Lec 58. Water Balance and Control of Body Fluid Osmolality, Dr. Yuri Zagvazdin - FS.pdf

Daily balance of water intake, production and output Intake and production ml/day Output ml/day intake 2,300 urine 1,500 metabolic production 200 sweat 100 feces 200 skin 350 lungs 350 Total 2,500 Total 2,500 1. Antidiuretic Hormone – ADH or arginine vasopressin (AVP) Retains...

Daily balance of water intake, production and output Intake and production ml/day Output ml/day intake 2,300 urine 1,500 metabolic production 200 sweat 100 feces 200 skin 350 lungs 350 Total 2,500 Total 2,500 1. Antidiuretic Hormone – ADH or arginine vasopressin (AVP) Retains water ADH increases: 1. H2O permeability* 2. Urea permeability** 3. Na+ reabsorption*** * late distal tubule and collecting duct ** inner medullary collecting duct ***thick ascending limb of Henle loop Body Fluid Osmolarity H2 O ECF (blood) Na+ 2. Renin – angiotensinaldosterone system Body Fluid Volume Retains Na+ ADH and RAAS conserve body fluids minimizing fluid loss 3. Atrial Natriuretic Peptide (ANP) increases H2O and Na+ excretion The role of ANP: decrease in fluid volume and osmolarity From the very beginning to the very end our life depends on fluids… Loss of fluid is a major cause of children death! “Each year, an estimated 2.5 billion cases of diarrhoea occur among children under five years of age... …diarrhoea remains the second most common cause of death among children under five globally” Source: The United Nation s Children’s Fund (UNICEF)/World Health Organization (WHO) WHO Library Cataloging – in- Publication Data Diarrhoea: Why children are still dying and what can be done, p. 5 Health authorities’ leadership reduces cholera deaths in Haiti Ag Ayoya, Mohamed, Lancet, The, Volume 380, Issue 9840, 473-474 Copyright © 2012 Niall Carson/PA Archive/Press Association Images A Hideous Milestone In The 21st Century': Cholera Cases In Yemen Pass 1 Million December 21, 2017 11:12 AM ET NPR https://www.npr.org/sections/thetwo-way/2017/12/21/572544447/a-hideous-milestone-in-the-21st-century-cholera-cases-in-yemen-pass-1-million An adolescent girl with severe dehydration from cholera. Characteristic features include obtundation (i.e. diminished alertness), sunken eyes, poor skin turgor and “tenting” of the abdominal skin and subcutaneous tissues after firmly pinching the abdomen. Cholera Shirley, Debbie-Ann T., Feigin and Cherry's Textbook of Pediatric Infectious Diseases, Chapter 117, 1548-1555.e2 Copyright © 2014 Copyright © 2014, 2009, 2004, 1998, 1992, 1987, 1981 by Saunders, an imprint of Elsevier Inc. Fluid and Electrolyte Imbalances ! Normally both extra- and intracellular fluids (ECF and ICF) have the same osmolarity close to 280-290 mOsM (even though they are composed of different ions and other solutes) Imbalances: 6 types - either addition or loss of isotonic, hypotonic (more water than salt) or hypertonic (more salt than water) fluid The initial changes always occur in the extracellular fluid - ECF Additions = Volume Expansion (ECF volume always increases!) 1. Gain of isotonic fluid Causes – administration of large volume of isotonic NaCl (normal saline 150 mmol/L) ECF ICF ECF ECF ICF Change - increase in ECF volume, no change in ECF osmolarity No fluid shift between compartments Effect: an increase only in ECF volume (rectangle shown by the red dashed line) Darrow - Yannet Diagrams 3 step approach: 1. Identify ECF volume change; 2. Find corresponding change in ECF osmolarity; 3. Decide on ICF osmolarity and volume changes Initial Normal State = bold line for both compartments ECF ICF C h a n g e Gain of Hypotonic Fluid (gain of water) Causes: water retention (SIADH) or infusion of hypotonic solution Changes: ECF volume up Decrease in ECF osmolarity Fluid shift from ECF to ICF, ICF volume up, ICF osmolarity down ECF ICF Gain of Hypertonic Fluid (gain of salt) Causes: infusion of hypertonic saline, hyperaldosteronism, etc. Changes: ECF volume up Increase in ECF osmolarity Fluid shift from ICF to ECF, ICF osmolarity up, ICF volume down ECF ICF ICF ECF increase Volume Change O s M ICF decrease Additions of Fluids Note an increase in Na+ excretion and a decrease in urine osmolarity after gain of water (hypotonic solution) Hypertonic saline Water Isotonic saline ECF volume ICF volume 0 Plasma osmolarity 0 Plasma Na+ 0 Urine Na+ excretion Urine osmolarity 0 Volume Contraction = Fluid Losses (ECF volume decreases) Loss of isotonic fluid Causes: hemorrhage, mild GI loses ECF ICF Changes: ECF volume down, no change in osmolarity No shift of fluid between compartments Effect: only ECF volume contraction ECF (red dashed line) ICF Volume Contraction = Fluid Losses Loss of hypotonic fluid (mainly loss of water) ECF ICF Causes: water deficit, diabetes mellitus and insipidus, excessive sweating Changes: ECF osmolarity increases due to predominant loss of water. Water shift from ICF to ECF Osmolarity ECF ICF ICF Volume (which does not compensate a decrease in ECF volume) Effect: ECF and ICF volume down, ECF and ICF osmolarity up Volume Contraction = Fluid Losses Loss of hypertonic fluid (mainly loss of salt) ECF ICF Causes: loss of NaCl with urine, insufficient renin secretion, adrenal insufficiency - Addison’s disease Changes: ECF volume contracts, and ECF osmolarity decreases due to predominant loss of salt. Water shifts from ECF to ICF Osmolarity ECF ICF ICF Volume Effect: ICF volume up, ECF volume down, ECF and ICF osmolarity down Up to 30% of students miss the right answer! Urine Concentration and Dilution 1. Kidneys maintain ECF osmolarity within a narrow range by regulating water excretion: a. when water intake is high, a large volume of diluted urine is produced – diuresis b. when water intake is low, our body conserves H2O, and a small volume of concentrated urine is formed – antidiuresis (This is physiological definition; medical dictionaries define antidiuresis as reduction or suppression of urine excretion, while diuresis is defined as increased excretion of urine) Urine Concentration and Dilution Plasma has osmolarity of around 290 mOsM when it enters the nephron. Empirical formula: plasma osmolality (mOsm/kg) = 2([Na+]) + ([BUN]/2.8) + ([Glucose]/18) Urine osmolarity can range from 50 mOsM (diuresis) to 1200 mOsM (antidiuresis) . Urine volume varies between 0.5 to 20 L per day, it depends on plasma ADH. ADH is produced in the hypothalamus and released in capillaries of the pituitary gland Osmoreceptors, specialized neurons in the hypothalamus, are activated by an increase in ECF osmolarity and stimulate ADH production by neurons of the supraoptic and paraventricular nuclei (another hormone, oxytocin, is also produced in these nuclei) ADH is released in the blood by axonal terminals in the posterior lobe of the pituitary gland Control of Body Fluid Osmolality and Volume Koeppen, Bruce M., MD, PhD, Berne and Levy Physiology, 35, 623-646 Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rights reserved. Circulation Only substantial decrease in blood pressure can stimulate ADH release Production of ADH in the Hypothalamus and its Release in the Hypophysis Hypothalamus, Pituitary, Sleep, and Thalamus Jones, H. Royden, MD, Netter Collection of Medical Illustrations: Brain, Section 5, 111-145 Copyright © 2013 Copyright © 2013 by Saunders, an imprint of Elsevier Inc. Mechanism of ADH action = Insertion of Aquaporins Vasopressin (AVP) binds to the basolateral membrane receptor (V2). c-AMP is activated and AQP2 is inserted on the apical membrane. AC, adenylyl cyclase; AP1, activator protein 1; CRE, cAMP response element. Cellular mechanism of AVP action in the collecting tubules and ducts. Urine Concentration and Dilution Giebisch, Gerhard, Medical Physiology, Chapter 38, 806-820.e2 Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved. Water Reabsorption in Nephron and ADH No ADH 70% H2O High ADH 100 120 150 500 70% H2O H2 O only if ADH is 300 present 300 300 Why filtrate osmolarity in the thick ascending limb is lower with high ADH? H2 O only if ADH is present 500 15% H2O 80 300 120 200 Na+K+2Cl- 600 600 15% H2O 800 75 mOsm Diuresis – hyposmotic or diluted urine 1200 Antidiuresis – hypersmotic or concentrated urine 1200 mOsM 1. Antidiuretic Hormone – ADH or arginine vasopressin (AVP) Retains water ADH increases: 1. H2O permeability* 2. Urea permeability** 3. Na+ reabsorption*** * late distal tubule and collecting duct ** inner medullary collecting duct ***thick ascending limb of Henle loop Body Fluid Osmolarity H2 O ECF (blood) Na+ 2. Renin – angiotensinaldosterone system Body Fluid Volume Retains Na+ ADH and RAAS conserve body fluids minimizing fluid loss 3. Atrial Natriuretic Peptide (ANP) increases H2O and Na+ excretion The role of ANP: decrease in fluid volume and osmolarity ADH helps to conserve water, increasing its reabsorption (lower curve. Numerical values indicate the approximate volumes in milliliters per minute) Early distal Changes in osmolarity of the filtrate as it passes through the different tubular segments in the presence of high levels of ADH (upper curve) and in the absence of ADH Antidiuresis: H2O loss 0.2 ml/min Diuresis: H2O loss 20 ml/min Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 29, 371-387 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. ADH increases water reabsorption and filtrate osmolarity largely in the collecting duct, but it also has an effect in the loop of Henle. ADH and Water Reabsorption in the Nephron No ADH 70% H2O High ADH 100 120 H2 O only if ADH is 300 present 300 150 300 500 70% H2O H2 O only if ADH is present 500 15% H2O 80 300 120 200 Na+K+2Cl- 600 600 15% H2O 800 75 mOsm Diuresis – hyposmotic or diluted urine Why osmolarity in the inner medulla increases with ADH despite increased water reabsorption? 1200 Antidiuresis – hypersmotic or concentrated urine 1200 mOsM 1. Antidiuretic Hormone – ADH or arginine vasopressin (AVP) Retains water ADH increases: 1. H2O permeability* 2. Urea permeability** 3. Na+ reabsorption*** * late distal tubule and collecting duct ** inner medullary collecting duct ***thick ascending limb of Henle loop Body Fluid Osmolarity H2 O ECF (blood) Na+ 2. Renin – angiotensinaldosterone system Body Fluid Volume Retains Na+ ADH and RAAS conserve body fluids minimizing fluid loss 3. Atrial Natriuretic Peptide (ANP) increases H2O and Na+ excretion The role of ANP: decrease in fluid volume and osmolarity Urea helps to reabsorb more water urea Cortex Na+K+2ClOuter medulla Urea is produced in the liver (protein metabolism). Filtered urea is reabsorbed regardless of ADH almost exclusively in the proximal tubule. urea only if ADH is present Inner medulla ADH enables H2O reabsorption in the distal tubule, cortical and medullary collecting duct. As a result, urea concentration rises and reaches its maximum at the level of inner medulla. At this point, ADH enables urea diffusion into the interstitium, which contributes to the build up of cortico-medullary osmotic gradient and an increase in water reabsorption. Cellular mechanism of vasopressin action in the inner medullary part of the collecting duct Vasopressin molecules (AVP) binds to V2 receptors (V2R) on the basolateral membrane of renal tubular epithelial cells and activates G proteins that initiate a cascade (cAMP, PKA) resulting in aquaporin 2 (AQP2) and urea transporter A1 (UT-A1) activation allowing urea and water reabsorption. Disorders of Water Metabolism Berl, Tomas, Comprehensive Clinical Nephrology, 8, 94-110.e1 Copyright © 2019 © 2019, Elsevier Inc. All rights reserved. Cortex H2O 400 mOsM Collecting duct 320 mOsm H2O 800 mOsM H2O 1100 mOsM H2O 1200 mOsm Urine 600 mOsM Vasa recta Urea, 900 Na+, mOsM K+, etc. 1200 mOsM Inner medulla Water is driven out of the renal tubule by osmosis and is carried away from the interstitium via the peritubular capillaries and (or) vasa recta. Urea and other solutes diffuse into the vasa recta and draw water back into circulation. Eventually, this influx of water returns blood osmolarity to ~ 300 mOsM at the cortical level. Vasa recta removes electrolytes, urea and water from the interstitium 50% of urea is reabsorbed Electrolytes and urea diffuse from the interstitium into the descending vasa recta down the concentration Cortex gradient. Influx of urea in the inner medulla helps to maximize plasma osmolarity (1200 mOsM) and water Ascending vasa recta uptake by osmosis into the ascending vasa recta. High Outer oncotic pressure also adds Medulla to reabsorption. in the proximal tubule 400 500 *Urea recycling (passage from the medullary collecting duct into the interstitium, and then into the descending and ascending limb) helps to maintain high osmolarity in the inner medulla * Inner Medulla What is % of urea excretion? A D H E How the Kidneys Handle Various Substances (average values) Substance Amount filtered per day Amount excreted per day Percent reabsorbed Water , L 180 1.8 99.0 Sodium, g 630 3.2 99.5 Bicarbonate 264 2.6 99.0 Glucose, g 180 0 100 Urea, g 54 27 50 Potassium, g 28 3.9 86 Phosphate, g 18 2.2 88 Inulin * * 0 * depends on the amount injected 60%? Yes, but vasopressin increases reabsorption of water and urea decreasing urine output Source: Bankir L et al., 2013 Vasopressin: A novel target for the prevention and retardation of kidney disease? Nat. Rev. Nephrol. 9, 223–239 Water balance: homeostatic changes in urine volume and osmolarity H2O deprivation H2O excess Plasma osmolarity Plasma osmolarity Osmoreceptor activity in the hypothalamus ADH secretion into blood H2O permeability and reabsorption in the late distal tubule and collecting duct Urine osmolarity volume Plasma osmolarity towards normal Osmoreceptor activity in the hypothalamus Thirst H2O drinking ADH secretion into blood H2O permeability and reabsorption in the late distal tubule and collecting duct Urine osmolarity volume Plasma osmolarity towards normal Thirst H2 O drinking Water diuresis in a human after ingestion of 1 liter of water. After water ingestion osmolarity of urine decreases and it becomes hyposmotic (i. e. urine osmolarity is less than plasma osmolarity), while urine flow rate increases, prompting excretion of a large volume of dilute urine. The total amount of solute excreted by the kidneys remains relatively constant, i.e. ADH helps to excrete mostly water. This response of the kidneys prevents plasma osmolarity from decreasing markedly during excessive water ingestion. In some cases, however, this homeostatic response is compromised (e.g. water intoxication). Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 29, 371-387 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. Is blood pressure decrease the most efficient stimulus for ADH release? Regulation of ADH secretion An increase in ADH release is stimulated by loss of bodily fluids or a decrease in water intake Plasma Osmolarity (mOsm) Increase in plasma osmolarity (decreased water intake) = major stimulus for ADH secretion - most sensitive (1-2% change) - detected by osmoreceptors in the hypothalamus Decrease in ECF volume or blood pressure not very sensitive (10% change) Other regulators of ADH secretion: Increased ADH secretion: a. angiotensin II (hemorrhage, hypotension etc.) b. stress and heat c. pain, nausea and vomiting Decreased ADH secretion: a. atrial natriuretic peptide b. cold temperature c. ethanol ADH Diseases of water balance related to abnormalities in ADH production ? ADH deficiency – Diabetes insipidus Symptoms - very large volume of dilute urine – diuresis, polyuria (passage of large volumes of dilute urine, in excess of 2 l/m2/24 h or approximately 40 ml/kg/24) - constant sensation of thirst, desire for drinking – polydipsia (does not increase blood volume or pressure) - even short lasting cut in water supply may result in severe problems (e.g. hypovolemic shock) Diabetes? Diabetes? Mellitus Insipidus? Diseases of water balance related to abnormalities in ADH production ADH deficiency – Diabetes insipidus Symptoms - very large volume of dilute urine – diuresis, polyuria - constant sensation of thirst*, voluminous drinking (does not increase blood volume or pressure) - even short lasting cut in water supply may result in severe problems (e.g. hypovolemic shock) - fluid intake reduction does not result in substantial increase in urine concentration Major consequence – Water loss and high plasma osmolarity! (Na+ is not lost) Constant sensation of thirst* and excessive drinking are also features of another illness – polydipsia (called primary or psychogenic polydipsia). Water deprivation decreases volume of urine in patients with polydipsia, but not so in patients with diabetes insipidus. Two Types of Diabetes Insipidus 1. central (neurogenic, hypothalamic) – insufficient ADH release from the hypothalamus - plasma ADH – low Causes: head injury, CNS infection, stroke in the pituitary gland 2. nephrogenic - decreased renal response to ADH due to abnormal vasopressin receptors or aquaporins in the renal tubule A typical ‘historical’ picture of a dehydrated and malnourished infant (a) with nephrogenic diabetes insipidus, looking healthy after rehydration and improved nutrition (b). This infant died a few years later due to repeated episodes of dehydration. This report was published years before the identification of the AVPR2 gene. The mother and sister both had the W71X mutation. Photograph is Fig. 2 of Perry et al. [35] reproduced with permission from the New England Journal of Medicine, 1967; 276. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant) Bichet, Daniel G., MD, Best Practice & Research: Clinical Endocrinology & Metabolism, Volume 30, Issue 2, 263-276 Copyright © 2016 Elsevier Ltd Mechanism of ADH action = insertion of aquaporins, specialized water channels or pores, in the distal nephron Vasopressin (AVP) binds to the basolateral membrane receptor (V2). c-AMP is activated and AQP2 is inserted on the apical membrane. Cellular mechanism of AVP action in the collecting tubules and ducts. URINE CONCENTRATION AND DILUTION Giebisch, Gerhard, Medical Physiology, CHAPTER 38, 835-850 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Two Types of Diabetes insipidus 1. central (neurogenic, hypothalamic) – insufficient ADH release from the hypothalamus - plasma ADH – low Causes: head injury, CNS infection, stroke in the pituitary gland, tumor such as craniopharyngioma 2. nephrogenic - decreased renal response to ADH due to abnormalities with vasopressin receptors or aquaporins in the renal tubule - plasma ADH high (or normal with plentiful water intake) Causes: kidney disease, drugs (lithium, amphotericin B), hereditary Desmopressin (DDAVP), a synthetic analog of ADH (AVP), is used to treat central diabetes insipidus. Patients with pure nephrogenic diabetes insipidus do not respond to DDAVP. Diabetes Insipidus Rittig, Soren, Genetic Diagnosis of Endocrine Disorders, Chapter 6, 67-73 Copyright © 2010 Copyright © 2010 Elsevier Inc. All rights reserved. Can diabetes insipidus and diabetes mellitus coexist? ADH excess – syndrome of inappropriate ADH secretion (SIADH) Abnormally high ADH release from hypothalamus (and other cites) Major consequence - water retention! - low plasma osmolarity and plasma Na+ (hyponatremia – severe cases “water intoxication”) - high urine osmolarity (paradoxically, Na+ excretion with urine increases despite its low plasma level) Why? 1. Antidiuretic Hormone – ADH or arginine vasopressin (AVP) Retains water ADH increases: 1. H2O permeability* 2. Urea permeability** 3. Na+ reabsorption*** * late distal tubule and collecting duct ** inner medullary collecting duct ***thick ascending limb of Henle loop Body Fluid Osmolarity H2 O ECF (blood) Na+ 2. Renin – angiotensinaldosterone system Body Fluid Volume Retains Na+ Role of ADH and RAAS – to conserve body fluids 3. Atrial Natriuretic Peptide (ANP) increases H2O and Na+ excretion The role of ANP: decrease in fluid volume and osmolarity ADH excess – syndrome of inappropriate ADH secretion (SIADH) Abnormally high ADH release from hypothalamus (and other cites) Major consequence - water retention! - low plasma osmolarity and plasma Na+ (hyponatremia – severe cases “water intoxication”) - high urine osmolarity (paradoxically, Na+ excretion with urine increases despite its low plasma level) Causes: lung diseases (tumor, tuberculosis, pneumonia) CNS diseases (tumor, trauma, infection), drugs (3,4 methylendioxymethamphetamine “ecstasy”, carbamazepine) Possible hazards of ecstasy and high water intake Ecstasy gained popularity at dances called “raves”. Intense thirst is one striking effect of this drug. TV News recently reported the death of a 16 –year old girl who drank herself into fatal hyponatremia (due to water intoxication) after her first try of ecstasy. A similarly sad story, also of a 16 year old girl and also, apparently, a first taker of ecstasy, was reported in the New York Times on February 12, 2002. Her breathing stopped before she was taken to a hospital. MJA 1997; 166: 136 Hyponatraemia and death after "ecstasy" ingestion M J A Parr, H M Low and P Botterill , Intensive Therapy Unit, Sydney A 15-year-old girl collapsed with respiratory arrest after taking "ecstasy" at a "dance party". She presented to hospital with hyponatraemia and cerebral oedema and later died. We postulate that ingestion of large amounts of water contributed to the hyponatraemia. Dtsch Med Wochenschr. 2001 Jul 13;126(28-29):809-11 Fatal brain edema after ingestion of ecstasy and benzylpiperazine. Balmelli C, Kupferschmidt H, Rentsch K, Schneemann M Medizinische Klinik B, Universitätsspital Zürich. A 23-year-old woman was hospitalized with headache, malaise and somnolence 7 hours after ingestion of ecstasy (MDMA), and large volume of fluids The patient had severe hypervolaemic hypotonic hyponatremia. 40 minutes after admission she seized twice and was intubated. Brain CT scan showed massive cerebral edema with beginning tonsillar herniation. Serum sodium concentration returned to normal within 38 hours, but the patient deteriorated neurologically with increasing tonsillar herniation detected in a second brain CT scan. The patient died 57 hours after admission. Lakartidningen. 2001 Feb 21;98(8):817-9. Young woman dies of water intoxication after taking one tablet of ecstasy. [Article in Swedish] B L Humble M. Low doses of ecstasy (3,4-methylenedioxymethamphetamine--MDMA) may induce life-threatening conditions, such as hyperthermia and water intoxication. These lethal states are rarely due to overdose, and young women seem to be at particular risk. This is a case report of a 20-year-old previously healthy Swedish girl. She died of water intoxication and cerebral edema approximately 24 hours after ingestion of one tablet of "ecstasy" at a rave club in Amsterdam. Clinical findings and laboratory data suggested a syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by MDMA in combination with excessive intake of water. CONCLUSION: Even low doses of MDMA and fluids may lead to a serious outcome. The only risk factor is female gender. Water Intoxication Excessive sweating, vomiting, or diarrhea coupled with voluminous intake of water (hypotonic gain) Decreased Na+ concentration of plasma (hyponatremia) Decreased plasma osmolarity Osmosis of water from plasma into intracellular fluid Cell swelling, brain edema and compression Convulsions, coma and possible death Plasma ADH Plasma Osmolarity Water deprivation SIADH High-normal abnormal Low Urine Osmolarity Urine Flow Rate Hyperosmotic Low Hyperosmotic Low Water drinking Low-normal Hyposmotic High Central diabetes insipidus High Hyposmotic High - normal High Hyposmotic High Nephrogenic diabetes insipidus In healthy individuals with restricted fluid intake, urine osmolality should be greater than 800 mOsm/kg, while a 24-hour urine osmolality should average between 500 and 800 mOsm/kg Conditions which increase osmolality Serum Urine •Dehydration/sepsis/fever/burns •Dehydration •Diabetes insipidus and mellitus •Syndrome Inappropriate ADH (hyperglycemia) secretion (SIADH) •Uremia •Adrenal insufficiency •Hypernatremia •Glycosuria •Ethanol, methanol, or ethylene •Hypernatremia glycol ingestion •High protein diet •Mannitol therapy Conditions which decrease osmolality Serum Urine •Excess hydration •Excess fluid intake •Hyponatremia •Acute renal insufficiency •Syndrome Inappropriate ADH •Glomerulonephritis secretion (SIADH) •Diabetes insipidus