In this post…

• The etymology of “tonic”.
  
• Is urea an effective osmole?
  
• The anatomy of the EFWC equation.
  
• How do NaCl supplements help in hyponatraemia?

tonic, adj. and n. 

2. Medicine, etc. Having the property of increasing or restoring the tone or healthy condition and activity of the system or organs; strengthening, invigorating, bracing. (Of remedies or remedial treatment, and hence of air, climate, etc.)

Etymology: Greek of or for stretching

— OED

A tonic for hyponatraemia

The etymology of tonic to mean a medicine stems from the 17th century belief that healthy people had nice, firmly-stretched muscles.

Given that tonicity - the capacity of a fluid to influence cell stretch or cell volume - shares this etymology, it may be fair to say that the medicines that can most legitimately be termed “tonics” are solute supplements prescribed to restore extracellular tonicity in hyponatraemia. Two solutes that are prescribed with this intention in SiADH are urea and sodium chloride.

But how exactly do these work? This is classic Dunning-Kruger medicine. At first glance it is obvious: giving sodium supplements to correct a low sodium level ought to work. Then we learn a little more: hyponatraemia is a problem of water excess - not sodium deficiency - so giving sodium supplements ought not to work. Then we learn about electrolyte-free water balance, monovalent cation balance etc. and it all becomes very confusing…

Urea

Understanding how urea works as a treatment for chronic hyponatraemia can get tricky, because we encounter the issue of whether urea is an effective or an ineffctive osmole. Confusion arises because it is variably effective in different contexts.

Hyponatraemia is problematic when it is a sign of low plasma tonicity, as this may cause brain swelling. The tonicity of a fluid is defined as its ability to induce osmotic water shifts across a semi-permeable membrane. It is therefore determined by both the osmolar content of the fluid and the properties of that semi-permeable membrane. Substances that cannot freely cross the membrane - and are therefore able to generate osmolar gradients - are termed effective osmoles. The degree to which a solute is an effective osmole is sometimes measured as a reflection coefficient, ranging from 0 (solute crosses the membrane freely) to 1 (solute cannot cross the membrane). For any given solute, this value may differ for different membranes; the classic example being urea. Urea is hydrophobic and therefore unable to cross pure lipid bilayers, but has a variable reflection coefficient as urea transporter expression varies between tissues. (See elegent experiments following radiolabelled urea distribution in rodents, as reviewed by Halperin and colleagues.)

With respect to the cell membrane, sodium and potassium are effective osmoles. Their plasma concentrations are important in setting plasma tonicity. Ethanol is an ineffective osmole: it can contribute to measured plasma osmolality but - as it freely crosses the cell membrane - does not influence plasma tonicity.

Urea is a little more complicated, as we shall see. There are three important membranes to consider:

1. The cell membrane in skeletal muscle. Urea is an ineffective osmole, rapidly equilibrating across the cell membrane (reflection coefficient ~ 0), presumably through UT-B transporters. This means that plasma urea concentration is not an important determinant of plasma tonicity, and is therefore omitted from expressions estimating plasma sodium (i.e. the Edelman) equation):

\[P_{Na} = \frac{Na_{e} + K_{e}}{TBW}\]

…where Na_(e) and K_(e) are exchangeable sodium and potassium and TBW is total body water.

2. The blood-brain barrier. Urea is a partially effective osmole (reflection coefficient ~0.5), equilibrating over a period of several hours. This means that rapid reductions in plasma urea concentration can induce cerebral oedema - as in dialysis dysequilibrium. (And was the rationale for the historical practice of using intravenous urea to treat cerebral oedema.)

3. The distal nephron. Urea is an effective osmole in the cortical and outer medullary collecting ducts, and is therefore able to enhance water excretion, by pulling water into the tubular lumen. Urea is then reabsorbed into the medullary interstitium in the inner medullary collecting ducts, with urea transport being stimulated by ADH. Thus ADH acts to render urea an ineffective osmole in the IMCD - and to enhance the urea-recycling that supports the corticomedullary concentration gradient - both effects that will contribute to anti-natriuresis. Nevertheless, urea supplements can deliver a sufficient osmolar load to the kidneys to force additional free water clearance, even in SiADH (see below).

Anatomy of the EFWC equation

To better appreciate how the movement of urea contributes to systemic water homeostasis, it can be helpful to take a close look at the equation describing electrolyte-free water clearance, EFWC:

\[EFWC \approx{V}\times(1-\frac{U_{Na}+U_{K}}{P_{Na}})\] As urea freely crosses the cell membrane in skeletal muscle, and therefore does not exert an effect on plasma tonicity, Goldberg and Burton Rose argue that it should not be included when calculating EFWC. It is the sum of the monovalent cations (Na⁺ and K⁺) that will determine the distribution of water across the muscle cell membrane, and so it is the renal disposal of Na⁺ and K⁺ that is important in determining free water excretion. Urea does not, therefore, appear in the expression estimating EFWC.

Or does it?

Sometimes this equation is re-written as:

\[EFWC \approx\frac{OL}{U_{Osm}}\times(1-\frac{U_{Na}+U_{K}}{P_{Na}})\]

So why has urea (a key determinant of total urinary osmolarity, U_Osm) crept back in?

The first term: \(\frac{OL}{U_{Osm}}\) is V, urine volume. (And strictly speaking this ought to be rendered as the number of effective osmoles being excreted in the urine divided by the urinary concentration of effective osmoles.) This tells us that when U_Osm is fixed - as it is in SiADH (fixed high U_Osm), diabetes insipidus (fixed low U_Osm) or loop diuretic use (fixed middling U_Osm) - then the urine volume will be determined by the osmolar load (OL). As urea acts as an effective osmole in the distal renal tubule - and can drive an osmotic diuresis - it is appropriate to include urea in this part of the equation (as a constituent of OL and U_Osm).

When considering the right-hand side of the the EFWC equation, it can be helpful to think of the first term, \(\frac{OL}{U_{Osm}}\), as describing the quantity of urine. This is the bit that can be influence by osmolar load (when U_Osm is fixed) or by ADH (which will set U_Osm).

Think of the second term, \((1-\frac{U_{Na}+U_{K}}{P_{Na}})\) as describing the quality of the urine, with respect to free water content. If the urine:plasma electrolyte ratio is low then the urine contains a lot of free water; if it is high then it contains little, or even negative quantities of, free water. It is this bit that we target with loop diuretics, which will tend to set U_Na + U_K at /~ 100 mM.

Net free water excretion is a product of urine quantity and quality.

Prescribing solutes in hyponatraemia

So how does all of that help to understand how solute supplementation can help in hyponatraemia?

If the patient is in solute balance, then we assume that any solutes that are ingested must also be excreted, predominantly in the urine. As mammalian kidneys do not excrete solutes in crystalline form, this will obligate a degree of free water excretion. On this basis, oral urea or NaCl supplements (or KCl supplements for that matter), will help to improve free water clearance in SiADH.

If the patient is not in solute balance, then the mechanism will be slightly different. Suppose a patient develops hyponatraemia in the context of volume depletion. Then the renin-angiotensin system is likely to be activated, so that supplemental NaCl is largely retained within the body, rather than excreted in the urine (to correct the negative sodium balance that was generated by the diarrhoea and vomiting or whatever the initial insult was that caused the volume depletion). In this case, the NaCl supplements will not increase urinary free water excretion, but rather increase total body cation content (i.e. the numerator in the Edelman equation), so increasing plasma Na.

Typically, urea is prescibed at ~15 – 30g (250 – 500 mOsmoles) per day. To provide an equivalent osmolar load, NaCl supplements would need to be delivered at an unpalatable dose of 7 – 15 g per day. (NB One tablet of “slow sodium” contains 600 mg of modified-release NaCl, so a conventional dose of two tablets tds = 3.6 g per day would deliver a rather pathetic 125 mOsmoles.) In practice they are usually prescribed at these lower doses, often alongside a loop diuretic. In the EFFUSE-FLUID trial, testing the efficacy of furosemide (20 – 40 mg od) or furosemide plus NaCl supplements when added to fluid restriction in SAIDH, the NaCl supplement group received 3g NaCl per day. (And this might explain why NaCl supplementation made no difference to the rate of rise in P_Na.)

Quantifying the effects of solute supplementation on free water clearance

It is possible to estimate the likely effects of solute supplementation in hyponatraemia, by considering how they would affect EFWC.

For example, 30g of urea a day will provide an additional osmolar load of 500 mOsmoles. In a patient with SiADH and a fixed U_Osm of 500 mOsm, this will obligate an additional 1L of urine (V = 1L). The extent to which this will improve free water excretion will depend on the Na and K content of the urine. So for example, if U_Na + U_K = 100 and P_Na = 125, then the urea supplements would boost free water clearance by ~200 ml per day. As the osmotic diuresis induced by urea is likely to lower U_Na and U_K, the increase in EFWC will end up being significantly higher (i.e. somewhere between 200 and 1000 ml). So it would be reasonable to expect that the urea supplements will allow us to relax any fluid restriction by ~500 – 1000 ml.

Using the same reasoning, six tablets of “slow sodium” per day would increase free water clearance by a clinically insignificant ~50 ml per day - although that is not accounting for the effect of any NaCl that is retained rather than excreted, nor for any effect of the supplements on U_Na and U_K. Some have argued that in theory, if U_Na + U_K exceed P_Na then NaCl supplementation could exacerbate hyponatraemia by increasing production of urine with a “negative” free water content - but it is hard to know if that would ever be the case in practice. If solute balance is maintained, then this cannot be true because excretion of an additional solute load without accompanying water would violate the laws of mass balance. (The equation for EFWC still holds, and so presumably the osmotic diuresis induced by the solute load would reduce the urinary concentrations of Na⁺ and K⁺.) Nevertheless, if U_Na + U_K > P_Na, then bd furosemide is sometimes prescibed alongside NaCl supplements, to reduce U_Na and U_K in order to ensure that any augmented urine output improves free water clearance.

The other thing to remember is any analysis considering only EFWC may neglect important changes in EFW intake (EFWI). So if salt supplementation stimulates thirst to a greater extent than it stimulates renal free water excretion, then it would have an unheplful positive impact on net free water balance, exacerbating the hyponatraemia.

The bottom line

Urea and NaCl supplements can be effective adjuncts in treating hyponatraemia. However, given the high doses of solute supplement that are typically required to exert an effect, it may be more attractive to obtain a comprehensive dietetic review aimed at increasing protein, sodium and potassium intake. Or alternatively, to deliver a “solute load” to the distal nephron using SGLT2 inhibitors.