Presentation on theme: "Water Homeostasis • The body maintains a balance of water intake and output by a series of negative feedback loops involving the endocrine system and autonomic."— Presentation transcript:
1 Water Homeostasis• The body maintains a balance of water intake and output by a series of negative feedback loops involving the endocrine system and autonomic nervous system.maintaining water homeostasis is a balancing act. The amount of water taken in must equal the amount of water lost.insensible loss• Every day we take in about 2300 milliliters of water in the form of food and beverages.• Approximately 200 milliliters of body water is generated through cell metabolism for an approximate 2500 milliliters of total intake.C6H12O6 + 6O2 → 6 H2O + CO2• At the same time, we lose water, mostly through the kidneys, but also through the lungs, skin, and GI tract.• We lose approximately 1500 milliliters per day from the kidneys in the form of urine.• We also lose about 600 milliliters of water per day through the skin and 300 milliliters from the lungs in the form of water vapor in exhaled air. These two forms of water loss are called insensible loss because we are unaware of the process.• We can lose much more than this insensible loss under conditions of extreme physical exertion. Under such conditions we can lose up to 5000 milliliters per day, through sweating.• Under normal circumstances we also lose 100 milliliters of water per day though the GI tract.• As you can see, maintaining water homeostasis is a balancing act. The amount of water taken in must equal the amount of water lost.
2 Disturbances of Water Homeostasis Hypervolemia• Hypervolemia occurs when too much water and solute are taken in at the same time. Although extracellular fluid volume increases, plasma osmolarity may remain normal.Overhydration• Overhydration occurs when too much water is taken in without solute. Volume increases, but because solute is not present, plasma osmolarity decreases.Hypovolemia• Hypovolemia occurs when water and solutes are lost at the same time. This condition primarily involves a loss of plasma volume. Plasma osmolarity usually remains normal even though volume is low.Dehydration• When water, but not solute, is lost, dehydration occurs.• Dehydration involves a loss of volume but, because solutes are not lost in the same proportion, plasma osmolarity increases.i.v., infussion ofisotonic solutionDrinking toomuch waterBlood losssweating
3 Mechanisms of Fluid Balance • Four primary mechanisms regulate fluid homeostasis:1)Antidiuretic hormone or ADH2)Thirst mechanism3)Aldosterone4)Sympathetic nervous systemThirst Mechanism• The thirst mechanism is the primary regulator of water intake and involves hormonal and neural input as well as voluntary behaviors.• Stimulation of the thirst center in the hypothalamus gives you the desire to drink.• There are three major reasons why dehydration leads to thirst:1. When saliva production decreases, the mouth and throat become dry. Impulses go from the dry mouth and throat to the thirst center in the hypothalamus, stimulating that area.2. When you are dehydrated, blood osmotic pressure increases, stimulating osmoreceptors in the hypothalamus and the thirst center in the hypothalamus is now further activated.3. Decreased blood volume causes a decrease in blood pressure that is signaled by baroreceptors and stimulates the release of renin from the kidney. This causes the production of angiotensin II which stimulates the thirst center in the hypothalamus.
4 Sympathetic Stimulation in the Nephron • Release of neurotransmitters from the sympathetic nerves in the kidney stimulates smooth muscle cells in the afferent arteriole to constrict.• This process causes a decrease in blood flow into the glomerulus and a drop in glomerular filtration rate and results in less urine formation. Less water leaves the body.• Sympathetic stimulation also causes the release of renin which, by stimulating aldosterone secretion, will increase the reabsorption of sodium.• As a result, blood volume will stop decreasing and blood pressure may stabilize. However because the blood pressure and blood volume have not yet returned to normal, the baroreceptors will continue to be stimulated to prevent further loss of blood volume.• In order to bring this person back into to homeostasis, we need to increase the blood volume by drinking fluids.
5 the thick ascending limb and the early distal tubule. FREE-WATER CLEARANCEFree water is defined as distilled water that is free of solutes (or solute-free water). In the nephron, free water is generated in the diluting segments, where solute is reabsorbed without water. The diluting segments of the nephron are the water-impermeable segments:the thick ascending limb and the early distal tubule.Measurement of free-water clearance (CH2O)provides a method for assessing the ability of the kidneys to dilute or concentrate the urine. The principles underlying this measurement are as follows:When ADH levels are low, all of the free water generated in the thick ascending limb and early distal tubule is excreted (since it cannot be reabsorbed by the collecting ducts). The urine is hyposmotic, and free-water clearance is positive.When ADH levels are high, all of the free water generated in the thick ascending limb and the early distal tubule is reabsorbed by the late distal tubule and collecting duct. The urine is hyperosmotic, and free-water clearance is negative.
6 Measurement of CH2O calculated by the following equation: CH2O can be zero, it can be positive, or it can be negative.CH2O is Zero– IsosthenuriawhereCH2OFree-water clearance (mL/min)VUrine flow rate (mL/min)CosmClearance of osmoles (mL/min)[U]osmUrine osmolarity (mOsm/L)[P]osmPlasma osmolarity (mOsm/L)CH2O is positive- Diabetes Insipidus.CH2O is negative- SIADH
7 Electrolyte Homeostasis • The fluid surrounding the cells in the body must maintain a specific concentration of electrolytes for the cells to function properly.• Electrolytes are a major component of body fluids. They enter the body in the food we eat and the beverages we drink.• While electrolytes leave the body mainly through the kidneys by way of the urine, they also leave through the skin and feces.• Severe vomiting and diarrhea can cause a loss of both water and electrolytes from the body, resulting in both water and electrolyte imbalances.• The concentrations of electrolytes in body fluids must be maintained within specific limits, and even a small deviation outside these limits can have serious or life-threatening consequences.• In this topic we will concentrate on the three most clinically significant electrolytes sodium ions, potassium ions, and calcium ions.
8 Sodium Homeostasis• The normal concentration range of sodium in the plasma is milliequivalents per liter, making sodium the ion with the most significant osmotic effect in the extracellular fluid.145136Hypernatremia• what will happen if the sodium concentration of the blood plasma increases, as in hypernatremia.• What effect would this increase in sodium concentration have on the cells that are bathed by the interstitial fluid?___ Cells swell___ Cells shrink• The high concentration of sodium in the extracellular fluid exerts osmotic pressure and helps determine the fluid levels in the intracellular space.Hyponatremia• What effect would this decrease in sodium concentration have on the cells that are bathed by the interstitial fluid?___ Cells swell___ Cells shrink• The water moves into the cell, and the cell expands slightly.
9 Roles of Sodium in the Body • nerve impulse conduction and muscle contraction,primary regulator of water movement in the body because water follows sodium by osmosis.• If sodium levels in the plasma change, those changes determine fluid levels in the other compartments.Causes and Symptoms of HypernatremiaWhich of these reasons would most likely cause hypernatremia in the marathon runner?____ Too much sodium added____ Too much water lostSymptoms of hypernatremia include non-specific signs of central nervous system dysfunction such as confusion and lethargy, and in severe cases, seizures and death.• What do you think causes these symptoms?___ Neurons shrink___ Neurons swellWhat will happen to urine output? Decreases• When plasma osmolarity increases, antidiuretic hormone is released, resulting in reabsorption of water and decreased urine output.
10 Sodium Balance This diagram shows how sodium is distributed in the body. Note the important role of the kidney in filtering andsubsequently reabsorbing that sodium. (Note: Although not listed in the diagram abovethere can also be significant losses of sodium from the gastrointestinal system (vomitingand diarrhea) and from the skin following burns and from the cardiovascular systemfollowing hemorrhage. Please note that you don’t need to know the numbers just therelative inputs and outputs.Understanding the mechanisms of renal sodium transport is important for several reasons. First,NaCl and water are filtered at the highest rates. Therefore there is an enormous amount ofwater and sodium reabsorption. You will come to see that the reabsorption of water and sodiumare related. Second, transport of sodium (down its electrochemical gradient) is linked to essentialtubular reabsorptive and secretory processes for many other substances. Third, mechanisms ofNaCl reabsorption are modified clinically by diuretics. Treatment with diuretics aims to reduceECF volume by increasing renal excretion of NaCl and water. Diuretics are commonly usedmedications in the treatment of pulmonary edema and hypertension. An easy way to rememberthe importance of sodium and water movement is that ‘water will follow sodium’ in the nephron.Increase sodium reabosrption will lead to increased water reabsorption while inhibition ofsodium reabsorption will lead to a diuresis.
11 Where Does Na+ Reabsorption Occur? FE = 10%[Na+] =145FE = 3%FE = 35%The filtered load of sodium is far greater than the daily requirement for sodium excretion.Typically the fractional excretion for sodium is about 1-2%. Filtration and reabsorption are theonly significant processes affecting NaCl and water excretion. Thus, regulation of excretion isachieved largely by varying the amount that escapes tubular reabsorption.The slide illustratessegmental handling ofsodium (FE values forchloride are similar). Theslide shows the proportion offiltered sodium remaining inthe nephron at the pointindicated (fractionalexcretion). For example, theproximal tubule extracts 65%of the filtered load ofsodium, so that the fractionremaining at the end of thissegment is 35%. The loop ofHenle typically reabsorbsanother 20-25% of thefiltered load, so that around10% of filtered NaCl entersthe distal tubule. The % of filtered NaCl delivered to the distal nephron does not change muchacross a wide range of NaCl intakes. This design allows for fine regulation of NaCl excretion inthe distal tubule and collecting duct, particularly by aldosterone.FE =%[Na+] units = mmole/LFE= Fractional excretion
12 The Na+/K+-ATPase Drives Na+ Reabsorption All Along The Renal Tubule LumenBloodNa+3Na+ATPADP2K+Active sodium reabsorption is the key driving force behind NaCl and water reabsorption alongthe nephron. Chloride absorption is passive or occurs via secondary active transport coupled tothe movement of sodium. Water reabsorption is coupled to the reabsorption of NaCl and occursby osmosis.The slide describes the basic process of transcellular sodium absorption, which is a two-stepprocess involving passive uptake across the apical membrane (through co-transporters,antiporters or channels) and active extrusion across the basolateral membrane. The latter isdriven by the sodium/potassium-ATPase, which in renal epithelial cells keeps intracellularsodium at a concentration of around 30 mEq/L. The energy in the large inward sodium gradientat the luminal membrane is coupled to the uptake of many other substrates. The sodium entrystep is the target of inhibition by the diuretics in most common clinical use.diureticsNa+
13 In Early Proximal Tubule Na+ Absorption Is Linked To Nutrient Transport….. LumenBlood3Na+Na+ATPADP2K+nutrientNutrient(a.a & gluc.)The mechanism for nutrient uptake inearly proximal tubule is shown. Its keyfeature is the presence of sodium linkedcotransport at the apical membrane. Thisconcentrates the nutrient molecule in thecell and allows it to diffuse out of the cellinto the blood via facilitated diffusion.Depending on the nutrient moleculethere are different cotransportersinvolved. For glucose the maintransporter is called SGLT2 (sodiumglucosetransporter 2) – See the Figureon the next page. This is the saturabletransporter that is overwhelmed inhyperglycemic patients when the filteredglucose load exceeds reabsorptive capacity, resulting in glucose in the urine. Mutations in SGLT2also account for an inherited condition in which there is large amounts of glucose in the urineunrelated to diabetes mellitus. In the case of amino acids, there are several sodium linkedcotransporters involved, each with different substrate specificity for particular classes of aminoacid (e.g. acidic amino acids). In some cases genetic disorders of amino acid wasting can be tracedto a failure of amino acid uptake in the kidney and GI tract due to defective cotransporters.Familial renal glycosuria – SGLT2 mutationsCystinuria – dibasic amino acid carrierHartnup’s disease – neutral amino acids
14 Absorption Mechanisms Change Along The Proximal Tubule inulin2.01.5Cl-[TFx/Px]Na+1.0osmThe transport processes that result inNaCl and water reabsorption in theproximal tubule cause the concentrationsof several solutes to change along theproximal tubule:Q. Why does the concentration of inulinincrease?Q. Why does osmolality stay the same?A striking feature of the graph is the fallin concentration of nutrient moleculessuch as glucose and amino acids alongthe proximal tubule. This shows that these solutes are preferentially reabsorbed from the filtrateat a very early site. In physiological states, glucose and amino acid reabsorption is almostcomplete one quarter of the way along the proximal tubule. The above slide also shows a markedfall in bicarbonate concentration in the early part of the proximal tubule. This recovery of filteredbicarbonate is an important feature of the renal contribution to acid-base homeostasis. In earlyproximal tubule sodium absorption is mostly coupled to the uptake of nutrients and tobicarbonate reabsorption, rather than to chloride recovery. This explains the rise in chlorideconcentration in the lumen in early proximal tubule. In the mid- to late proximal tubule sodiumabsorption is coupled to chloride absorption.There is a very important point to be seen in this graph that is not entirely obvious at firstglance. We stated previously that the proximal tubule reabsorbs approximately 65% of thefiltered sodium load. You will see that although there is an enormous amount of sodiumreabsorption taking place there is little change in the sodium concentration and osmolarity.How does this happen ? In the proximal tubule of the kidney there is ‘isosmotic’ reabsorptionof sodium and water. That is 65% of sodium and 65% of water reabsorption take place in theproximal tubule. This is an important point to remember as we will later deal with themechanisms which alter sodium and water reabsorption.HCO3-0.5Glucose/amino acids0.0Length of proximal tubule
15 + Na+ Uptake In The TALH Is Via A Cotransport Mechanism Blood Lumen NKCC22Cl-2K+K+Cl-ROMKCLC-Kb+cationsNa, Ca and MgLoop of HenleIn the thin limbs of Henle’s loop there is no active transport of NaCl. The descending andascending thin limbs have differences in passive permeability, which are important to the urineconcentration mechanism. The thick ascending limb is metabolically very active.The sodium and chloride uptake intothe cell are coupled via a cotransportmechanism, which also includes uptakeof potassium. The process is electricallyneutral since it involves 1 sodium, 2chloride and 1 potassium ions. At thebasolateral membrane sodium ispumped out via the Na/K-ATPase,whereas chloride leaves via an ionchannel. At the apical membrane thepresence of a potassium channel torecycle potassium that enters duringNaCl uptake is important. First, theconcentrations of sodium chloride intubular fluid entering the thickascending limb are much higher than potassium concentration. This means that there would notbe sufficient potassium available to load the cotransporter for sodium chloride uptake, ifpotassium was not recycled. The second reason the apical potassium conductance is important isthat, in conjunction with the basolateral chloride conductance a lumen positive tranepithelialelectrical potential difference is generated. This potential difference is important because the tightjunctions in this region are cation permeable, particularly to magnesium ions. The lumen positivepotential allows for a significant paracellular cation flux.The molecular identity of all the transporters in the thick ascending limb cell model are known(see slide). If a loss of function mutation arises in the cotransporter, the apical potassium channelor the basolateral chloride channel, a rare inherited condition called Bartter’s Syndrome occurs.This disease is associated with urinary wasting of NaCl due to the loss of reabsorption in thethick ascending limb. Bartter’s Syndrome patients also lose large amounts of calcium andmagnesium, reflecting the importance of this segment in divalent cation handling.Mutations in any of NKCC2, ROMK or CLC-Kb= BARTTER’S SYNDROMEADH targets NKCC2 & ROMK‘loop diuretics’ Bumetanide & Furosemide block NKCC2
16 Early Distal Tubule Uses Na/Cl Cotransport For Na+ Absorption LumenBlood3Na+Na+NCCT2K+Cl-Cl-Distal TubuleThe distal tubule is a heterogeneous segment. Early distal tubule (“distal convoluted tubule”) islined by epithelial cells with the transport proteins shown below. The late distal tubule mergeswith a connecting tubule, which in turn merges with a cortical collecting duct. During thistransition the epithelial lining becomes a mixture of cell types, including those seen in the earlydistal tubule and the renal principal cells, which are described in the section on collecting ductbelow.In early distal tubule sodium andchloride are coupled directly viaa cotransporter. Uphill sodiumexit is via the usual pathway ofthe Na/K-ATPase, while thatfor chloride is via an ionchannel. The molecular identityof the cotransporter is knownand mutations in this protein arethe basis for a rare salt wastingdisease called Gittelman’sSyndrome.NCCT mutations causeGITTELMAN’S SYNDROMEThiazide Diuretics block NCCT
17 Na+ Entry In The Collecting Duct Is Via An Ion Channel LumenBloodPrincipal cellNa+ENaC3Na+K+ROMK2K+Cortical Collecting DuctThis segment has two distinct cell types. Principal cells are the most abundant cells and areassociated with NaCl reabsorption. Intercalated cells are the other cell type present and areinvolved with acid-base balance.Principal cells are the only sitein the nephron where sodiumuptake from the lumen occursvia simple diffusion through anion channel. The presence ofpotassium channels in theapical membrane is importantto the overall function of thiscell. Aldosterone signals to thekidney to conserve sodium andexcrete more potassium.Principal cells are the majortarget for aldosterone, whichincreases the activity of all thetransporters shown.The sodium channel in the apical membrane of renal principal cells is ENaC. In Liddle’ssyndrome ENaC is mutated so that it becomes more active than it should be. Liddle’s Syndromeis associated with salt-sensitive hypertension because patients reabsorb too much salt in the latedistal tubule and cortical collecting duct. This leads to expansion of the ECF volume and toincreased blood pressure. ENaC channels can also be mutated so that function is lost. Thiscauses a syndrome that appears to be the same as having no aldosterone productionENaC gain of function = LIDDLE’S SYNDROMEENaC loss of function =PSEUDOHYPOALDOSTERONISM (PHA)Aldosterone activates ENaC & ROMK while Amiloride like diuretics block ENaC