Physiology, Plasma Osmolality and Oncotic Pressure


The plasma osmolality and oncotic pressures in an organism can determine the direction of fluid movement within the system; therefore, the relative concentration of ions and protein in the solvent. As a result, we can observe the fluid movement results, which can typically manifest as edema, dehydration, changes in blood pressure, seizures, and changes in intracranial pressure. Furthermore, osmolality disturbances can be used as an indication for the use of intravenous fluids, which can be used to quickly alter the plasma osmolality and oncotic pressures in the vascular system.[1]

Osmolarity is the number of milliosmoles of solute per liter solution. This is different from osmolality (osm), which is the milliosmoles of solute per kilogram of solution.[2]

Water flows from a compartment of low osmolality to a compartment with high osmolality. This can only occur if the membrane between the two compartments is permeable to water. An example of this is when comparing plasma osm and interstitial fluid osm. At the cellular level, we can compare the intracellular osm to the extracellular matrix. In this system, the phospholipid bilayer serves as the semipermeable membrane through which water can flow. 

Issues of Concern

Osmolarity is the number of osmoles of solute per liter solution, which is different than osmolality, which is the osmoles of solute per kilogram of solution. Osmoles are different from moles in that it takes into account the dissociation of cations and anions in water.

For example:

If  1 kg of water gets added to 1 mole of NaCl salt, then we observe the salt separate into its ions. As a result, there will be 1 mol of Na and 1 mol of Cl. Restated, this means there are 2 osmoles of ions in 1 kg of water, which results in a solution with an osmolality of 2osm/1kg.

Components that contribute to plasma osmolality:

Any solute in the plasma will contribute to the osmolality. Examples include proteins, ions, urea, and sugars. The relative osmoles of each are summed to give the total osmolality per 1 kg of plasma.

How to calculate plasma osmolality?

The Dorwart and Chalmers formula is widely used to estimate plasma osmolality. It utilizes the basic metabolic panel (BMP) to measure sodium, glucose, and blood urea nitrogen.

Serum Osmolality=1.86 (Na)+(Glucose)/18 +(BUN)/2.8+9

Normal serum osmolality ranges from 275 to 295 mmol/kg.[3][4]


Water flows from a compartment of low osmolality to a compartment with high osmolality; this can only occur if the membrane in between the two compartments is permeable to water. An example of this is when comparing plasma osmolality and intracellular fluid osmolality.

For example, if a cell is in a relatively hyperosmolar solution, fluid will diffuse out of the cell towards the highly concentrated environment to reach homeostasis. As a result, the cell will shrivel.

Organ Systems Involved

Posterior Pituitary/Renal Systems

  • The posterior pituitary and renal organ systems are crucial to maintaining appropriate plasma osmolality. Although albumin contributes to the oncotic pressure, it only makes up to 5% of the plasma, which means it has a lesser effect. Albumin gets formed in the liver and, in pathologic processes, can be underproduced or lost in the extracellular matrix and urine. See the Mechanism section below for details. 

Renin Angiotensin Aldosterone System (RAAS) 

The RAAS system is crucial because it maintains extracellular volume, sodium concentration, and blood pressure. It does this by secreting a hormone called renin by the kidneys. Renin then circulates to the adrenal glands, and downstream effects occur. See the Mechanism section below for details. 


The function of albumin in the serum is multifaceted. Albumin is a protein that can carry lipid-soluble substances such as thyroid hormone, sex hormones, and triglycerides. It also serves a major role in contributing to the plasma oncotic pressure as it can comprise up to 50% of all circulating serum proteins.[5] It has been used as an agent to expand intravascular volume and control both intracranial pressure and intraocular pressure. 

Ions and glucose contribute to 95% of the osmotic pressure as they are the most abundant in the serum. Osmolality, and subsequently, osmotic pressure, is not affected by the size or charge of the solutes but only the number of solutes. 

The function of osmolality and oncotic pressure is to keep the ions suspended in solution at optimal concentrations, which are set by the cells in the body, which helps create ion gradients leading to action potential generation, muscle contractions, and adequate glucose supply in the serum. 


Posterior Pituitary/Renal Systems

  • The dehydrated state, an example of hyperosmolar plasma: When the body is dehydrated, there is less fluid in the plasma, making the plasma more concentrated. As a result of an increase in plasma osmolality, cells begin to have water flow out, and cells shrivel because they are now hypoosmolar compared to the surroundings. Neurons in the organum vasculosum terminalis and supraoptic and paraventricular nuclei of the thalamus act as osmoreceptors. When these neurons experience the stretch and negative pressure suction, which manifests as they shrink, they depolarize via transient receptor potential vanilloid (TRVP) cation channels. These channels increase the charge inside the cells and cause depolarization, which results in signaling the posterior pituitary to release antidiuretic hormone (ADH). ADH works at the renal collecting ducts and principal cells via the V2 receptors, which induce an increase in the intracellular cAMP. The increase in cAMP induces aquaporin two-channel insertion in the apical side of the plasma membrane, which creates a channel where water can be reabsorbed from the filtrate, leading to a reduced plasma osmolality and thus achieving homeostasis.[6]
  • The Hypo-Osmolar state: In this state, there is no stretch or negative pressure suction created in the cells responsible for osmoregulation. This state results in hyperpolarization of the cell and decreases ADH release from the posterior pituitary, allowing the kidneys to excrete more urine and increase the plasma osmolality back to the physiologic set point.

Renin Angiotensin Aldosterone System (RAAS) 

Macula densa cells are present in the wall of the distal convoluted tubule of the kidney; their primary function is to sense the concentration of sodium chloride in the filtrate. Only two physiologic scenarios exist: 

  1. The filtrate has a decreased NaCl concentration: The macula densa senses this, and it signals for the dilation of the afferent renal arterioles, which increases the hydrostatic pressure and increases the NaCl concentration. The macula densa also secretes prostaglandins, which signal the juxtaglomerular cells to release renin. Renin functions to convert angiotensinogen, made in the liver, to angiotensin 1 in the vasculature. Angiotensin 1 is inactive and will be converted to angiotensin 2 in the lungs by the angiotensin-converting enzyme (ACE).  
    • Effects of angiotensin 2
      1. Signals the Posterior Pituitary to release ADH. See the mechanism above. 
      2. Contraction of vascular myocytes results in increased blood pressure, resulting in higher hydrostatic pressure, which increases filtrate production and filtrates NaCl concentration. 
      3. Angiotensin 2 increases sympathetic activity.
      4. Angiotensin 2 increases tubular NaCl reabsorption and Potassium and water excretion - the net result is an increased plasma NaCl concentration, which increases plasma osmolality. 
  2. The filtrate has an increased NaCl concentration: In this scenario, the cells of the macula densa decrease their secretion of prostaglandins, which inhibits the RAAS pathway. See point 1 above.[7]

Related Testing

Physical Exam

  • Skin turgor: An indicator of dehydration, skin turgor is assessed by pinching the skin between the thumb and forefinger and then releasing it. The time it takes for the skin to return to its normal contour can indicate dehydration and solute depletion.[8]
  • Blood pressure: In dehydration, the total volume of water becomes reduced, and therefore, low blood pressure can occur. There may also be a reflex tachycardia present. 
  • Examination of mucous membranes: Dehydration can manifest as dry mucous membranes. 

Laboratory Tests 

  • CBC with Differentials: The hematocrit is a measure of blood concentration, and if it is increased or decreased, it indicates the fluid status is in the vasculature. 
  • Basic Metabolic Panel and Arterial Blood Gas: This will provide the clinician with information regarding the patient's acid-base status and the concentrations of the major ions that contribute to plasma osmolality. 
  • Urinalysis: The clinician will be able to see the number of electrolytes in the urine and the proteins, which can help identify nephrotic syndromes. 


  • Water deprivation test: The patient will undergo fluid deprivation, and the entire volume of urine will be collected, which is then analyzed for osmolality and electrolytes, and then there will be a challenge ADH. The effects of subsequent urine collection will also undergo analysis, which will determine the cause of diabetes insipidus in the patient.[9]


Hypoosmolar Plasma: The pathologies decrease the osmolality of plasma

Psychogenic polydipsia: This is a psychiatric condition characterized as self-induced water intoxication. There are three phases to the disease process. First, there is a polyuria and polydipsia phase in which the patient is thirsty and has excessive urine output. The second phase appears as hyponatremia in the blood as the kidney cannot excrete all the water, which results in the hypo-osmolar plasma. The final phase consists of the sequelae from water intoxication and hyponatremia, including delirium, ataxia, seizures, nausea, and vomiting. Death may result if the electrolyte abnormalities are not corrected promptly. One must be aware that central pontine myelinolysis as deadly sequelae of quick sodium correction.[10]

Syndrome of inappropriate ADH (SIADH): This condition occurs when the human body produces and secretes an excessive amount of ADH via CNS tumors, lung cancers, and medications, resulting in the kidneys reabsorbing too much water and manifests as a dilutional hypo osmolar plasma and hypertension. Treatment can involve vasopressin receptor blockers such as tolvaptan, removing cancer, creating the ADH, removing the medications inducing SIADH, and therapy with hypertonic saline.[11]

Nephrotic Syndrome: This general term describes disease processes that result in proteinuria (over 3grams/day), accompanied by hypoalbuminemia, hypertriglyceridemia, and a hypercoagulable state. The characteristic proteinuria occurs when there is damage to the glomerular basement membrane or podocyte foot processes, which results in decreased plasma osmolality and oncotic pressure. Edema is frequently a presenting sign because there is not enough oncotic pressure to draw water into the vasculature from the extracellular matrix.[12]

Liver Cirrhosis: Albumin production occurs in the liver and is then secreted out of the hepatocytes and into the extravascular space and then returned to the blood via lymphatic drainage and directly released into a blood vessel, the space of Disse. When the liver incurs damage, it is unable to produce albumin and results in a hypoosmolar plasma.[13]

Hyper Osmolar States:

Diabetes Insipidous (DI): This disease demonstrates excretion of a large volume of urine, which results in concentrated, hyperosmolar plasma (greater than 300 mOsm/liter) and dilute, hypoosmolar urine (less than 300mOsm/liter). It can result from central damage to the neurons which are responsible for the creation of ADH. Examples of sources of damage include infarcts, germinomas, Langerhans histiocytosis, and sarcoidosis. Another cause for DI is end-organ resistance. Although ADH is present, the patient will have a genetic mutation in the vasopressin receptors, which render the hormone ineffective.[14]

Dehydration: see above.

Clinical Significance

There are many clinical implications of alterations to the plasma osmolar state and the oncotic pressure.

Clinicians can monitor the following:

  • Change in intracranial pressure
  • Look for edema
  • Seizures

Pathologies include (but are not limited to): 

  • Diabetes insipidus: A disease characterized by excretion of a large volume of urine, resulting in concentrated, hyperosmolar plasma (over 300 mOsm/liter) and dilute, hypoosmolar urine (less than 300mOsm/liter). 
  • Liver Cirrhosis: This is the final result of various hepatic insults which render the liver damaged, fibrosed, and ineffective at completing its functions. A few of its functions include synthesizing proteins, clearing bilirubin, and metabolizing drugs for excretion.[15]
  • Congestive Heart Failure: This is a pathology characterized by the dilatation and hypertrophy of the left ventricle of the heart, which prevents forward blood flow, which results in decreased end-organ perfusion and increases hydrostatic oncotic pressure, which leads to hepatic congestion and pulmonary edema. Decreased renal perfusion will activate the RAAS system (see above) and alter the composition of solutes in the blood and urine.[16]
  • Dehydration: Acutely, this will cause a hypertonic state as discussed above in the "Mechanism" section. 
  • Kwashiorkor: This disease presents with the lack of amino acids in an individual's diet, due to severe malnutrition. The liver is unable to synthesize proteins because of the lack of amino acids, and this results in decreased plasma oncotic pressure.
  • Nephrotic Syndrome: An insult to the renal system results in the spilling of proteins into the urine resulting in hypo-osmolar blood plasma.
  • Psychogenic Polydipsia: See above in the "Pathophysiology" section. 

It is essential to consider all differential diagnoses; ultimately, further lab testing will be necessary to reach a diagnosis. 

Article Details

Article Author

Maulik M. Shah

Article Editor:

Pujyitha Mandiga


10/9/2021 10:32:01 AM



Kok B,Karvellas CJ, Management of Cerebral Edema in Acute Liver Failure. Seminars in respiratory and critical care medicine. 2017 Dec;     [PubMed PMID: 29262439]


Rasouli M, Basic concepts and practical equations on osmolality: Biochemical approach. Clinical biochemistry. 2016 Aug;     [PubMed PMID: 27343561]


Dorwart WV,Chalmers L, Comparison of methods for calculating serum osmolality form chemical concentrations, and the prognostic value of such calculations. Clinical chemistry. 1975 Feb;     [PubMed PMID: 1112025]


Gennari FJ, Current concepts. Serum osmolality. Uses and limitations. The New England journal of medicine. 1984 Jan 12;     [PubMed PMID: 6361557]


Valerio C,Theocharidou E,Davenport A,Agarwal B, Human albumin solution for patients with cirrhosis and acute on chronic liver failure: Beyond simple volume expansion. World journal of hepatology. 2016 Mar 8;     [PubMed PMID: 26981172]


Danziger J,Zeidel ML, Osmotic homeostasis. Clinical journal of the American Society of Nephrology : CJASN. 2015 May 7;     [PubMed PMID: 25078421]


Barajas L, Anatomy of the juxtaglomerular apparatus. The American journal of physiology. 1979 Nov;     [PubMed PMID: 386808]


SKIN TURGOR in dehydration. Nutrition reviews. 1957 Nov;     [PubMed PMID: 13484138]


Nigro N,Grossmann M,Chiang C,Inder WJ, Polyuria-polydipsia syndrome: a diagnostic challenge. Internal medicine journal. 2018 Mar     [PubMed PMID: 28967192]


Bhatia MS,Goyal A,Saha R,Doval N, Psychogenic Polydipsia - Management Challenges. Shanghai archives of psychiatry. 2017 Jun 25;     [PubMed PMID: 28904515]


Peri A,Grohé C,Berardi R,Runkle I, SIADH: differential diagnosis and clinical management. Endocrine. 2017 Jan;     [PubMed PMID: 27025948]


Liebeskind DS, Nephrotic syndrome. Handbook of clinical neurology. 2014;     [PubMed PMID: 24365309]


Gatta A,Verardo A,Bolognesi M, Hypoalbuminemia. Internal and emergency medicine. 2012 Oct;     [PubMed PMID: 23073857]


Di Iorgi N,Napoli F,Allegri AE,Olivieri I,Bertelli E,Gallizia A,Rossi A,Maghnie M, Diabetes insipidus--diagnosis and management. Hormone research in paediatrics. 2012;     [PubMed PMID: 22433947]


Zhou WC,Zhang QB,Qiao L, Pathogenesis of liver cirrhosis. World journal of gastroenterology. 2014 Jun 21     [PubMed PMID: 24966602]


Lee CS,Auld J, Heart Failure: A Primer. Critical care nursing clinics of North America. 2015 Dec     [PubMed PMID: 26567488]