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Water and electrolyte احمد حسين جاسم.د Water and electrolyte distribution In a typical adult male, total body water (TBW) is approximately 60% of body weight (somewhat more for infants and less for women). Of a TBW of 40 L, more than half is located inside cells (the intracellular fluid or ICF) while the remainder, some 15 L, is in the extracellular fluid (ECF) compartment. Of the ECF, the plasma is itself a small fraction (some 3 L). The dominant cation in the ICF is potassium, while the dominant cation in the ECF is sodium. Phosphates and negatively charged proteins constitute the major intracellular anions, while chloride and, to a lesser extent, bicarbonate dominate the ECF anions. An important difference between the plasma and interstitial compartments of the ECF is that only plasma contains significant concentrations of protein. The major force maintaining the difference in cation concentration between the ICF and ECF is the activity of the sodium-potassium pump (Na,K-activated ATPase) integral to all cell membranes. Maintenance of the cation gradients across cell membranes is essential for many cell processes, including the excitability of conducting tissues such as nerve and muscle. The difference in protein content between the plasma and the interstitial fluid compartment is maintained by the impermeability of the capillary wall to protein. This protein concentration gradient (the colloid osmotic, or oncotic, pressure of the plasma) contributes to the balance of forces across the capillary wall that favour fluid retention within the circulating plasma. Functional anatomy and physiology of renal sodium handling Since the great majority of the body's sodium content is located in the ECF, where it is by far the most abundant cation, total body sodium is a principal determinant of ECF volume. Regulation of sodium excretion by the kidney is crucially important in maintaining normal ECF volume, and hence plasma volume, in the face of wide variations in sodium intake, typically in the range 50250 mmol/day. The functional unit for renal excretion is the nephron. The glomerulus is the site of ultrafiltration of the blood, resulting in the generation of a cell- and protein-free fluid, resembling plasma in electrolyte composition, that is delivered into the initial part of the tubular system. The glomerular filtration rate (GFR) is approximately 125 mL/min (equivalent to 180 L/day) in a typical adult. Nephron segments At least four different functional segments of the nephron can be defined in terms of their mechanism for sodium reabsorption . Proximal tubule This is responsible for the reabsorption of some 65% of the filtered sodium load.. The basolateral membrane contains a high density of Na,K-ATPase pump units which remove sodium from the cell into the blood. The filtered sodium in the luminal fluid enters the cell via several transporters in the apical membrane. Cotransporters couple sodium to the entry of glucose, amino acid, phosphate and other organic molecules. A quantitatively more significant mechanism is the entry of sodium by countertransport with H+ ions, using the sodium-hydrogen exchanger (NHE-3). Water and electrolyte احمد حسين جاسم.د Intracellular H+ ions are generated from carbonic acid, the product of the enzyme carbonic anhydrase, which hydrates carbon dioxide. Overall, fluid and electrolyte reabsorption is almost isotonic in this segment, as water reabsorption is matched very closely to sodium fluxes. A component of this water flow also passes through the cells, via aquaporin-1 (AQP-1) water channels, which are not sensitive to hormonal regulation. The loop of Henle The thick ascending limb of the loop of Henle reabsorbs a further 25% of the filtered sodium but is impermeable to water, resulting in dilution of the luminal fluid. Again, the primary driving force for sodium reabsorption is the Na,K-ATPase on the basolateral cell membrane, but in this segment sodium enters the cell from the lumen via a specific carrier molecule, the Na,K,2Cl cotransporter ('triple cotransporter', or NKCC2), which allows electroneutral entry of these ions. Some of the potassium accumulated inside the cell recirculates across the apical membrane back into the lumen through a specific potassium channel (ROMK), providing a continuing supply of potassium to match the high concentrations of sodium and chloride available in the lumen. Early distal tubule Some 6% of filtered sodium is reabsorbed in the early distal (also called distal convoluted) tubule, again driven by the activity of the basolateral Na, K-ATPase. In this segment, entry of sodium into the cell from the luminal fluid is via a sodium-chloride cotransport carrier (NCCT). This segment is also impermeable to water, resulting in further dilution of the luminal fluid. There is no significant transepithelial flux of potassium in this segment, but calcium is reabsorbed through the a basolateral sodium-calcium exchanger leads to low intracellular concentrations of calcium, promoting calcium entry from the luminal fluid through a calcium channel. Late distal tubule and collecting ducts The late distal tubule and cortical collecting duct are anatomically and functionally continuous. Here sodium entry from the luminal fluid is via the epithelial sodium channel (ENaC) This sodium reabsorptive flux is balanced by excretion of potassium and hydrogen ions and by reabsorption of chloride ions. Potassium is accumulated in the cell by the basolateral Na,K-ATPase, and passes into the luminal fluid down its electrochemical gradient, through an apical potassium channel (ROMK). Chloride ions pass largely between cells. Hydrogen ion secretion is mediated by an H +ATPase located on the luminal membrane of the intercalated cells, which constitute approximately one-third of the epithelial cells in this nephron segment. This part of the nephron has a variable permeability to water, depending on the availability of antidiuretic hormone (ADH, or vasopressin) in the circulation. All ion transport processes in this segment are stimulated by the steroid hormone aldosterone. This can increase the sodium reabsorption in this segment to a maximum of 2-3% of the filtered sodium load. Less than 1% of sodium reabsorption occurs in the medullary collecting duct, where it is inhibited by natriuretic peptides such as ANP (atrial) and BNP (brain). Regulation of sodium transport Water and electrolyte احمد حسين جاسم.د Important sensing mechanisms include volume receptors in the cardiac atria and the intrathoracic veins, as well as pressure receptors located in the central arterial tree (aortic arch and carotid sinus) and the afferent arterioles within the kidney. A further afferent signal is generated within the kidney itself; the enzyme renin is released from specialised smooth muscle cells in the walls of the afferent and efferent arterioles, at the point where they make contact with the early distal tubule (at the macula densa) to form the juxtaglomerular apparatus. Renin release is stimulated by: reduced perfusion pressure in the afferent arteriole increased sympathetic nerve activity decreased sodium chloride concentration in the distal tubular fluid. Renin released into the circulation activates the effector mechanisms for sodium retention which are components of the renin-angiotensin-aldosterone (RAA) system. Renin acts on the peptide substrate angiotensinogen (manufactured in the liver), producing angiotensin I in the circulation. This in turn is cleaved by angiotensin-converting enzyme (ACE) into angiotensin II, largely in the pulmonary capillary bed. Angiotensin II has multiple actions: stimulation of proximal tubular sodium reabsorption, release of aldosterone from the zona glomerulosa of the adrenal cortex, and direct vasoconstriction of small arterioles. Aldosterone acts to amplify sodium retention by its action in the cortical collecting duct. The net effect is to restore ECF volume and blood pressure towards normal, thereby correcting the initiating hypovolaemic stimulus. The sympathetic nervous system also increases sodium retention, both through haemodynamic mechanisms (afferent arteriolar vasoconstriction and GFR reduction) and by direct stimulation of proximal tubular sodium reabsorption. Other humoral mediators, such as the natriuretic peptides, inhibit sodium reabsorption, contributing to natriuresis during periods of sodium and volume excess. DISORDERS OF WATER BALANCE Daily water intake can vary over a wide range, from 500 mL to several litres a day. While a certain amount of water is lost ('insensible losses', approximately 800 mL/day) through the stool, sweat and the respiratory tract, and some water is generated by oxidative metabolism ('metabolic water', approximately 400 mL/day), the kidneys are chiefly responsible for adjusting water excretion to maintain constancy of body water content and body fluid osmolality (normal range 280-295 mmol/kg). Functional anatomy and physiology of renal water handling While regulation of total ECF volume is largely achieved through the kidneys' control of sodium excretion, These functions are largely achieved by the properties of the loop of Henle and the collecting ducts. The counter-current configuration of flow in adjacent limbs of the loop, involving osmotic water movement from the descending limbs and solute reabsorption from neighbouring ascending limbs, sets up a gradient of tissue osmolality from isotonic (like plasma) in the renal Water and electrolyte احمد حسين جاسم.د cortex through to hypertonic (around 1200 mmol/kg) in the inner part of the medulla. At the same time, the fluid emerging from the thick ascending limb is hypotonic compared to plasma, because it has been diluted by the reabsorption of sodium, but not water, from the thick ascending limb and early distal tubule. As this dilute fluid passes from the cortex through the collecting duct system to the renal pelvis, it traverses the medullary interstitial gradient of osmolality set up by the operation of the loop of Henle, and water is avidly reabsorbed. Further changes in the urine osmolality on passage through the collecting ducts depend on the level in the plasma of the peptide ADH, which is released by the posterior pituitary gland under conditions of increased plasma osmolality or other stimuli such as hypovolaemia. Parallel to these changes in ADH release are changes in water-seeking behaviour triggered by the sensation of thirst, which also becomes activated as plasma osmolality rises from normal to above normal levels. In summary, for adequate dilution of the urine there must be: adequate solute delivery to the loop of Henle and early distal tubule normal function of the loop of Henle and early distal tubule no ADH in the circulation. If any of these processes is faulty, water retention and hyponatraemia may result. Conversely, to achieve concentration of the urine there must be: adequate solute delivery to the loop of Henle normal function of the loop of Henle ADH release into the circulation ADH action on the collecting ducts. Failure of any of these steps may result in inappropriate water loss and hypernatraemia.