water balance and regulation of osmolality
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Water Balance andWater Balance and
Regulation of OsmolalityRegulation of OsmolalityInolynInolyn
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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
Vanders Renal Physiology, Fig. 1-4, pp. 11
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Anatomy of the glomerulusAnatomy of the glomerulus
Vanders Renal Physiology, Fig. 1-4, pp. 8
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Basic renal processBasic renal process
Vanders Renal Physiology, Fig. 1-7, pp. 17
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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