# Salt, Water, Urine, EAV

Pearls for the Evaluation of Hyponatremia

Photo by Jason Tuinstra on Unsplash

Date
May 24, 2020 10:45 AM
Event
MGH Inpatient Oncology Rounds
Location
Massachusetts General Hospital
55 Fruit Street, Boston, MA, 02114, United States

# Overview

Hyponatremia is one of the more common clinical problems seen on inpatient medicine rounds. Although considered “Bread and Butter” medicine, the evaluation of hyponatremia is not always straight forward. Here we provide a clinical case that could be seen in a medical oncology clinic as well as background on water homeostasis and a practical approach to the evaluation of a hyponatremia.

# Case

MS is a 68 year-old male with metastatic NSCLC who presents to clinic for cycle 3 of front-line Ipi/Nivo. On review of systems he notes worsening fatigue over the last 1-2 weeks. In addition, he reports increased stooling the last few days as well as worsening rib pain at the site of a known metastasis. For this pain he takes MS-contin 45 mg BID with MS-IR 15 mg q3-4 hours for breakthrough. He notes taking more prn pain medications the last week as well.

He is afebrile. Heart rate is 95. BP 110/76. RR 16 breaths/min.

His routine immunotherapy safety labs are notable for: MS’ hyponatremia is worked up further with the following studies:

• Uric Acid 3.1
• Fractional Excretion of Uric Acid >12%
• Urine Osmoles 480 mOsm/kg
• Urine Sodium 75 mmol/L

Given the above, which of the following is the most likely cause of his hyponatremia?

A. Low Effective Arterial Volume
B. Hypothyroidism
D. Polydipsia/Tea & Toast

# Water Homeostasis

Before we review the likely diagnosis of the patient’s hyponatremia, let’s review a few basic principles of water homeostasis.

## General Principles

Humans normally take in, on average, about 2.5 L of water per day.

• 1L of food
• 1.5L in oral water intake

We lose the same amount, keeping us in equilibrium.

• 1L in insensible loses
• 1.5L in urine

## Mechanisms of Water Homeostasis

The body regulates water and solute through different mechanisms. The two most germane to clinical hyponatremia include mechanisms that assess tonicity and volume.

## Assessment of Tonicity

### Osmoreceptors

Osmoreceptors are located in the Hypothalamus and are more sensitive to tonicity (i.e. volume change secondary to change in effective osmoles) than they are to osmolality (the number of dissociated particles per kilogram). Thus, effective osmoles (e.g. electrolytes and mannitol) matter more than non-effective osmoles (e.g. urea). Effective osmoles do not pass through cellular membranes; thus, they cause fluid to move from cell to interstitium and vice versa. Glucose is a relative osmole, as it can act as a non-effective osmole in the setting of insulin or in the brain. However, glucose can act as an effective osmole in the periphery in the absence of insulin because it cannot pass through the cell membrane without a glucose transporter.

Osmoreceptors respond to alterations in tonicity in the following fashion:

• When tonicity increases (e.g. after one ingests a high salt load - as I do on most nights. And yes, the title of this lesson is a derivation of Samin Nosrat’s excellent Salt Fat Acid Heat) the osmoreceptor cell shrinks as it loses water to the interstitium. This then signals to the posterior pituitary to secrete ADH.
• Conversely, decreased tonicity in the serum (i.e. if you just drank a liter of water to quench the above salt load-induced thirst) leads to swelling of the osmoreceptors and consequently the shutting off of ADH.

## Assessment of Blood Volume

### Baroreceptors

Baroreceptors are located in the arterial system (e.g. the carotid sinus and aortic arch) and respond to changes in Blood Pressure. Fluctuations in BP lead to a host of responses, including the release of ADH (aka vasopressin).

Very importantly, baroreceptors can trump the osmoreceptors and lead to the release of ADH even if the osmoreceptors are giving a different signal in the setting of hypotonicity. This makes sense, since if the body is hypotensive, we want to restore the body’s Mean Arterial Pressure at the expense of tonicity, if need be.

### Macula Densa

Another mechanism the body uses to regulate blood volume begins in the kidney at the Juxtaglomerular Apparatus (JGA). Decreased delivery of solute to the distal nephron and macula densa (e.g due to a drop in BP or Effective Arterial Volume) leads to release of renin by the JGA and activation of RAA system. Renin catalyzes angiotensinogen to Angiotensin I, which leads to upregulation of aldosterone. Aldosterone acts on the distal convoluted tubule and causes an upregulation of ENaC channels (Epithelium sodium channel), which results in increases in blood volume.

# Approach to Hyponatremia

## Take Home Points

When approaching a patient with Hyponatremia ask the following questions:

• Is the patient Hypotonic?
• Is the process ADH dependent?

## First Step

### Assess the Serum Osmolality

The normal serum Osmolality is between 275 - 290 mOsm/kg

• NORMAL Osmolality Hyponatremia (aka pseudohyponatremia)

• This is a less common finding; if you see it, think about the following etiologies:

• Hyperlipidemia, hyperproteinemia
• HIGH Osmolality Hyponatremia

• This occurs in 10-20% of hyponatremia (again less common), think:

• Hyperglycemia (most common of the hypertonic hyponatremia)

• Azotemia (high BUN)

• Urea is an ineffective osmole (it does not contribute to tonicity because it passes in and out of cells)
• Alcohol intoxication (EtOH is an ineffective osmole)
• TURP procedures: glycine infusion as nonconductive irrigation fluid
• LOW Osmolalilty Hyponatremia

• This if by far the most common situation and the one with the broadest DDx
• To work up Hypotonic Hyponatremia, go to the next step

## Next Step

### Take Home Points

• Evaluate the urine osmolality

• Evaluate the volume status of the patient

• Don’t simply rely on the Urine Sodium

• High urine osmoles and high urine sodium does not = SIADH

• You cannot distinguish between SIADH and hypovolemia because there are numerous situations where you can get “falsely elevated” urinary sodium with hyponatremia (see more below)

### Assess the Urine Osmolality

• You can use the urine specific gravity to estimate the urine osmoles

• Each point of urine specific gravity is ~ 30 urine mOsm/kg

• 1.020 is ~ 600 mOsm
• 1.010 is ~ 300 mOsm
• 1.005 is ~ 150 mOsm

Low Urine Osmolality (<100 - 150 mOsm/kg)

If a patient has LOW urine osmoles in the setting of hyponatremia, the patient is making dilute urine and thus ADH is NOT driving the process (i.e. the osmoreceptors turn off ADH production & consequenlty the urine is dilute)

• E.g. abnormal intake of water (primary polydipsia)
• Decreased solute intake (tea and toast diet)
• Infusion of hypotonic IVF
• Procedures with a high amount of irrigation (TURP)

High Urine Osmolality (>100 - 150 mOsm/kg)

If a patient has HIGH urine osmoles in the setting of hyponatremia, the patient is holding on to water despite the osmoreceptors negative feedback (thus something else is driving the ADH production).

The question you then have to ask is:

1. Is that ADH production appropriate (i.e. the baroreceptors are overriding the process to maintain BP) or
2. Is that ADH production inappropriate (i.e. the body is making ADH for no physiologic reason)

To determine if the ADH secretion is appropriate or not do not simply look at the urine sodium (as this can be confounded, see more below), but focus on trying to determine the Effective Arterial Volume (EAV)

• Low EAV = appropriate ADH production
• High/Nl EAV = inappropriate ADH production

### Assess the Effective Arterial Volume

Overview

If ADH is produced in settings of Low EAV, this is appropriate ADH production, as Baroreceptors override the osmoreceptors:

• Causes

• Volume loss

• Renal

• Diuretics
• Extra-renal

• Bleeding
• Decreased PO
• CHF, Cirrhosis, nephrotic syndrome

• All situations where there is low EAV

• You can still be total volume overloaded but have low effective arterial volume

If ADH is produced in settings of Normal or High EAV, this is inappropriate ADH production. This is because in these situations the osmoreceptors and baroreceptors are both signaling for decreased ADH, but ADH is produced nevertheless.

• Causes:

• Hypothyroidism
• Pearl: If the clinical picture looks like SIADH, you must rule out hypothyroidism and adrenal insufficiency because both can decrease the amount of water the kidney secretes

Methods to Assess EAV

Physical Exam

• Examine the patient, assess volume status (of note, the physical exam is still the best measurement). Assess skin turgor, JVP, peripheral edema.

• Hypervolemic

• Think: CHF, Renal Failure, Liver Failure, Pregnancy
• Euvolemic

• Hypovolemic

• Think: Volume depletion, Cerebral salt wasting, Thiazide Diuretics

Markers of GFR

• In low EAV (appropriate ADH) patients typically have markers of decrease GFR such as:

• Increased BUN and increased creatinine

• These values don’t have to be abnormal, just increased over the patient’s baseline
• Patients also have decreased fractional excretion of uric acid, and consequently higher uric acid, because they are not filtering as much

• In high/nl EAV (inappropriate ADH) patients typically are slightly volume expanded because they are holding on to more water than they need and thus they have markers of increased GFR such as:

• Decreased BUN and decreased creatinine

• slightly better than the patient’s baseline
• Patients also have increased fractional excretion of uric acid

• Often >12%

• This is better than FE urea

• Results in serum UA of less than 4 often

• Fractional excretion of uric acid

• In patients on diuretics, FE UA <12% had the best discriminant function to r/o SIADH
• Uric Acid is a marker of filtration, but also ADH, as ADH causes secretion of UA, thus if ADH is high you get more UA excreted

Markers of Aldosterone Production

• In low EAV (appropriate ADH) patients typically have markers of increased aldosterone such as:

• Decreased urine sodium (with the caveat of falsely elevated UNa as mentioned elsewhere)
• In high/nl EAV (inappropriate ADH) patients are typically slightly volume expanded because they are holding on to more water than they need; thus, they have markers of decreased aldosterone such as:

• Increased urine sodium (UNA > 30)
• Aldosterone causes you to absorb sodium, so low aldo = high urine sodium

Caveat for Urine Sodium

Don’t simply rely on urine Sodium. High urine osmoles and high urine sodium does not = SIADH. You cannot distinguish between SIADH and hypovolemia because there are numerous situations where one can get “falsely elevated” urinary sodium with hyponatremia. Don’t get confused with hypervolemic hyponatremia, as patients with CHF, cirrhosis, and nephrosis can have high urine sodium if they take their diuretics, but low sodium if they do not. Other causes of “falsely high” UNa:

• Metabolic alkalosis

• High Bicarb situations result in filtering of bicarb; thus, you need a cation to accompany the bicarb and sodium gets excreted
• ATN

• Post ATN diuresis d/t tubular defects
• Hypoaldosteronism

• Recent IVF

• Even a sodium avid kidney can be overwhelmed by a sodium load

### Response to Saline Infusion in SIADH

Overview

Although, it is not necessarily recommended to give a fluid challenge if you don’t know what’s causing the hyponatremia - as it can worsen the hyponatremia - the patient’s response to a fluid challenge can sometimes be informative. That said, a patient’s response to IVF in the setting of hyponatremia is complicated and depends on the urine osmolality. If a patient with hyponatremia is euvolemic or slightly volume expanded, as is the case with SIADH, they need the sodium, but their Aldosterone and Renin are shut off. Thus, they will dump the osmoles you just infused. The question is in what volume will they dump those osmoles (see chart below). If the urine output is low and concentrated (because they have a lot of aquaporins in the collecting duct secondary to ADH) they just retain the 1 liter of water. In that situation, the serum sodium will decrease. Therefore, it is a function of them being euvolemic and not needing the sodium. More specifically, this occurs if the urine osomes are greater than the plasma osomes (b/c they’re concentrating the urine).

This chart explains the effect of 1 liter of NS with 308 mOsm (154 mOsm Na and 154 mOsm Cl) This chart explains the effect of 1L of 3% NS (1026 mOsm/L (513 mEq Na + 513mEq Cl-) The ideas behind 3NS is that the patient will dump free water along with the solute and this will increase the serum Na. Thus you’re not really giving solute, you’re getting rid of free water.

Summary of EAV Assessment

# Case Review

MS is a 68 year-old male with metastatic NSCLC who presents to clinic for cycle 3 of front-line Ipi/Nivo. On review of systems he notes worsening fatigue over the last 1-2 weeks. In addition, he reports increased stooling the last few days as well as worsening rib pain at the site of a known metastasis. For this pain he takes MS-contin 45 mg BID with MS-IR 15 mg q3-4 hours for breakthrough. He notes taking more prn pain medications the last week as well. He is afebrile. Heart rate is 95. BP 110/76. RR 16 breaths/min.

His routine immunotherapy safety labs are notable for: From the above work up. MS’ labs are notable for hyponatremia with a mildly elevated TSH (probably not high enough to drive this process), signs of slight fluid expansion (low UA, high FE Uric Acid, slightly improved BUN/Creatinine). Looking at the remainder of his urine studies, the high urine osmoles means that ADH is active (i.e. there are aquaporins absorbing water in the collecting ducts thus concentrating the urine) and signs of low aldosterone (elevated Urine Sodium). This coupled with pain and narcotics, is suggestive of SIADH. Whether or not adrenal insufficiency is also playing a role has not been determined, but certainly could be, as two doses of Ipi/Nivo could result in adrenalitis/addison’s disease. So this must be considered.

I hope this brief lesson was helpful. Please provide any feedback you have (especially if there seems to be any inaccuracies in the material).