Water Balance and Regulation of Osmolality

8/6/2019 Water Balance and Regulation of Osmolality

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Water Balance andWater Balance and

Regulation of OsmolalityRegulation of OsmolalityInolynInolyn


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Inolyn, 2007Inolyn, 2007

Cont nt :Cont nt :

R nal m chani m for urine concentrationRenal mechani m for urine concentration

Countercurrent multiplication by the loop of HenleCountercurrent multiplication by the loop of Henle

Action of ADH in the collecting ductsAction of ADH in the collecting ducts

Feedback control of plasma osmolalityFeedback control of plasma osmolality

Mechanism of ADH action in the kidneyMechanism of ADH action in the kidney

Failure to concentrate the urineFailure to concentrate the urine

Differential diagnosis of hypernatremiaDifferential diagnosis of hypernatremiaFailure to dilute the urineFailure to dilute the urine

Differential diagnosis of hyponatremiaDifferential diagnosis of hyponatremia


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The Urinary SystemThe Urinary System

Vanders Renal Physiology, Fig. 1-1, pp. 5


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Structure of theStructure of the

kidneykidney



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Anatomy of the glomerulusAnatomy of the glomerulus



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Basic renal processBasic renal process



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Renal mechanisms for urineRenal mechanisms for urine

concentrationconcentrationN plasma osmolality: 290 mosm/kg (5 mosm/ kgN plasma osmolality: 290 mosm/kg (5 mosm/ kgBB)BB)

Homeostatic maintenanceHomeostatic maintenance kidneykidney adjust theadjust the

rate of water excretionrate of water excretion A zone must be created within the renal medullaA zone must be created within the renal medulla

where the tissue fluid osmolality is highwhere the tissue fluid osmolality is high

Loop of HenleLoop of Henle

The tubules forming the final segment of the nephronThe tubules forming the final segment of the nephronmust conduct the urine through this concentratedmust conduct the urine through this concentrated

zone (water reabsorption can occur passively byzone (water reabsorption can occur passively by

osmosis)osmosis)

Collecting ductsCollecting ducts

Vasopressin (ADH)Vasopressin (ADH)


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Countercurrent multiplication by theCountercurrent multiplication by the

loop of Henleloop of HenleLoop structureLoop structure longitudinal gradient oflongitudinal gradient of

concentrationconcentration

Countercurrent: fluid flowCountercurrent: fluid flow descendingdescending

limb (limb ()) ascending limb (ascending limb ())


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Properties of the descending andProperties of the descending and

ascending limbs of a long Henles loopascending limbs of a long Henles loop

The descending limbThe descending limb

Highly permeable to H2OHighly permeable to H2O

Does not actively extrude NaDoes not actively extrude Na

The ascending limbThe ascending limb

Actively transports NaCl out of tubular lumenActively transports NaCl out of tubular lumen

into the surrounding interstitial fluidinto the surrounding interstitial fluid Impermeable to H2OImpermeable to H2O salt leaves the tubularsalt leaves the tubular

fluid without H2O following alongfluid without H2O following along


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Mechanism of countercurrentMechanism of countercurrent

multiplicationmultiplicationStep 1Step 1 -- 66

Human Physiology, Sherwood, Fig. 14-28, pp. 542-3


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Action of ADH in the collecting ductAction of ADH in the collecting duct

Distal and collecting tubuleDistal and collecting tubule impermeableimpermeable

to water except in the presence of ADHto water except in the presence of ADH

Vasopressin (ADH)Vasopressin (ADH) produced by specific neuronal cell bodies inproduced by specific neuronal cell bodies in

the hypothalamusthe hypothalamus stored in the posteriorstored in the posterior

pituitary glandpituitary gland SecretionSecretion stimulated by a H2O deficitstimulated by a H2O deficit


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VasopressinVasopressin the basolateral membrane of the tubularthe basolateral membrane of the tubular

cells (the distal and collecting tubules) through thecells (the distal and collecting tubules) through the

circulatory systemcirculatory system

Human Physiology, Sherwood, Fig. 14-29, pp. 544 The Renal System, Fig. 3.7; pp. 43


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Mechani of action in the i neyMechani of action in the i ney

Other intrarenal actionof :Other intrarenal actionof :

oo activity of NaCl reabsorptive mechanism in the thickactivity of NaCl reabsorptive mechanism in the thick

ascending limb of loop of Henleascending limb of loop of Henle

oo permeability of the inner medullary collecting duct topermeability of the inner medullary collecting duct to

ureaurea

intensification of the medullary interstitialintensification of the medullary interstitial

concentration gradientconcentration gradient

ADHADH separate actionseparate action -- different receptor (V1)different receptor (V1)

intracellularCa mobilizationintracellularCa mobilization vasoconstriction ofvasoconstriction of

the arteriolsthe arteriols BPBPoo


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Feedbackcontrol of lasmaosmolalityFeedbackcontrol of lasmaosmolality

WaterdeprivationWaterdeprivation plasma osmolalityplasma osmolality oo

detected by osmoreceptor (specialized neuraldetected by osmoreceptor (specialized neural

cells in the hypothalamus)cells in the hypothalamus)

thirstthirst seek and ingest waterseek and ingest water

activate supraoptic and paraventricularactivate supraoptic and paraventricular

hypothalamic nucleihypothalamic nuclei ADH secretionADH secretion

Ingestion of large volume of waterIngestion of large volume of water plasmaplasma

osmolalityosmolality qq osmoreceptor reduce activityosmoreceptor reduce activity Thirst suppressedThirst suppressed

Inhibit ADH releaseInhibit ADH release


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Inolyn, 2007Inolyn, 2007 The Renal System, Fig. 3.5 & 3.6; pp. 42


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Feedbackcontrol ofplasmaosmolalityFeedbackcontrol ofplasmaosmolality

ADHADH effective in regulation of plasma osmolalityeffective in regulation of plasma osmolality

Small peptide (9 AA), very short halfSmall peptide (9 AA), very short half--life in circulationlife in circulation notnot

prolonged after its releaseprolonged after its release

Release of ADH from hypothalamus (osmoreceptor signal)Release of ADH from hypothalamus (osmoreceptor signal) action in kidney: rapid events (minute, no delay)action in kidney: rapid events (minute, no delay)

NonNon--osmotic stimuliosmotic stimuli secrete ADHsecrete ADH

Haemodynamic changesHaemodynamic changes 55--10% (hypovolemia10% (hypovolemia baroreceptor)baroreceptor)

hypothalamushypothalamus ADH secretionADH secretion oo Pain, nausea, and stressPain, nausea, and stress ADH secretionADH secretion oo

AlcoholAlcohol ADH secretionADH secretion qq


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Inolyn, 2007Inolyn, 2007 Vanders Renal Physiology, Fig. 7-14, pp. 123


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Condition required for urinaryCondition required for urinary

concentrationconcentration

To concentrate the urineTo concentrate the urine

Adequate solute delivery to the loop of HenleAdequate solute delivery to the loop of Henle

Normal function of the loop of HenleNormal function of the loop of Henle

ADH release into the circulationADH release into the circulation

ADH action on the collecting ductsADH action on the collecting ducts

To dilute the urineTo dilute the urine

Adequate solute delivery into the loop of Henle andAdequate solute delivery into the loop of Henle and

early distal tubuleearly distal tubule

Normal function of the loop of Henle and early distalNormal function of the loop of Henle and early distal

tubuletubule

No ADH in the circulationNo ADH in the circulation


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AcaseofpolyuriaAcaseofpolyuria

RU, 46RU, 46--yo manyo man For several weeksFor several weeks ppassing large volume of urine (colourless likeassing large volume of urine (colourless like

water) and excessive thirst (drink 5 ls/ more water/ d)water) and excessive thirst (drink 5 ls/ more water/ d) passingpassing

similar volume of urinesimilar volume of urine

No history of similar complain, never diagnosed with DM, never hadNo history of similar complain, never diagnosed with DM, never had

known kidney diseaseknown kidney disease He has some emotional problems over the yearsHe has some emotional problems over the years

Family history: unremarkableFamily history: unremarkable

Patient: reformed smoke, does not drink alcoholPatient: reformed smoke, does not drink alcohol

Examination:Examination:

Little agitatedLittle agitated-- but quite wellbut quite well

Skin, lips, mouth: rather drySkin, lips, mouth: rather dry

BP: 130/80, pulse: 84 x/BP: 130/80, pulse: 84 x/

Urine specimen: very pale colour, glucose (Urine specimen: very pale colour, glucose (--), blood (), blood (--), protein (), protein (--))


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What might be causing his polyuria andWhat might be causing his polyuria and

thirst?thirst?

What determines how concentrated theWhat determines how concentrated the

urine is under normal condition?urine is under normal condition?


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Failure to concentrate the urineFailure to concentrate the urine

MechanismMechanism Clinical exampleClinical example

Failure to generate medullaryFailure to generate medullary

concentration gradientconcentration gradient

Poor solute deliver to the loop ofPoor solute deliver to the loop ofHenleHenle

Low GFR (chronic renal failure)Low GFR (chronic renal failure)

Impaired action of thick ascendingImpaired action of thick ascending

limb of Looplimb of Loop

Loop diuretic therapy (Furosemide)Loop diuretic therapy (Furosemide)

Failure of ADH EffectFailure of ADH Effect

No ADH releasedNo ADH released Central DI (hypothalamic/ pituitaryCentral DI (hypothalamic/ pituitary

lesion)lesion)

No ADH action in kidneyNo ADH action in kidney Nephrogenic DI (collecting duct cellNephrogenic DI (collecting duct cell

dysfunction)dysfunction)

The Renal System, Tab. 3.3; pp. 43


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Distinguishing central DI and nephrogenic DI Distinguishing central DI and nephrogenic DI

Water deprivation testWater deprivation test

Initially well hydrated (urine osm quite low)Initially well hydrated (urine osm quite low) water deprivation periodwater deprivation period N: in 9N: in 9--12 h12 h urineurine

osmosm oo administration of exogenous ADHadministration of exogenous ADH

The Renal System, Fig. 3.8 & 3.9; pp. 44


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Failure toconcentrate theurineFailure toconcentrate theurine

Causes ofcentral DI:Causes ofcentral DI:

Tumours, trauma, irradiation of cerebrovascular accidentTumours, trauma, irradiation of cerebrovascular accident destroydestroy

relevant regions of hypothalamus/ pituitary stalk/ posterior pituitaryrelevant regions of hypothalamus/ pituitary stalk/ posterior pituitary

SarcoidosisSarcoidosis

Causes of nephrogenic DICauses of nephrogenic DI

Inherited: faulty structure and impaired function of V2 receptor/Inherited: faulty structure and impaired function of V2 receptor/

AQP2 water channelAQP2 water channel

Acquired:Acquired:

Infection/ obstruction of the collecting ductInfection/ obstruction of the collecting duct interference steps afterinterference steps aftergeneration of cAMPgeneration of cAMP prevent AQP translocation to apical membraneprevent AQP translocation to apical membrane

HypokalemiaHypokalemia

HypercalcemiaHypercalcemia


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Differential diagnosisofhypernatremiaDifferential diagnosisofhypernatremia

Waterdeficit withproportionatelysmaller NadeficitWaterdeficit withproportionatelysmaller Nadeficit

Renal: osmotic/ loop diretic (during water restriction)Renal: osmotic/ loop diretic (during water restriction)

Extrarenal: skin (excessive sweating); gut (colonicExtrarenal: skin (excessive sweating); gut (colonic

diarrhea)diarrhea)

Water deficit aloneWater deficit alone

Renal: central or nephrogenic DIRenal: central or nephrogenic DI

Sodium loading with normal or reduced bodySodium loading with normal or reduced bodywaterwater

Enteral/ parenteral alimentationEnteral/ parenteral alimentation

Intravenous/ oral salt administrationIntravenous/ oral salt administration


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Differential diagnosisofhypernatremiaDifferential diagnosisofhypernatremia

Whatever the underlying cause, sustained/Whatever the underlying cause, sustained/

severehypernatremiaseverehypernatremia impaired thirstimpaired thirst

mechanism (~ brain damage, impairedmechanism (~ brain damage, impairedavailability of/ access to water)availability of/ access to water)

The finding of hyperNaThe finding of hyperNa no guide to theno guide to the

total body Na statustotal body Na status

independentlyindependentlyassess using clinical cluesassess using clinical clues hypo/hypo/

hypervolaemiahypervolaemia


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Failure todilute theurineFailure todilute theurine

Inappropriate water retentionInappropriate water retention

Rule out low GFRRule out low GFR

Exclude the use of diuretic drugs acting onExclude the use of diuretic drugs acting onthe thick asc limb (furosemide)/ early distalthe thick asc limb (furosemide)/ early distal

tubule (thiazide)tubule (thiazide)

Determine that ADH is not released (ADHDetermine that ADH is not released (ADH stimulated bystimulated by oo plasma osmolality,plasma osmolality,

hypovolaemia, stress, nausea, pain)hypovolaemia, stress, nausea, pain)


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Differential diagnosisofhyponatremiaDifferential diagnosisofhyponatremia

Sodiumdeficit with relative water retentionSodiumdeficit with relative water retention

Renal: thiazides & loop diuretics (during water drinking),Renal: thiazides & loop diuretics (during water drinking),

adrenocortical failureadrenocortical failure

Extrarenal: gut (vomiting)Extrarenal: gut (vomiting)

Water retention aloneWater retention alone

SIADH: ectopic ADH secretion from tumour, lung disease, CNSSIADH: ectopic ADH secretion from tumour, lung disease, CNS

disease, drugs (phenothiazines, vincristine, cyclophosphamide)disease, drugs (phenothiazines, vincristine, cyclophosphamide)

HypothyroidismHypothyroidism

Sodium retention with relatively greater water retentionSodium retention with relatively greater water retention

Generalized oedema states: CHF, cirrhosis, nephrotic syndromeGeneralized oedema states: CHF, cirrhosis, nephrotic syndrome

Chronic renal failureChronic renal failure


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Differential diagnosisofhyponatremiaDifferential diagnosisofhyponatremia

Management ofhyponatremia:Management ofhyponatremia:

Define the aetiology and reverse the causativeDefine the aetiology and reverse the causative

conditioncondition

Hypovolaemic statesHypovolaemic states volume replacement and ivvolume replacement and ivNaCl infusionNaCl infusion

Hypervolaemic statesHypervolaemic states Na restriction, waterNa restriction, water

restrictionrestriction

SIADH and related conditionSIADH and related condition restriction of waterrestriction of waterHyponatremiaHyponatremia no reliable guide to the totalno reliable guide to the total

body Na and volume statusbody Na and volume status clinical cluesclinical clues


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Thecase..Thecase..

Severe renal impairementSevere renal impairement excluded (N plasmaexcluded (N plasma

Cr, never used loop diuretics)Cr, never used loop diuretics)

Hypothalamic DIHypothalamic DI excluded (plasma ADH levelexcluded (plasma ADH level

when patient was dehydrated and hyperosmolar;when patient was dehydrated and hyperosmolar;

cerebral CT scancerebral CT scan no structural damage inno structural damage in

hypothalamus/ pituitary fossa)hypothalamus/ pituitary fossa)

Patient had been receiving psychiatric treatmentPatient had been receiving psychiatric treatmentfor 1 month (agitated and hypomanic)for 1 month (agitated and hypomanic) LithiumLithium

carbonate 500 mg bdcarbonate 500 mg bd plasma [Li]: 0,9 mmol/lplasma [Li]: 0,9 mmol/l


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Thecase..Thecase..

Diagnosis: lithiumDiagnosis: lithium--induced nephrogenic DIinduced nephrogenic DI

Result of plasma ADH: high ~Result of plasma ADH: high ~ oo plasma osmolalityplasma osmolality

Cerebral CT scan: NCerebral CT scan: N

Management:Management:

Maintain adequate water intakeMaintain adequate water intake

If Lithium th/ to be continuedIf Lithium th/ to be continued close monitoring of plasma Li level:close monitoring of plasma Li level:

0,40,4--0,8 mmol/ L0,8 mmol/ L

If polyuria and thirst persistIf polyuria and thirst persist amiloride (blocks uptake of Li andamiloride (blocks uptake of Li andNa through the apical cation channel on the cortical collectingNa through the apical cation channel on the cortical collecting

duct)duct)


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Thank YouThank You


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Clinical features of hypovoalemia &Clinical features of hypovoalemia &

hypervolaemiahypervolaemia

HypovolaemiaHypovolaemia HypervolaemiaHypervolaemia

SymptomsSymptoms ThirstThirst

Dizziness on standingDizziness on standingConfusionConfusion

Ankle swellingAnkle swelling

BreathlessnessBreathlessness

SignsSigns Low JVPLow JVP

Postural hypotensionPostural hypotension

Dry mouthDry mouth

Reduced skin turgorReduced skin turgor

Reduced urine outputReduced urine output

Weight lossWeight loss

OedemaOedema

Raised JVPRaised JVP

Pulmonary crepitationsPulmonary crepitations

HypertensionHypertension

(sometimes)(sometimes)

Weight gainWeight gain

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Water Balance and Regulation of Osmolality