Body Fluids and Nephron Function

8/10/2019 Body Fluids and Nephron Function

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BODY FLUIDS AND

NEPHRON FUNCTION


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Kidney function

Regulate volume and composition of bodyfluids within narrow limits

HOMEOSTASIS, state of equilibrium This results in the excretion of urine as a

byproduct

Many diseases and pharmacologicalagents can interfere with normal nephronphysiological mechanisms


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Body fluids compartments andcomposition

----------------------------------Total body water / TBW 42 L--------------------------------Intracellular fluid------------------------------------ --------------extracellular fluid ICF 28 L (2/3 rd ) ECF 14 (1/3 rd )

Red cells Plasma Interstitial1/4 th ECF Fluid 3/4 th

Blood

70 kg adultTBW 60% =42L


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Body fluids compartments and composition

Major control mechanism for adjusting water loss fromthe body to match daily water intake is in the KIDNEY

The kidney has a highly regulated capacity to vary thedaily output of urine, while losses from the other sites are

largely fixed ECF and ICF are in osmotic equilibrium, zero net flux of

water across the cell membrane ECF Cation = Na, Anions = Cl & HCO3

ICF Cation = K, Anions = PO4 & other organic anions(proteins) Maintaining Cation gradient between ICF & ECF,

Na-K pump, Na-K-activated ATPase, K-channels


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Gradient of Na & K across cell membranes

High IC [K] essential for many enzymesystems which drive cell metabolism

Basis for electrical excitability ofneuromuscular and cardiac membranes

Capacity of epithelia which line interfacesbetween the body and exterior to carry outnet transepithelial solute transportdepends on Na & K gradient in cells ofthese tissues


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Plasma contains substantial concentration of proteins,presence of a permeability barrier at the capillary wall

Oncotic / colloid-osmotic pressure of plasma

Na = dominant ION in ECF + accompanying anions >95% of the solutes present in ECF Na is responsible for nearly all the osmotic activity in the

ECF Thus when water is added to the body, the amount held in

the ECF is largely determined by the bodys Na content,since the majority of Na are confined to the ECFcompartment

Factors that deplete the body Na will be associated with alow ECF volume, while Na retention is associated withexpanded ECF volume

Pure disturbances in body mechanism for regulating wateritself are uncommon causes of hypo-& hypervolaemia, butare more likely to cause changes in plasma Naconcentration and osmolality


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Clinical features of hypovolaemia and hypervolaemia

Symptoms Thirst Dizziness on standing Confusion

Signs Low JVP Postural hypotension

Dry mouth Reduced skin turgor Reduced urine output Weight loss

Symptoms Ankle swelling Breathlessness

Signs Raised JVP Oedema

Pulmonary crepitations Hypertension (sometimes) Weight gain

HYPOVOLAEMIA HYPERVOLAEMIA


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Functional Anatomy of the Nephron

2 Fundamental steps in nephron function Glomerular filtration Modification of filtered fluid as it passes through the

tubular system Ultrafiltrate from glom. filtration contains

electrolytes and small solutes in plasma-likeconcentrations (primary urine)

Tubular modification involves the alteration ofvolume and composition of the glomerular filtratecarried out along the length of the tubularsystem


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> 99% of the filtered fluid is reabsorbed , andmost of its solute content (Na)

Some electrolytes and many foreign organicmolecules undergo transport into the tubularfluid ( secretion )

Final urine reflects net effect of all these tubulartransport processes

Of the plasma flow delivered to each nephron,20% becomes glomerular filtrate, 80% emergesfrom the glomerulus and is carried bypostglomerular capillaries around the tubularstructures, where it is available for transportexchanges with the luminal fluid


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Filtration fraction / FF= GFR/RPF ~0.2 in man Kidney receives 1/5 th of cardiac output Eg. CO 4.5 L/min, RBF 900 ml/min, Hct 0,45,

RPF = (1-0.45) x 900 = 500 ml/min FF = 0.2, GFR ~ 100 ml/min ~144 L/24H 99% reabsorbed ~ urine flow rate of 1 ml/min

1.4 L/24H


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Nephron Segments


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Contribution of different nephron segments to solute and water homeostasis

Nephron segment Major functionGlomerulus---------------- Forms an ultrafiltrate

Proximal Tubule --------- Reabsorbs isoosmotically 65-70% of the filtered NaCl & waterReabsorbs 90% of the filtered HCO3, mostly in early PTMajor site of ammonia production in nephronReabsorbs almost all of the filtered glucose & AAReabsorbs K, PO4, Ca, Mg, Urea, Uric acidSecretes org. anions (eg.urate) and cations, incl. many protein bound drugs

Loop of Henle ------------ Reabsorbs 15-25% of filtered NaClCountercurrent multiplier, as NaCl reabsorbed in excess of waterMajor site of active regulation of Mg excretion

Distal Tubule ------------- Reabsorbs a small fraction of filtered NaClMajor site, with Conn. Segment, of active regulation of Ca excretion

Connecting segment Principal cells reabsorbs Na+ &Cl-, secretes K+, in part under influence of Aldosterone

& CCD Intercalated cells secrete H+, reabsorbs K+, and, in metab alkalosis secrete HCO3-Reabsorbs water in presence of ADH

Medullary Coll.Tub.----- Site of final modification of urineReabsorbs NaCl, urine [NaCl] can be reduced to < 1meq/LReabsorbs water and Urea relative to amount of ADH present, allowing adilute or concentrated urine to be excreted

Secretes H+ and NH3, urine Ph can be reduced to as low as 4.0 4.5Can contribute to K balance by reabsorption or secretion of K+


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Transport propertiesProximal Tubule

Process occurs almost isotonically, i.e. the osmolality ofthe tubular fluid falls only very slightly below that of theplasma along the length of the tubule

Na reabsorption is associated with completereabsorption of filtered glucose and amino acids (whenplasma concentrations are normal), and almost completereabsorption of HCO3 & PO4

Reabsorption of all solutes and water is very sensitive tometabolic poisons

There is a very high water permeability across theproximal tubular cell layer

There is a low electrical potential difference across thetubular epithelial cells


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GlucosePO4 Amino acids


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Primary active transport step = Na,K-ATPase This pump lowers [Na] IC to 5-10 mmol/L

Creates the electrochemical gradient across the apicalmembrane Secondary active transport of glucose, amino acids,

phosphate

Na-glucose, Na-AA, Na-PO4 cotransport Na-H+ Countertransport (NHE-3), proximal bicarbonate

absorption Shunt pathway occurs between cells by transepithelial

electrical gradients & solvent drag Water flux is partly driven by oncotic and hydrostatic

pressure gradients


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Loop of Henle

Thin descending limb LoH ; Act aspassive equilibrators in the process ofcountercurrent multiplication

Thick ascending limb LoH : responsiblefor reabsorption of 25% of the filtered Na,contributes to the build up of the medullaryinterstitial concentration gradient which isessential in the mechanism for ultimateconcentration of the urine


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Transport properties ThickAscending limb

Extensive transepithelial reabsorption of Na & Clis accompanied by smaller fluxes of K, Mg, Ca

This nephron segment is impermeable to waterunder all conditions; acts as a site of dilution ofthe luminal fluid, and lowers luminal osmolality

Transport of all ions across this segment ispowerfully inhibited by loop-acting diuretic drugs,e.g. furosemide

A small lumen-positive transepithelial potentialdifference normally exists across this segment Vital role in building the concentrating capacity

of the renal medulla, contribute to the regulationof the osmolality of the body fluids


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Distal TubuleEarly DT / D Convoluted T

Na is reabsorbed with Cl, but with little netK movement

Water permeability is very low under allconditions

A further component of filtered Ca isreabsorbed

Na transport is inhibited by thiazides andrelated drugs


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NCT


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Cortical Collecting DuctLate DT

Reabsorption of 2-3% filtered Na load, accompanied inpart by Cl reabsorption, K secretion, Acid secretion intothe lumen

All of these transport processes are stimulated byaldosterone

Water permeability is variable, being increased by ADH /vasopressin

Na reabsorption in this segment is inhibited by amiloride& spironolactone; in their presence secretion of K & H+are reduced

There is normally an appreciable lumen-negativetransepithelial potential difference, but this is largelyabolished by the action of amiloride and spironolactone


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Amiloride blocks the apical Na channel inthe principal cells, results in inhibition ofNa reabsorption, and greatly reduces K+ &acid secretion which are partly dependenton the negative lumen-potential generated

by Na reabsorption Spironolactone blocks the binding of

aldosteron to its cytoplasmic receptor

interfering with the receptors activation


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ENaC


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Principal cell Site of Na reabsorption & K secretion Primary active transport step = basolateral Na-K-ATPase Na enters the cell down its electrochemical gradient,

passing through an epithelial Na channel / ENaC &generates a lumen-negative diffusion potential

This cell type is the target for aldosterone, that interactswith a receptor in the cytoplasm, resulting in activation ofall transport steps

This cell also has basolateral membrane receptors forvasopressine / ADH, the action of which results inincreased transepithelial water transport in this segment


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Intercalated Cells

Site of acid secretion into the lumen Active hydrogen pump, H(+)-ATPase on

the apical cell membrane These H-ions are generated within the cell

by the action of Carbonic Anhydrase H(+) + HCO3(-) -- H2O + CO2 This process of acid secretion is also

activated by aldosterone


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Regulation of Na Transport

Several mechanisms interact to ensurethat Na excretion by the kidney isappropriately matched to changes in Na

intake and ECF volume Various sensory systems detect changesin ECF volume (& related parameters)

Number of Effector mechanisms capableof altering the kidneys Na excretion rate


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Sensing Mechanisms

Volume receptors in the cardiac atria(increased stretch,releases ANP) andintrathoracic veins (reduced distension,

activates eff. mech.) Pressure receptors in the central arterial

(aortic arch & carotid sinus) & afferentarterioles within the kidney

Tubular fluid NaCl concentration withinthe distal nephron, the Macula Densa


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Renin Angiotensin AldosteronSystem / RAAS

Renin, an enzym contained withinspecialized smooth muscle cell in the wallsof Aff. & Eff. Arterioles

Stimuli to its release Reduced perfusion pressure in the aff. art. Increased sympathetic nerve activity in fibers

innervating the aff. & eff. Art. Decreased Na concentration flowing through

the DT


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Action of RAAS

Directly acts to vasoconstrict smallarterioles

Directly stimulates PT Na reabsorption Cause the zona glomerulosa cells of the

adrenal cortex to release aldosteron Aldosterone stimulates salt reabsorption in

the CCD, reducing Na and water excretion


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Sympathetic Nervous System

Activated in response to hypovolaemia Stimulus for Renin release

Releases noradrenaline around the PTcells, where it directly stimulates tubularNa reabsorption

Vasoconstricts the afferent arteriole,reducing GFR and further limiting Na andwater loss


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Atrial Natriuretic Peptide / ANP

Released from the cardiac atria inresponse to stretch during high volumestates

Dilates the Aff. Art., increases GFR Inhibits Na reabsorption by PT &

Medullary Collecting Duct

Secretion of renin and aldosterone isreduced, further switching off Na retainingsystems


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Brain Natriuretic Peptide /BNP

Has ouabain- / digoxin-like properties Inhibits Na-K-ATPase in both VSM &renal

epithelial cells In VSM results in increased IC Na & Ca

concentration leading vasoconstriction In the kidney the effect is an inhibition of

Na reabsorption, promoting natriuresis


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Other Mediators affecting Na reabsorption Intrarenal PG system, PGE2, Prostacycline

Increases GFR Decreases Na reabsorption in the TALH, CCD, thus increases Na

excretion Dopamine , Kinins, NO, Endothelin, Insulin ADH, Arginin Vasopressin acts both to

Increase water reabsorption (V2 receptor) Vasoconstrict blood vessels (V1 receptor)

Tubuloglomerular Feedback / TGF; Plays important role in autoregulation Alteration in GFR induced by changes in tubular flow rate Mediated by specialized cells in the Macula Densa Senses changes in the delivery and subsequent reabsorption of Cl Enhanced by myogenic stretch induced vasoconstriction, cooperativity

among adjacent nephrons, & pressure natriuresis Mediators: R-AII, Adenosine, Thromboxane, changes in IC [Cl-] or

osmolality Glucosuria impairs TGF


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WATER BALANCE &

REGULATION OF OSMOLALITY


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POLYURIA Primary increase in solute excretion / water excretion Solute diuresis / osmotic diuresis

Mannitol Diseases, uncontrolled DM (CRF, Urea) Diuretic drugs

Water based / dilute polyuria High water intake (psychogenic polydipsia) Diabetes Insipidus

High protein tube feeding

Uosm


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Mechanism for urine concentration

Normal Plasma Osmolality, Posm ~ 285-295 mosm/kg Kidney adjust the rate of water excretion over a wide range,

generating a dilute urine when water is abundant,

most dilute 50 mosm/kg, a concentrated urine when water is

scarce, max osmolality 1200-1400 mosm/kg


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Countercurrent multiplicationby the Loop of Henle

A loop structure can generate a longitudinalgradient of concentration

Flow is countercurrent The walls of the descending limb are permeable

to water The walls of the ascending limb are

impermeable to water The walls of the ascending limb contain a pump

mechanism capable of removing NaCl from thelumen to the surrounding interstitiasl fluid suchthat a gradient of 200 mosm/kg can be createdacross the tubular wall at any point


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Th fl id l i g th di g li b f th l d it H


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The fluid leaving the ascending limb of the loop ends up quite Hypo-osmolar, 100 mosm/l, compared to the fluid entering it

The osmolality near the bend of the loop is raised several fold abovethe osmolality of the entering fluid

There is ultimately a continuous gradient of tissue osmolality from300 mosm/kg 1200 mosm/kg

Providing an oppurtunity for water extraction from the collectingducts by osmosis

3 factors increase the concentrating power An increased length of the loop

An increased capacity of the pump in the thick ascending limb A reduced flow rate through the loop Osmolality gradient within the medulla is comprised of NaCl and

urea Urea is trapped within the renal medulla because of the different

permeability of segments of the nephron to urea high in the thin

descending and ascending limbs of the loop deep in the medulla,and in the medullary segment of the collecting duct when ADH ispresent, but low in the TALH and cortical DT.

Under ADH condition, urea recycles from the medullary coll duct(OUT) to the turn of the deep loops of henle (IN), adding to the innermedullary osmolality


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A capillary blood supply that crosses the kidney from


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A capillary blood supply that crosses the kidney fromcortex to medulla allows for dissipation of the build upsolute gradient by diffusion into the capillary blood

Thus, while medullary solutes enter these vessels in thedescending limb, it exits the capillaries in the ascendinglimb, while water moves in the opposite direction in eachcase countercurrent exchange.

In the steady state the operation of the loop of Henle

results in the loss of more solutes than water from thetubular lumen, it follows that the vasa recta must removemore solute than water through the medulla

Countercurrent multiplication occurs even in the deepesthairpin part of the loop within the inner medulla, beforethe start of the thick ascending limb


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Action of ADH / Vasopressin Increases the water permeability of all segments of the collecting duct, from

its earliest parts within the cortex through to the medullary segment. This reabsorbed water is carried away by the capillaries forming the vasa

recta, leaving the medullary interstitial osmolality gradient intact Loop diuretics have the capacity to impair the kidneys ability to both

concentrate and dilute the urine

Thiazide diuretics interfere with maximum dilution of the urine Other action of ADH which amplify its capacity to cause concentratio of theurine ADH can increase the activity of the NaCl reabsorptive mechanism

located in the TALH ADH increases the permeability of the innermedullary collecting duct to

urea Both lead to an intensification of the medullary interstitial concentration

gradient ADH through the V1 receptor involving intracellular Ca mobilization

promotes vasoconstriction of arterioles throughout the body, and increasesblood pressure in the central circulation at the same time as its renal tubularactions serve to retain water


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Supraoptic &P t i l N


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Paraventricular Nc


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Two factors make this ADH system very effective in theshort term regulation of plasma osmolality

ADH is a small peptide which has a very short half life inthe circulation, so that its action is not unduly prolongedfollowing its release

The release of ADH from the hypothalamus in responseto osmoreceptor signals and its action are extremely

rapid events, such that the system tracks minute-to-minute changes in the osmolality of the plasma,correcting them towards the norm without undue delays

Non-osmotic stimuli may also cause secretion of ADH,independent of the plasma osmolality Haemodynamic changes associated with a fall in circulating

plasma volume hypovolaemia, hypotension Pain, nausea, stress, pregnancy, hypoglycmia, nicotine,

morphine Alcohol, phenytoin inhibits ADH release


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Causes of Central DI Idiopathic , Familial, Congenital Tumors, trauma,Irradiation Cerebrovascular accidents, aneurysms Post SVT, anorexia nervosa Inflammation, e.g. sarcoidosis, TB, meningitis,..

Causes of Nephrogenic DI Inherited / congenital : abnl V2 rec, AQP2 Acquired: CKD, infections, obstruction, sickle cell

anemia, analgesic nephropathy, amyloidosis,sjogrens syndromehypokalemia, hypercalcemia,lithium therapy, demeclocycline, amphotericine B,colchicine, vinblastine, glyburide, ofloxacine

Gestational, transient, 2nd

half of pregnancy


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Pregnancy

Osmotic threshold for ADH secretion isdecreased

Threshold for thirst is reduced

Plasma osmolality falls ~ 10 mosm/kg H2O Enhanced plasma clearance of vasopressin by

the placenta vasopressinase

Sheehans syndrome or postpartum pituarynecrosis


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Disturbances in ECF [Na] reflect primary alteration in body water content.Primary disturbances in body Na content are usually accompanied by parallelchanges in the ECF volume status, detected by clinical examination ratherthan plasma analysis.


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Therapy Correction of ECF volume depletion with isotonic solutions untill restorationof ECF volume, hypotonic solution can then be used to correct plasma

osmolality Correction of ECF volume expansion diuresis, dialysis may be needed Water replacement e.g. 75 kg man Na 154 meq/L

TBW = 60% body weight 0.6x75= 45L

current [Na] / desired [Na] X TBW = 154/140x 45=49.54.5L positive water balance would correct the plasma [Na]current [Na] / desired [Na] = TBW (with current [Na]) / TBW (with desired[Na])

Rate of correction depends on the rate of development of hyperNa &associated symptoms

More neurological signs & symptoms are associated with acute hyperNa,and should be corrected rapidly over a few hours

Chronic hyperNa idiogenic osmoles accumulate in brain cells is bestcorrected gradually at a rate not to exceed 2mosm / hour; total correctiontime should be 48 hours / longer


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Failure to dilute the urine

ECF becomes hypoosmolar because of impairment ofthe mechanisms normally involved in excreting excessingested water, that is , in diluting the urine

Requires adequate delivery of filtrate through thesegments of the nephron capable of lowering theosmolality of the luminal fluid by removing Na whileremaining impermeable to water ascending limb ofHenle, early part of DT.

ADH secretion must be suppressed appropriately by thelow Posm, so that water is not reabsorbed from the

collecting duct system. Its necessary to rule out renal failure (low GFR), exclude use of diuretics acting on TALH (furosemide) and early

distal tubule (thiazides) To determine that ADH is not being released


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SIADH

Pulmonary disease CNS disorders, infection, tumor, stroke,

etc

AIDS Drugs: phenothiazines, vincristine,

cyclophosphamide, indomethacin,

carbamazepine,chlorpropamide, nicotine,morphine, clofibrate,barbiturates,isoproterenol


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Therapy Specific treatment of hyponatremia: drugs, stress, heart failure,

uncontrolled diabetic, Restriction of water intake to an amount less than urine output &estimated insensible losses

Demeclocycline Acute symptomatic hyponatremia & CNS symptoms: furosemide

and NaCl 3% Na def = 60% x lean body weight (kg) x ( 140 plasma Na),

50% in women Calculation of desired negative water balance, 70 kg man Na 115 to

130TBW = 60% body weight ~ 0.6X70=42Lcurrent [Na] / desired [Na] = TBW (at current [Na]) / TBW ( at desired[Na])115/130 = TBW/42, TBW=36.55.5 L negative water balance will be needed to raise [Na] to 130

Rate of correction should not exceed 0.5 - 1 mmol/L/Hr CPM , central pontine myelinolysis


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Osmolality and [Na]

Posm ~ 2 x [Na] + [glucose]/18 + BUN/2.8 Effective Posm ~

2 X [Na] + [glucose]/18 Eff Posm ~ 2X [Na] Glucose normally accounts for only

5mosm/kg

Eff Posm = effective osmolality of TBW

= (ECsolute + ICsolute)/ TBW= (2xNa e + 2xK e)/TBW Plasma [Na] = (Na e + K e)/TBW


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OSMOREGULATION VOLUME REGULATION

What is being sensed Plasma osmolality Effective Circulating Volume

Sensors Hypothalamic Carotid SinusOsmoreceptor Afferent Arteriole

Atria

Effectors Antiduiretic RAAShormone Sympatetic NS

Thirst ANPPressure Natriuresis

ADH

What is affected Water excretion Urine Na excretionvia thirst Water intake


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Renal water excretion

V = Cosm + C H2O , Cosm = (Uosm x V)/Posm CH2O = V [1- Uosm/Posm]

E ti f f t i t t


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Excretion of free water occurs in two steps

Solute free water is generated by NaCl reabsorptionwithout water in the medullary and cortical aspects of theascending loop of henle

This water is then excreted by keeping the collectingtubules relatively impermeable to water

Diminished water excretion can occur in 3 settings If less free water is generated because the rate of fluid delivery

to the loop of henle is reduced, as with oliguric renal failure orvolume depletion

If less free water is generated because NaCl reabsorption isinhibited by diuretics, particularly the thiazide type If ADH is present, as with volume depletion, SIADH,

hypothyroidism, or adrenal insufficiency


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Renal water reabsrption

V = C osm TH2O TH2O = C osm V TH2O = V [U osm /P osm 1]

CH2O = -T H2O

c

c

c

c

Renal water conservation depends on 2


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Renal water conservation depends on 2basic steps

The formation and maintenance ofmedullary osmotic gradient

Equilibration of the urine in the collectingtubules with the hyperosmotic medullaryinterstitium


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Clinical application of urine chemistries

Parameter UsesNa retention ------- assesment of volume status

diagnosis of hypoNa & ARFdietary compliance in patients with HTN

evaluation of Ca & Uric acid excretion in stone formersCl retention -------- similar to that of Na excretion

diagnosis of metabolic alkalosisurine anion gap (RTA)

K excretion --------- diagnosis of hypoK

Osmolality / sg----- diagnosis of hypoNa, hyperNa, ARFpH -------------------- diagnosis of RTA

efficacy of treatment in metabolic alkalosis & uric acid stoneds

Fractional excretion of Na


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Fractional excretion of Na

Quantity of Na excretedQuantity of Na filtered X 100FE Na (%) =

FENa (%) =UNa x V

P Na x (U Cr x V/P Cr ) X 100

= UNa x P Cr P Na x U Cr

X 100

Body Fluids and Nephron Function

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