Ebook Fluid, electrolyte, and acid–base physiology: Part 2

(BQ) Part 2 book Fluid, electrolyte, and acid–base physiology has contents: Hyperglycemia, hyperglycemia, potassium physiology, polyuria, hyponatremia with brown spots, concentrate on the danger, hyperkalemia in a patient treated with trimethoprim,... and other contents.

10 c h a p t e r Hyponatremia Introduction 266 Objectives 266 Case 10-1: This catastrophe should not have occurred! 267 Case 10-2: This is far from ecstasy! 267 Case 10-3: Hyponatremia with brown spots .268 Case 10-4: Hyponatremia in a patient on a thiazide diuretic 268 P A R T A BACKGROUND 269 Review of the pertinent physiology 269 Basis of hyponatremia 273 P A R T B ACUTE HYPONATREMIA 275 Clinical approach 275 Specific causes 278 P A R T C CHRONIC HYPONATREMIA 284 Overview 284 Clinical approach 285 Specific disorders 289 Treatment of patients with chronic hyponatremia 296 P A R T D DISCUSSION OF CASES 302 Discussion of questions .306 265 266 salt and water Introduction ABBREVIATIONS PNa, concentration of sodium ions (Na+) in plasma PK, concentration of potassium ions (K+) in plasma PCl, concentration of chloride ions (Cl−) in plasma PHCO3, concentration of bicarbonate ions (HCO3− ) in plasma PGlucose, concentration of glucose in plasma PAlbumin, concentration of albumin in plasma POsm, osmolality in plasma BUN, blood urea nitrogen PUrea, concentration of urea in plasma PCreatinine, concentration of creatinine in plasma UOsm, urine osmolality ADH, antidiuretic hormone AQP, aquaporin water channels EABV, effective arterial blood volume dDAVP, desmopressin (1-deamino 8-D-arginine vasopressin), a synthetic long acting vasopressin TRPV, transient receptor potential vanilloid SIADH, syndrome of inappropriate antidiuretic hormone PCT, proximal convoluted tubule ECF, extracellular fluid ICF, intracellular fluid MDMA, 3,4-methylenedioxy-­ methamphetamine DCT, distal convoluted tubule CRH, corticotropin-releasing hormone CCD, cortical collecting duct MCD, medullary collecting duct CDN, cortical distal nephron, which consists of nephron segments in the cortex, the late DCT, the connecting segment, and the CCD UNa, concentration of Na+ ions in the urine UCl, concentration of Cl− ions in the urine UK, concentration of K+ ions in the urine TURP, transuretheral resection of prostate Hyponatremia is defined as a concentration of sodium (Na+) ions in plasma (PNa) that is less than 135 mmol/L Hyponatremia is the most common electrolyte disorder encountered in clinical practice It can be associated with considerable morbidity and even mortality The initial step in the clinical approach to the patient with hyponatremia must focus on what the danger is to the patient rather than on the cause of hyponatremia Regardless of its cause, acute hyponatremia may be associated with swelling of brain cells and increased intracranial pressure and the danger of brain herniation, necessitating inducing a rapid rise in PNa to shrink brain cell size In contrast, in a patient with chronic hyponatremia, the danger is a too rapid rise in PNa, which may lead to the development of osmotic demyelination syndrome (ODS) Hence, the clinician must be vigilant to avoid a rise in PNa that exceeds what is considered a safe maximum limit It is also important to recognize that hyponatremia is not a diagnosis but rather is the result of diminished renal excretion of electrolytefree water because of a number of disorders Hyponatremia may be the first manifestation of a serious underlying disease such as adrenal insufficiency or small cell carcinoma of the lung Hence, a cause of hyponatremia must always be sought Hyponatremia has been associated with increased mortality, morbidity, and length of hospital stay in hospitalized patients with a variety of disorders Whether these associations reflect the severity of the underlying illness, a direct effect of hyponatremia, or a combination of both remains unclear OBJECTIVES    n To emphasize that a low effective plasma osmolality (POsm) implies that the intracellular fluid (ICF) volume is expanded Brain cells adapt to swelling by extruding effective osmoles, and if the time course is greater than 48 hours, brain cells have had time to export a sufficient number of effective osmoles to return their size toward normal n To emphasize that, from a clinical perspective, hyponatremia is divided into acute hyponatremia (48 hour duration), and chronic hyponatremia with an acute component The importance of this classification is that the danger to the patient, and hence the design of therapy, is different in the three groups In the patient with acute hyponatremia, the danger is brain cell swelling with possible brain herniation In the patient with chronic hyponatremia, the danger is development of osmotic demyelination syndrome due to a large rise of PNa In the patient who develops an acute component on top of chronic hyponatremia, the danger is twofold There is the danger of brain cell swelling and brain herniation due to the acute component of the hyponatremia, and there is the danger of development of osmotic demyelination if the rise of PNa exceeds what is considered a maximum safe limit In many patients, the duration of hyponatremia is not known with certainty and therefore, the design of therapy is based on the presence of symptoms that may suggest an increased intracranial pressure n To emphasize that hyponatremia is a diagnostic category and not a single disease; rather, it is the result of diminished renal excretion of electrolyte-free water caused by a number of disorders A cause of hyponatremia must always be sought and treatment in patients with chronic hyponatremia should be directed to the specific pathophysiology in each patient 10 : hyponatremia Case 10-1: This Catastrophe Should Not Have Occurred! A 25-year-old woman (weight 50 kg) developed central diabetes insipidus 18 months ago There was no obvious cause for the disorder Treatment consisted of desmopressin (dDAVP) to control her polyuria and maintain her PNa close to 140 mmol/L Her current problem began after she developed the flu, with low-grade fever, cough, and runny nose, which started about 1 week ago To alleviate her symptoms, she sipped ice-cold liquids Because she felt progressively unwell over time, she visited her physician yesterday afternoon She was noted to have gained close to 3 kg (7 lb) in weight Accordingly, her PNa was measured and it was 125 mmol/L Although she was advised by her physician not to drink any fluids and to go to the hospital immediately, she waited until the next morning before acting on this advice On arrival in the emergency department, she complained of nausea and a moderately severe headache There were no other new findings on physical examination; unfortunately, her weight was not measured Her laboratory data are summarized in the following table: Na+ K+ Cl− BUN (urea) Creatinine Glucose Osmolality mmol/L mmol/L mmol/L mg/dL (mmol/L) mg/dL (μmol/L) mg/dL (mmol/L) mosmol/kg H2O PLASMA URINE 112 3.9 78 (2.0) 0.6 (50) 90 (5.0) 230 100 50 100 120 mmol/L 0.6 g/L (5 mmol/L) 420 Questions What dangers to the patient are there on presentation? What dangers should be anticipated during therapy, and how can they be avoided? Case 10-2: This Is Far From Ecstasy! A 19-year-old woman suffers from anorexia nervosa She went to a rave party, where she took the drug Ecstasy (MDMA) Following advice from others at the party, she drank a large volume of water that night to avoid dehydration from excessive sweating As time passed, she began to feel unwell, with her main symptoms were lassitude and an inability to concentrate After lying down in a quiet room for 2 hours, her symptoms did not improve and she developed a severe headache Accordingly, she was brought to the hospital In the emergency department, she had a generalized tonic-clonic seizure Blood was drawn immediately after the seizure and the major electrolyte abnormality was a PNa of 130 mmol/L; a metabolic acidemia (pH 7.20, PHCO3 10 mmol/L) was also present Questions Is this acute hyponatremia? Why did she have a seizure if the PNa was only mildly reduced at 130 mmol/L? What role might anorexia nervosa have played in this clinical picture? What is your therapy for this patient? 267 268 salt and water Case 10-3: Hyponatremia With Brown Spots A 22-year-old woman has myasthenia gravis In the past 6 months, she has noted a marked decline in her energy and a weight loss of 7 lb, from 110 to 103 lb (50 to 47 kg) She often felt faint when she stood up quickly On physical examination, her blood pressure was 80/50 mm Hg, her pulse rate was 126 beats per minute, her jugular venous pressure was below the level of the sternal angle, and there was no peripheral edema Brown pigmented spots were evident on her buccal mucosa The electrocardiogram was unremarkable The biochemistry data on presentation are shown in the following table: Na+ K+ BUN (urea) Creatinine Osmolality mmol/L mmol/L mg/dL (mmol/L) mg/dL (μmol/L) mosmol/kg H2O PLASMA URINE 112 5.5 28 (10.0) 1.7 (150) 240 130 20 (130 mmol/L) 0.7 g/L (6 mmol/L) 430 Questions What is the most likely basis for the very low effective arterial blood volume (EABV)? What dangers to the patient are present on presentation? What dangers should be anticipated during therapy, and how can they be avoided? Case 10-4: Hyponatremia in a Patient on a Thiazide Diuretic A 71-year-old woman was started on a thiazide diuretic for treatment of hypertension She had ischemic renal disease with an estimated glomerular filtration rate (GFR) of 28 mL/min (40 L/day) She consumed a low salt, low protein diet and drank eight cups of water a day to remain hydrated A month after starting the diuretic, she presented to her family doctor feeling unwell Her blood pressure was 130/80 mm Hg, her heart rate was 80 beats per minute, there were no postural changes in her blood pressure or heart rate, and her jugular venous pressure was about 1 cm below the level of the sternal angle Her PNa was 112 mmol/L Her other laboratory data are summarized in the following table: Na+ K+ HCO3− BUN (urea) Creatinine Osmolality PLASMA URINE mmol/L mmol/L mmol/L 112 3.6 28 22 mg/dL (mmol/L) mg/dL (μmol/L) mosmol/kg H2O 28 (10.0) 1.3 (145) 240 0.7 g/L (6 mmol/L) 325 Questions What is the most likely basis for the hyponatremia in this patient? What dangers should be anticipated during therapy, and how can they be avoided? 10 : hyponatremia PART A BACKGROUND REVIEW OF THE PERTINENT PHYSIOLOGY The Plasma Na+ Concentration Reflects the ICF Volume Water crosses cell membranes rapidly through aquaporin (AQP) water channels to achieve equal sum of concentration of effective osmoles in the extracellular fluid (ECF) compartment and ICF compartment Effective osmoles are particles that are largely restricted to either the ECF compartment or the ICF compartment The effective osmoles in the ECF compartment are largely Na+ ions and their attendant anions (Cl− and HCO3− ions) The major cation in the ICF compartment is potassium (K+) ions; electroneutrality of the ICF compartment is achieved by the anionic charge on organic phosphate esters inside the cells (RNA, DNA, phospholipids, phosphoproteins, adenosine triphosphate [ATP], and adenosine diphosphate [ADP]) These are relatively large molecules, and hence exert little osmotic pressure Other organic solutes contribute to the osmotic force in the ICF compartment The individual compounds differ from organ to organ The organic solutes that have the highest concentration in skeletal muscle cells are phosphocreatine and carnosine; each is present at ∼25 mmol/kg Other solutes include amino acids (e.g., glutamine, glutamate, taurine), peptides (e.g., glutathione), and sugar derivatives (e.g., myoinositol) Because particles in the ICF compartment are relatively fixed in number and charge, changes in the concentration of particles in the ICF compartment usually come about by changes in its content of water Water enters cells when the tonicity in the ICF compartment exceeds that in the ECF compartment Because the concentration of Na+ ions in the ECF compartment is the major determinant of ECF tonicity, the concentration of Na+ ions in the ECF compartment is the most important factor that determines the ICF volume (except when the ECF compartment contains other effective osmoles, e.g., glucose [in conditions of relative lack of insulin actions], mannitol) Hence, hyponatremia (whether caused by the loss of Na+ ions or the gain of water) is associated with an increase in the ICF volume (Fig 10-1) The Content of Na+ Ions Determines the ECF Volume The number of effective osmoles in each compartment determines that compartment’s volume because these particles attract water Water gain Na+ deficit Loss Na+ Na+ Na+ H2O H2O H2O ϩ H2O Input Figure 10-1  Cell Swelling During Hyponatremia The circle with the solid line represents the normal intracellular fluid (ICF) volume Whether the basis for hyponatremia is a deficit of Na+ ions (left) or a gain of water (right), the ICF volume is increased (circle with a dashed line) The ovals represent aquaporin (AQP) water channels in the cell membrane 269 270 salt and water molecules via osmosis The most abundant effective osmoles in the ECF are Na+ ions and their attendant monovalent anions, and therefore they determine the ECF volume However, the concentration of Na+ ions in the ECF compartment depends on the ratio between the content of Na+ ions and the volume of water in the ECF compartment Hyponatremia may be seen in patients with a reduced ECF volume, normal ECF volume, or increased ECF volume A reduced concentration of Na+ ions (i.e., hyponatremia) may be present in a patient with reduced ECF volume, in which case the content of Na+ ions is reduced and so is the volume of water, but the reduction of the content of Na+ ions is proportionally larger For instance, consider a patient who starts with an ECF volume of 10 L and PNa of 140 mmol/L, and so a content of Na+ ions in the ECF compartment of 140 mmol/L × 10 L or 1400 mmol If this patient develops a reduced ECF volume of 8 L and a PNa of 120 mmol/L, then the content of Na+ ions in her ECF compartment would now be 960 mmol This means the patient’s ECF volume has fallen by 20%, but content of Na+ ions in her ECF compartment would have fallen by (1400 − 960)/1400 = 440/1400 = 31% A patient may have a normal ECF volume of 10 L but a reduced PNa of 120 mmol/L, in which case the content of Na+ ions in the ECF compartment is reduced by 200 mmol Finally, a patient may have an expanded ECF volume and an increased content of Na+ ions in the ECF compartment, yet the concentration of Na+ ions in the ECF compartment may be reduced if the increase in the content of Na+ ions in the ECF compartment is proportionally smaller than the increase in the ECF volume Consider a patient with congestive heart failure who may have an increase in ECF volume from 10 to 14 L (an increase of 40%), who has a fall in PNa from 140 mmol/L to 120 mmol/L The content of Na+ ions in her ECF compartment is now 14 L × 120 mmol/L = 1680 mmol, which is an increase of (1680 − 1400)/1400 = 280/1400 = 20% Hence, hyponatremia can be associated with low, normal, or increased ECF volume Stated another way, one cannot make c­ onclusions about the ECF volume simply by looking at the patient’s PNa Regulation of Brain Volume Defense of brain cell volume is necessary because the brain is contained in the skull, a rigid box (Fig 10-2) When hyponatremia develops quickly over several hours, brain cells swell The initial defense is to expel as much NaCl and water as possible from the interstitial space in the brain into the cerebrospinal fluid to prevent a large rise in intracranial pressure If brain cells continue to swell, this defense mechanism will be overcome Hence, the intracranial pressure will rise, and because of the physical restriction imposed by the rigid skull, the brain will be pushed caudally, which may result in compression of the cerebral veins against the bony margin of the foramen magnum Therefore, the venous outflow will be diminished Because the arterial pressure is likely to be high enough to permit the inflow of blood to continue, the intracranial pressure will rise further and abruptly This may lead to serious symptoms (seizures, coma) and eventually herniation of the brain through the foramen magnum, causing irreversible midbrain damage and death If hyponatremia develops more slowly, the brain cells adapt to swelling by exporting effective osmoles to shrink their volume This process takes at least 24 hours, and by approximately 48 hours, these adaptive changes have proceeded sufficiently to shrink the volume of brain cells back toward their normal size Approximately half of the particles exported are electrolytes (K+ ions and accompanying anions see Chapter 9), and the other half is organic solutes of 10 : hyponatremia Normal brain cell volume Acute fall in the PNa Skull Osmotic demyelination K+ + A– organic osmoles Rapid rise in the PNa Slow rise in the PNa K+ + A– Swollen brain cells and higher intracranial pressure Adaptive changes Organic osmoles Brain cell volume almost normal Figure 10-2  Changes in Brain Cell Volume in a Patient With Hyponatremia The structure represents the brain; its ventricles are depicted as hexagons and the bold line represents the skull When the PNa falls, water enters brain cells, and there is a rise in intracranial pressure (ICP; site 1) This rise in ICP squeezes some of the extracellular fluid of the brain out into the cerebrospinal fluid As the PNa approaches 120 mmol/L, the danger of herniation mounts enormously If, however, the fall in PNa has been more gradual (site 2), adaptive changes have time to occur (export K+ salts and organic molecules), and brain cell size is now close to normal despite the presence of hyponatremia If the PNa rises too quickly at this stage, osmotic demyelination may develop (site 3) This complication can be prevented if the rise in the PNa occurs over a long period of time sufficient for brain cells to reaccumulate the lost K+ ions and their anions and the lost organic osmolytes (site 4) diverse origin The major organic osmoles that are lost from brain cells are the amino acids glutamine, glutamate, taurine, and myoinositol, which is a sugar derivative If hyponatremia is corrected too rapidly in this setting, brain cells may not have sufficient time to regain their lost organic osmolytes, and this may lead to osmotic demyelination The pathophysiology of this very serious neurological complication is not well understood but seems to be related to the osmotic stress caused by a rapid rise in PNa, causing shrinkage of cerebral vascular endothelial cells This leads to a disruption of the blood–brain barrier, allowing lymphocytes, complement, and cytokines to enter the brain, damage oligodendrocytes, and cause demyelination Microglial activation also seems to contribute to this process Synopsis of Water Physiology Regulation of water balance has an input arm and an output arm The ingestion of water is stimulated by thirst When enough water is ingested to cause a fall in the PNa and swelling of cells of the hypothalamic osmoreceptor (which is really a tonicity receptor), the release of vasopressin is inhibited In the absence of vasopressin actions, AQP2 are not inserted in the luminal membranes of principal cells of the cortical and medullary collecting ducts, which leads to the excretion of a hypotonic urine The main osmosensory cells appear to be located in the organum vasculosum laminae terminalis and the supraoptic and paraventricular nuclei of the hypothalamus The mechanism of osmosensing appears to be at least in part caused by activation of nonselective calcium-permeable cation channels of the transient receptor potential vanilloid (TRPV), which can serve as stretch receptors The osmoreceptor is linked to both the thirst center and the vasopressin release center via nerve connections Polymorphism in the gene 271 272 salt and water encoding for TRPV4 may confer genetic susceptibility to hyponatremia Healthy aged men with a certain TRPV4 polymorphism are more likely to have mild hyponatremia than are men without this polymorphism Vasopressin is synthesized by the magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus and is transported down the axons of the supraoptic-hypophyseal tract to be stored in and released from the posterior pituitary (neurohypophysis) Binding of vasopressin to its vasopressin receptor (V2R) in the basolateral membrane of principal cells in the cortical and medullary collecting ducts stimulates adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A(PKA) PKA phosphorylates AQP2 in their endocytic vesicles, which causes their shuttling via microtubules and actin filaments to the luminal membrane of principal cells (see Fig 9-16) In the presence of AQP2 in their luminal membrane, principal cells in the collecting ducts become highly permeable to water Water is reabsorbed until the effective osmolality in the lumen of the collecting duct is equal to that in the surrounding interstitial compartment at any horizontal plane Although the main trigger for the release of vasopressin is a rise in PNa, large changes in the EABV and/or the blood pressure can also cause its release Baroreceptors located in the carotid sinus and aortic arch are stretch receptors that detect changes in EABV When EABV is increased, afferent neural impulses inhibit the secretion of vasopressin In contrast, when EVAB is decreased, this inhibitory signal is diminished, leading to vasopressin release Notwithstanding, acutely decreasing EABV by 7% in healthy adults had little effect on plasma vasopressin level; a 10% to 15% decline in EABV is required to double the plasma vasopressin level Furthermore, even a larger degree of decreased EABV is required for this baroreceptor-mediated stimulation of vasopressin release to override the inhibitory signals related to hypotonicity Nausea, pain, stress, and a number of other stimuli, including some drugs (e.g., carbamazepine, selective serotonin reuptake inhibitors, and 3,4-methylenedioxy-methamphetamine [ecstasy]) can also cause the release of vasopressin Once a water load leads to a fall in the arterial PNa and the absence of circulating vasopressin, principal cells of the cortical and the medullary collecting ducts lose their luminal AQP2 channels As a result, a large water diuresis ensues The limiting factors for the excretion of water in this setting are the volume of filtrate delivered to the distal nephron and the amount of water reabsorbed in the inner MCD by pathways that are independent of vasopressin (called residual water permeability) Distal delivery of filtrate The volume of filtrate delivered to the early distal convoluted tubule (DCT) is estimated to be about 27 L/day in a healthy young adult (see Table 9-3) Because the descending thin limb of the loop of Henle of the majority of nephrons lacks AQP1 and therefore is largely water impermeable, the volume of distal delivery of filtrate is determined by the volume of glomerular filtration (GFR) less the volume of filtrate that is reabsorbed in the proximal convoluted tubule (PCT) As discussed in Chapter 9, close to 83% of the GFR is reabsorbed in the entire PCT In the presence of a low EABV, a larger fraction of the GFR is reabsorbed in the PCT as a result of sympathetic nervous system 10 : hyponatremia 273 activation and the release of angiotensin II Therefore, the absence of a contracted EABV is needed for maximal excretion of water Conversely, when there is both a low GFR and an enhanced reabsorption of filtrate because of a low EABV, the volume of distal delivery of filtrate may be very low If the volume of distal delivery of filtrate is not sufficiently large to exceed the volume of water that is reabsorbed via residual water permeability in the inner MCD to allow for the excretion of the daily water load, chronic hyponatremia may develop, even when the daily water load is modest and in the absence of vasopressin actions Residual Water Permeability There are two pathways for transport of water in the inner MCD: a vasopressin-responsive system via AQP2 and a vasopressin-independent system called residual water permeability Two factors may affect the volume of water reabsorbed by residual water permeability First, the driving force that is the enormous difference in osmotic pressure between the luminal and the interstitial fluid compartments in the inner MCD during a water diuresis Second, contraction of the renal pelvis In more detail, each time the renal pelvis contracts, some of the fluid in the renal pelvis travels in a retrograde direction up toward the inner MCD; some of that fluid may be reabsorbed via residual water permeability after it enters the inner MCD for a second (or a third) time From a quantitative perspective, we estimate that in an adult, somewhat in excess of 5 L of water would be reabsorbed per day in the inner MCD by residual water permeability during water diuresis (see Chapter 9) The appropriate renal response to hyponatremia (i.e., to an excess of water in the body) is to excrete the largest possible volume (∼10 to 15 mL/min or ∼ 15 to 21 L/day) of maximally dilute urine (urine osmolality [UOsm] ∼ 50 mosmol/kg H2O; see margin note) If this response is not observed, one should suspect that either vasopressin is acting and/or that the volume of distal delivery of filtrate is low BASIS OF HYPONATREMIA In patients with acute hyponatremia, vasopressin is commonly present and acting One must, however, look for a reason why so much water was ingested, because normal subjects have an aversion to drinking large amounts of water when the thirst center is intact and mental function is normal (Table 10-1) In fact, most cases of acute hyponatremia occur in a hospital setting, particularly in the perioperative period, and hence this defense mechanism of aversion to drinking large amounts of water is bypassed with the intravenous administration of fluids In a patient with chronic hyponatremia, the major pathophysiology is a defect in the excretion of water (Table 10-2) The traditional approach to the pathophysiology of hyponatremia centers on a reduced electrolyte-free water excretion caused by actions of vasopressin In some clinical settings, release of vasopressin is thought to be caused by decreased EABV Notwithstanding, at least in some patients, the degree of decreased EABV does not seem to be large enough to cause the release of vasopressin We suggest that hyponatremia may develop in some patients even in the absence of vasopressin action Two important factors in this regard are diminished volume of filtrate URINE OSMOLALITY DURING A WATER ­DIURESIS • In the absence of vasopressin actions, the UOsm depends on the number of osmoles to excrete and the urine volume The latter is determined by the volume of distal delivery of filtrate and the volume of water that is reabsorbed in the inner MCD via its residual water permeability • Consider two subjects who excrete urine with an UOsm that is much less than the POsm, indicating that vasopressin is not acting • Each patient excretes 600 mosmol/day Subject has a lower volume of distal delivery of filtrate because of a lower GFR and an enhanced reabsorption in the PCT due to a low EABV Notice the difference in the values for their UOsm SUBJECT URINE VOLUME UOsm 10 L/day 5 L/day 60 120 274 salt and water TABLE 10-1 SOURCES OF A LARGE INPUT OF WATER IN A PATIENT WITH HYPONATREMIA Ingestion of a Large Volume of Water • Aversion to a large water intake is suppressed by mood-altering drugs (e.g., MDMA) • Drinking too much water during a marathon to avoid dehydration • Beer potomania • Psychotic state (e.g., paranoid schizophrenia) Infusion of a Large Volume of 5% Dextrose in Water Solution (D5W) • During the postoperative period (especially in a young patient with a low muscle mass) Infusion of a Large Volume of Hypotonic Lavage Fluid • Input of water and organic solutes, with little or no Na+ ions (e.g., hyponatremia following transurethral resection of the prostate) Generation and Retention of Electrolyte-Free Water (“Desalination”) • Excretion of a large volume of hypertonic urine caused by a large infusion of isotonic saline in a setting where vasopressin is present In these patients, look for a reason why the aversion to drink water was “ignored.” Also, look for a reason for a decreased rate of excretion of water (e.g., release of vasopressin and/or a low distal delivery of filtrate [see Table 10-2]) MDMA, 3,4-Methylenedioxy-methamphetamine TABLE 10-2 CAUSES OF A LOWER THAN EXPECTED RATE OF EXCRETION OF WATER Lower Rate of Water Excretion Because of Low Volume of Distal Delivery of Filtrate • States with a very low GFR • States with enhanced reabsorption of filtrate in the PCT caused by low EABV: • Loss of Na+ and Cl− in sweat (e.g., patients with cystic fibrosis, a marathon runner) • Loss of Na+ and Cl− via the gastrointestinal tract (e.g., diarrhea) • Loss of Na+ and Cl− via the kidney (diuretics, aldosterone deficiency, renal or cerebral salt wasting) • Conditions with an expanded ECF volume but low EABV (e.g., congestive heart failure, liver cirrhosis) Lower Rate of Excretion of Water Because of Vasopressin Actions • Baroreceptor-mediated release of vasopressin because of markedly low EABV • Nonosmotic stimuli including pain, anxiety, nausea • Central stimulation of vasopressin release by drugs, including MDMA, nicotine, morphine, carbamazepine, tricyclic antidepressants, serotonin reuptake inhibitors, antineoplastic agents such as vincristine and cyclophosphamide (probably via nausea and vomiting) • Pulmonary disorders (e.g., bacterial or viral pneumonia, tuberculosis) • Central nervous system disorders (e.g., encephalitis, meningitis, brain tumors, subdural hematoma, subarachnoid hemorrhage, stroke) • Release of vasopressin from malignant cells (e.g., small-cell carcinoma of the lung, oropharyngeal carcinomas, olfactory neuroblastomas) • Administration of dDAVP (e.g., for urinary incontinence, treatment for diabetes insipidus) • Glucocorticoid deficiency • Severe hypothyroidism • Activating mutation of the V2R (nephrogenic syndrome of inappropriate antidiuresis) GFR, Glomerular filtration rate; PCT, proximal convoluted tubule; EABV, effective arterial blood volume; MDMA, 3,4-methylenedioxy-methamphetamine; V2R, vasopressin receptor delivered to the distal nephron and enhanced water reabsorption in the inner MCD through its residual water permeability In the absence of a low distal delivery of filtrate in a patient with chronic hyponatremia, the diagnosis is the syndrome of inappropriate antidiuretic hormone secretion (SIADH) A rare cause of SIADH is a genetic disorder in which there is a gain of function mutation in the gene encoding V2R, causing its constitutive activation This disorder is called nephrogenic syndrome of inappropriate antidiuresis The diagnosis is suspected in a patient with chronic SIADH of undetermined etiology in whom vasopressin levels are undetectable and who does not respond with a water diuresis to the administration of V2R antagonist (e.g., tolvaptan) ... body osmolality mosmol/kg H2O Added glycine osmoles to each liter of ECF volume New PNa mmol/L 11 22 8400 8400 25 4 127 GLYCINE 1.5% (20 0 mmol/L) 12. 3 20 .7 8400 600 9000 27 3 49 115 In this example,... Osmolality PLASMA URINE mmol/L mmol/L mmol/L 1 12 3.6 28 22 mg/dL (mmol/L) mg/dL (μmol/L) mosmol/kg H2O 28 (10.0) 1.3 (145) 24 0 0.7 g/L (6 mmol/L) 325 Questions What is the most likely basis for... effective osmoles in each compartment determines that compartment’s volume because these particles attract water Water gain Na+ deficit Loss Na+ Na+ Na+ H2O H2O H2O ϩ H2O Input Figure 10-1  Cell