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Assuming that fractional reabsorption of sodium in the distal segments is unchanged,more sodium will be excreted. Conversely, if GFRdecreases, the absolute amount of sodium entering theloop of Henle will decrease, as will sodium excretion (iffractional reabsorption in later segments is unchanged).Tubular fluid flow rate: While the tubular fluid flowrate may change, compensatory mechanisms within thekidney serve to regulate it within a normal range.
Thisis necessary, because low flow rates will result indecreased delivery of sodium to the loop of Henle, lowosmolar gradient in the interstitium, and poor ability toreabsorb water in the collecting duct. On the other hand,rapid tubular flow rates will wash out the osmolar gradient in the medullary interstitium. For this reason, tubuloglomerular feedback mechanisms are important incontrolling the flow rate. When tubular flow is rapid, themacula densa cells of the juxtaglomerular apparatussecrete a vasoactive substance (adenosine or ATP) intothe interstitial fluid adjacent to the afferent arteriole.The afferent arteriole constricts, which reduces HPGC,and thus decreases the pressure for filtration, reducingGFR and tubular flow.Baroreceptors located in the afferent arteriolar vesselwalls respond to changes in blood pressure.
Whenstretched, they stimulate juxtaglomerular cells, causingthe release of renin (this is an intrarenal mechanism, anddoes not involve the CNS vasomotor center).Medullary blood flow: If blood flow in the vasa rectaincreases, the medullary interstitial concentration gradient will be reduced, resulting in decreased solute reabsorption (Na+-K+-2Cl−) in the thick ascending limb ofNEUROHUMORAL CONTROL OF RENALSODIUM REABSORPTIONThe kidneys constantly respond to changes in blood pressureand ECF volume status, and this regulation is accomplishedby intrarenal controls noted earlier, as well as several important neural and humoral mechanisms:■■■Sympathetic nerves increase sodium reabsorptionthrough several mechanisms.
Sympathetic nerves innervate afferent and efferent arterioles (via α-adrenergicreceptors). During sympathetic stimulation, arteriolesconstrict, decreasing GFR, and thus decreasing sodiumexcretion. There is also direct sympathetic innervationof the proximal tubule and loop of Henle, which, whenactivated, stimulates sodium reabsorption.The renin-angiotensin-aldosterone system (RAAS) hasan important role in regulation of the renal retention ofsodium and water, and thus, in the regulation of ECFvolume and solute composition. In response to lowtubular sodium concentration and low tubular fluidflow, juxtaglomerular cells produce the proteolyticenzyme renin and secrete it into the afferent arterioles(Fig. 19.1).
Renin cleaves angiotensinogen (a plasmaprotein secreted by the liver) to angiotensin (Ang) I,which is converted to Ang II by angiotensin-convertingenzyme (ACE) in the lung (and other tissues); Ang IIstimulates adrenal medullary release of the mineralocorticoid aldosterone. In the kidney, Ang II has dual effects:it directly stimulates sodium (and thus, water) reabsorption in the proximal tubule and has vasoconstrictoreffects on afferent and efferent arterioles, which result ina lower GFR, and sodium retention.Aldosterone binds to the cytoplasmic mineralocorticoidreceptors in the late distal tubules and collecting tubulesand stimulates Na+ and water retention (and K+226Renal PhysiologyStimulationInhibitionBlood pressureBlood pressureFluid volume1-SympatheticANPFluid volume1-SympatheticAngiotensinogenAngiotensinogenReninReninAngiotensin IAngiotensin IACEACEAngiotensin IIH2ONaClAngiotensin IIH2ONaClNaCl/H2OreabsorptionNaCl/H2OreabsorptionVasoconstrictionAVasoconstrictionAldosteroneAldosteroneMechanisms of Renin ReleaseJuxtaglomerular(JG) cellsMacula densaNaClAfferent arterioleEfferent arterioleNaClNaClNaClBBaroreceptor mechanism:Increased pressure in afferent arteriole inhibitsrenin release from JG cells (red arrows); decreasedpressure promotes renin release (green arrows)Sympathetic nervemechanism:1-Adrenergic nerves stimulaterenin release (green arrows)Macula densa mechanism:Increased NaCl in distal nephron inhibits reninrelease (red arrows); decreased load promotesrenin releaseFigure 19.1 Mechanism of Renin Secretion and Factors Regulating the Renin-AngiotensinAldosterone System Renin is secreted from the juxtaglomerular cells in response to reduced sodiumconcentration and flow in the distal tubule (B).
The cascade of events initiated to promote sodium and waterreabsorption is illustrated in A.■secretion). Aldosterone increases apical Na+ channelsand Na+/H+ antiporters and increases basolateral Na+/K+ATPase activity. This further increases sodium and waterretention and limits urinary losses.Atrial natriuretic peptide (ANP) is primarily producedby myocytes in the right atrium of the heart and isreleased into the blood in response to atrial stretch (aswith increased blood volume).
ANP opposes the actions■of Ang II by increasing GFR and inhibiting collectingtubule Na+ reabsorption. ANP causes natriuresis anddiuresis, reducing ECF volume.Urodilatin is a natriuretic peptide related to ANP that isproduced in the renal tubular cells and secreted into thetubules (not found in blood).
The peptide acts at thecollecting tubules to decrease Na+ reabsorption, resulting in natriuresis/diuresis.Regulation of Extracellular Fluid Volume and Osmolarity227Volume contractionSympatheticactivityReninGlomerularfiltration rateAngiotensin INa+ resorptionin proximaltubuleLungHeartACEAngiotensin IIANPNa+ and H2Oresorption incollecting ductBrainAdrenal glandAldosteroneADHNa+, H2OexcretionFigure 19.2 Renal Response to Volume Contraction In response to volume contraction (dehydration), the renin-angiotensin-aldosterone system is activated, stimulating renal sodium and fluid retention;antidiuretic hormone secretion from the anterior pituitary is stimulated to increase water reabsorption in therenal collecting ducts, and the sympathetic nerves are stimulated to increase renal sodium reabsorption anddecrease glomerular filtration rate.RENAL RESPONSE TO CHANGES IN PLASMAVOLUME AND OSMOLARITYAs discussed earlier, control of ECF is a continual process,with changes in plasma osmolarity and volume signalingmultiple neural and hormonal systems to regulate the renalconcentration and dilution of the urine.
The integration ofthese systems is illustrated in the overall response to ECFvolume contraction and expansion (Figs. 19.2 and 19.3).When plasma volume is contracted, fluid and sodium conservation systems are activated. During volume contraction,the kidneys respond to:■Increased sympathetic nervous system (SNS) activity,which increases renal vascular resistance and decreases■■GFR; proximal tubular sodium (and water) reabsorption increases.Activation of the RAAS, which increases Ang IIand aldosterone, enhancing sodium (and water)reabsorption in the proximal tubules and CDs,respectively.The increase in antidiuretic hormone (ADH), whichincreases water channels in the CDs, enhancing solutefree water absorption.These systems limit further volume contraction by decreasing the loss of fluid in urine.
When plasma volume isexpanded, these systems are reversed, allowing elimination offluid and reduction of plasma volume and ECF (Fig. 19.3).Furthermore, the increase in ANP from the right228Renal PhysiologyVolume expansionNa+ resorptionin proximaltubuleSympatheticactivityReninGlomerularfiltration rateAngiotensin ILungHeartUrodilatinACEAngiotensin IIANPNa+ and H2Oresorption incollecting ductAdrenal glandBrainAldosteroneADHNa+, H2OexcretionFigure 19.3 Renal Response to Volume Expansion In response to volume expansion, sodiumand fluid-retaining mechanisms are decreased (RAAS, ADH), and the increased stretch on the cardiac rightatrium releases atrial natriuretic peptide, which acts at the kidneys to decrease sodium and water retention,creating a diuresis and natriuresis, eliminating the excess fluid.Because of the potent vasoconstrictor and sodiumretaining effects of angiotensin II on the kidney, inhibition of Ang II is a major therapeutic intervention for treatmentof hypertension.
Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) prevent conversion of Ang I toAng II, whereas angiotensin receptor blockers (ARB) (e.g.,losartan, candesartan) block Ang II AT1 receptors. Both interventions decrease systemic vascular resistance and increaseurinary sodium and water excretion.To maintain homeostasis, almost all of the filteredsodium must be reabsorbed—loss of even a few percentof the filtered sodium can result in severe sodium deficiency.Although the fine-tuning by aldosterone increases sodium reabsorption only about 2% to 3%, in aldosterone insufficiency(Addison’s disease), these losses can lead to severe ECF sodiumdepletion, ECF volume contraction, and circulatory collapse.Regulation of Extracellular Fluid Volume and Osmolarity■cardiac atrium has a key role in producing natriuresis anddiuresis by:Increasing GFR by relaxing mesangial cells (and alsothrough renovascular effects).Decreasing sodium (and water) reabsorption in the CDsby reducing Na+ channels (ENaC).■■■Inhibiting aldosterone secretion.Decreasing ADH.Fluid intake must increase to compensate for the urinary losses,which can range from 3 to 18 liters per day.
Mortality is rare,although children and elderly people are at greater risk, fromsevere dehydration, cardiovascular collapse, and hypernatremia.ADH analogs such as DDAVP (e.g., desmopressin) are used totreat central DI. The analogs act like endogenous ADH andincrease water channels in the collecting ducts. Nephrogenic DIcan respond to indomethacin as well as dihydrochlorothiazide,which is a diuretic that has a paradoxical effect to increase waterreabsorption in DI.CLINICAL CORRELATEDiabetes InsipidusADH allows the kidneys to concentrate urine.
Insufficiency ofADH secretion results in diabetes insipidus (DI), a disease inwhich large volumes of hypotonic urine are excreted. Centraldiabetes insipidus is usually caused by trauma, disease, or surgeryaffecting the posterior pituitary gland or hypothalamus. Nephrogenic DI is rare and involves a reduction in ADH V2 receptors orreduction in the AQP2 water channels in the collecting ducts ofthe kidney, reducing sensitivity of the cells to ADH.Failure ofosmoreceptorsTumorCraniopharyngiomaMetastatic carcinomaInflammationMeningitisTuberculosisSyphilisGranulomaXanthomaSarcoidHodgkin’s diseaseEtiology TraumaSkull fractureHemorrhageConcussionOperativeVascular lesionSclerosisThrombosis (?)UnknownNephrogenicFailure to respondto ADHWater-losingnephritisReabsorption ofwater in distalconvoluted tubuleand in collectingtubule diminishedor lost in absenceof antidiuretichormoneeusuclnpticaouprIn sopticoIn supraactysial trhypophIn neurohypophysisAntidiuretichormoneabsent ordeficientACTHReabsorption inproximal convolutedtubule normal (80%of filtrate reabsorbedhere with or withoutantidiuretic hormone)AdrenalcorticalhormonesGlomerularfiltrationnormalIf adenohypophysisis destroyed(growth of tumoror of granuloma)Decreased ACTHDecreasedcortical hormonesDecreasedfiltrationRelief ofdiabetes insipidusUrine outputgreatly increased(5 to 15 liters/24 hours)Corticosteroid administrationmay bring out latent diabetesinsipidusCentral Diabetes Insipidus The causes of central diabetes insipidus, with the effects on the kidneys,are depicted in this scheme.229This page intentionally left blank231CHAPTER20Regulation of Acid–Base Balanceby the KidneysCONTROL OF EXTRACELLULAR FLUID pHWhy is systemic acid–base status important, and what is therole of the kidneys? As noted in Chapter 15, the blood (andextracellular fluid [ECF]) pH must be maintained within anarrow range (7.35 to 7.45) to allow normal cellular functions.This physiologic pH range corresponds to a narrow range inH+ concentration (45 to 35 nanomoles per liter [nM/L]).
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