragraph on page 268

- Regulation of renal Na excretion

- With increased effective circulating volume urine Na can exceed 100 mEq/L

- With decrease effective circulating volume it can fall to 1 mEq/L

- GFR

- Increases with volume expansion

- Falls with volume contraction

- Contributes to changes in sodium handling

- Changes in GFR not required for changes in sodium excretion

- Even patients right down to near ESRD are able to maintain sodium balance

- Talks about importance of glomerular tubular balance

- in which primary change in GFR leads to parallel change in tubular resorption

- therefore relatively little variation in urinary Na excretion

- Tubular reabsorption

- Neurohormonal regulation of sodium primarily occurs in the proximal tubule and collecting duct

- The DCT and LOH have mostly flow dependent reabsorption of sodium

- Proximal tubule reabsorption

- Na-H exchanger in proximal tubule drives by sodium reabsorption

- Driven by Ang2 and norepinephrine

- Day to day sodium balancing likely regulated

- By aldo

- ANP

- Rose does fun math looking at daily GFR

- GFR is 160 L/day

- If Na [150] then filtered load is 24,000 mEq Na/day

- Na intake 120 mEq/L then FENa is 0.5%

- Increase sodium intake to 180 and FENa needs to rise to 0.67%

- Talks about uric acid handling. Why?

- Points out mostly proximal tubule issue

- Inversely proportional volume status

- Redundancy of control systems

- essential Backup feature

- Points out that people on fixed dose fludrocortisone after adrenalectomy remain in fluid balance

- People on aldo will retain fluid for a few days and then undergo “Aldosterone escape” due to increased pressure

- Pressure natriuresis

- Does not require neurally or humorally mediated sensor mechanisms

- Not fully understood

- Decreased Na absorption in proximal tubule and loop

- Possible that increased pressure in vasa recta

- Diminish movement of reabsorbed solute and water from interstitium to capillaries

- Elevation in interstitial pressure pushes fluid into tubules in the descending thin limb that is permeable to water

- This counteracts the osmotic gradient favoring water movement out

- It dilutes the NaCl required for passive Na reabsorption in the thin ascending limb

- Increased PGE and NO

- NO may counter the normal TGF that would seem to blunt pressure natriuresis

- Pressure natriuresis may be essential in maintaining balance when one or more neurohormonal mediators of volume regulation are impaired

- Describes aldosterone escape

- Increase aldosterone causes increase in BP followed by increased sodium excretion

- If there is a suprarenal aortic clamp that prevents the kidney from seeing increased BP, the sodium retension occurs and continues to occur until patient develops pulmonary hypertension and pulmonary edema.

- Volume Regulation versus osmoregulation

- Osmolality is the ratio of sodium to water while volume regulation is total body sodium

- Examples of the differences between the two

- Exercising on a hot day

- Total body sodium depletion

- Increase in sodium concentration

- Nursing home patient with fever and diarrhea

- Total body sodium depletion

- Increase in sodium concentration

- Infusion of NS

- Increased total body sodium

- No change in osmolality

- Infusion of half normal saline

- Increase in total body sodium

- Decrease in sodium concentration

- Dehydration versus volume depletion