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Introdution
Although readers of this book should have already completed a course on normal renal physiology, a brief review of the basic principles involved is helpful in understanding the mechanisms by proximal tubule and loop of henle; however; day-to-day regulation primarily occurs in the collecting ducts, where the final composition of the urine is determined.
This regulatory system for solute excretion is highly efficient. For example, the filtered sodium load in a patient with a gfr of 180 l/day and a plasma eater sodium concentration of 140 meq/l is 25, 200 meq. Normal dietary sodium intake ranges from 80 to 250 meq/day. Thus, more than 99% of the filtered sodium must be reabsorbed to remain in balance. Furthermore, increasing sodium intake by 25 meq/day requires
4. An adjustment in the rate of sodium reabsorption of less than 0.1% (25 25, 200 = 0.1%).
Which disease might occur. Tubular functions will be discussed with a major emphasis on sodium and
Water reabsorption. The glomerular filtration rate including its regulation and how it is estimated in the clinical setting will also be reviewed. The kidney performs two major functions:
-it participates in the maintenance of a relatively constant extracellular environment that is necessary for the cells (And organism) to function normally. This is achieved by excretion of some waste products of metabolism (Such as urea, creatinine, and uric acid) and of water and electrolytes that are derived principle in understanding renal functions. Balance is maintained by keeping the rate of excretion equal to the sum of net intake plus endogenous production:
Excretion = intake + endogenous production
-as will be seen, the kindly is able to individually regulate the excretion of water and solutes (Such as sodium, potassium, amd hydrogen) largely by changes in tubular reabsorption or secretion. If, for example, sodium intake is increased, the excess sodium can be excreted without requiring alterations in the excretion of water or other electrolytes.
-it secretes hormones that participate in the regulation of systemic and renal hemodynamics (Rennin, angiotensin ii, and prostaglandins), red cell production (Erythropoietin), and mineral metabolism [calcitriol, (1, 25-oh dihydroxyvitamin d), the major active metabolite of vitamin d].
The kidney also performs a number of miscellanous functions such as the catabolism of peptide hormones and the synthesis of glucose (Gluconeogenesis) under fasting conditions.
Relation between filtration and excretion
The normal glomerular filtration rate (Gfr) ranges from 130 to 145 l/day (90 to 100 ml/min) in women and from 165 to 180 l/day (155 to 125 ml/min) in men. This represents a volune that is more than 10 times that of extracellular fluid and approximately 60 times that of plasman; as a result, survival requires that virtually all of the filtered solutes and water be returned to the systemic circulation by tubular reabsorption.
Preventing excessive urinary sodium loss is essential to maintenance of the extracellular and plasma volumes (See chapter 2). Figure 1.1 shows the organization of the nephron, and table 1.1 lists the relative contribution of the different nephron segments to the reabsorption of filtered sodium and the neurohumoral factors involved in regulating transport at
Figure 1.1. Anatomy of the nephron. Filtrate forms at the glomerulus and entres the proximal tubule. It them flows down the descending limb of the loop of henle into the medulla, makes a hair turn, and then ascends back into the cortex. The next segment of the tubule is the distal convoluted tubule that becomes the cortical collecting duct and then the outer and inner medullary collecting duct brfore entering the papilla through the papillary duct. The sites and mechanisms of sodium reabsorption are summarized in table 1.1.
That site. The bulk of the filtered sodium is reabsorbes in the proximal trbule and loop of henle; howewer; day-to-day regulation primarily occurs in the collecting ducts, where the composition of the urine is determined.
This regulatory system for solute excretion is highly efficient. For example, the filtered sodium load in a patient with a gfr of 180 l/day and a plasma water sodium concentration of 140 meq/l is 25, 200 meq. Normal dietary sodium intake ranges from 80 to 250 meq/ day. Thus, more than 99% of the filered sodium must be reabsorbed to remain in balance. Furthermore, increasing sodium intake by 25 meq/day requires
4 table 1.1
An adjustment in the rate of sodium reabsorption of less than 0.1% (25 25, 200=0.1%).
The following discussion will emphasize the mechanisms which sodium is reabsorbed in different nephron segments. The regulation of water, hydrogen, potassium, calcium, and phosphate handling in the kidney will be reviewed in the following chapters.
Genral mechanism of transtubular sodium reabsorption
The reabsorption of filtered sodium from the tubular lumen into the peritubular capillary occurs in two steps; sodium must move from the lumen into the cell across the apical (Or luminal) membrane; it must then move out of the cell into the interstitium and peritubular capillary across the basolateral (Or peritubular) membrane.
As with any charged particle, sodium is unable to freely diffuse across the lipid bilayer of the cell membranes. Thus, transporters or channels are required for sodium reabsorption to proceed.
For example, the active transport of sodium out of the cell is mediated by the na+-k+-atpase pump in the basolateral membrane, which pumps three sodium ions out of the cell and two potassium ions into the cell.
A general model for transcellular sodium transport is show in figure 1.2. Sodium enters the cell via a transmembrane carrier (That may
5. Review of renal physiology
Figure 1.2. General model for transtubular sodium reabsorption and schematic model of ion transport in the proximal tubule. Filtered sodium enters the cell across the apical membrane via either (1) a transmembrane carrier that can also reabsorb (As with sodium glucose or sodium-phosphate cotransport) or secrete (As with sodium-hydrogen ex-change) another substance or (2) a selective sodium channel. This sodium is then returned to the systemic circulation by the na+-k+-atpase pump in the basolateral membrane. This pump also maintains the cell sodium concentration at a low level and creates a cell-interior negative potential, both of which result in a favorable electrochemical gradient that promotes passive sodium entry into the cell in all nephron segments.
6 renal pathophysiology: the essentials
Also transport another solute such as glucose) or via a selective sodium channel. Removal of sodium from the cell by the na+-k+-atpase pump has two important additional effects. First, the cell sodium concentration is maintained at 10 to 30 meq/l, well below the 140 meq/l concentration in the extracellular fluid and the glomerular filtrate. Second, the netremoval of cell cations generates a cell-interior negative electrical potential. This effect is related to the 3:2 stoichiometry of the pump (With more sodium leaving than potassium entering) and to the diffusion of the potassium back out of the cells through selective potassium channels in the basolateral membrane.
The combination of the low sodium concentration and the cell-interior negative potential results in a favorable electrochemical gradient for sodium entry into the active reabsorption or secretion of other sub-stances (Such as glucose cotransporter) rather than by a separate energy-requiring process.
Tight junctions and membrane polarity
Normal functioning of the transepithelial transport system requires the proper localization of the transporters in to the apical or basolateral membrane domains (Membrane polarity). The sodium entry mechanisms must be on the apical membrane, while the na+-k+-atpase pump must be on the basolateral membrane. How correct localization occurs is not completely understood, but the tight junction between the cells plays an important role in the maintenance of normal membrane polarity. The tight junction acts as a gate, preventing the lateral movement of transporters or channels form one membrane domain to the other. The tight junction also prevents the paracellular movement of solutes and water through uniqeintegral membrane proteins (Claudins) within the tight junction. Epithelia vary significantly in the paracellular movement of water and solutes (“leakiness”), and these differences depend upon the unique claudins expressed in a particular epithelil cell. For example, mutations in paracellin-1, a claudin uniquely expressed in the thick ascending limb, leads to familial hypomagnesemia and urinary magnesium wasting.
Segmental sodium reabsorption
The major nephron segments (Fig. 1.1) reabsorb sodium by a mechanism similar to the general model in figure 1.2. However, the apical membrane carrier or channel responsible for sodium entry into the cell is different in each segment (Figs.1.2 to 1.5). An understanding of these different entry mechanisms in part explains some of the function performed by each
7.
Segment; it also assumes clinical importance with the use of diuretics, which inhibit tubular sodium reabsorption and lower the extracellular fluid volume in edematous states or in hypertension (See chapter 4). The physiologic factors that regulate segmental sodium transport are listed in table 1.1; how they interact to maintain sodium balance will be discussed in chapter 2.
Proximal tubule
The proximal tubule has two major reabsorptive functions: it reabsorbs 50% to 55% of the filtered sodium and water, and it reabsorbs almost all of the filtered glucose, phosphate, amino acids, and other organic solutes by linking their transport to sodium.
Filtered sodium enters the proximal tubular cell via a series of transporters that also transport other solutes. Thus, there are specific sodium-glucose, sodium-phosphate, sodium-citrate, and several different sodium-amino acid cotransporters. Binding of the cotransported so lute appears to lead to a conformational change in the carrier protein that results in an opening of the gate for transmembrane sodium movement.
Reabsorption via these transporters represents a form of secondary active transport. Although the cotransport process itself is passive, the energy is indirectly supplied by the na+-k+-atpase pump, which, as described above, creates the favorable electrochemical gradient that allows sodium to passively diffuse into the cell.
From a quantitative viewpoint, howecer, sodium-hydrogen exchange is of greatest importance. This transporter results in sodium reabsorbption and hydrogen secretion; much of the secreted hydrogen then combines with filtered bicarbonate. Leading to the reabsorption of appeoximately 90% of the filtered bicarbonate (See chapter 5 for a detailed discussion of the role of the kidney in acid-bade homeostasis).
The removal of solutes from the lumen initially lowers the tubular fluid osmolality, thereby creating an osmotic gradient that promotes an equivalent degree of water reabsorption. Osmotic water transport can occur because the apical and basolateral membranes are highly permeable to water due to the presence of transmembrane water channels (Aquaporins). Water reabsorption can also occur between the cells across the relatively “leaky”tight junction that is present in the proximal tubule.
The net effect of this permeable epithelium is that concentration or osmotic gradients cannot be maintained in this segment. As a result, the sodium concentration and osmolality of the fluid leaving the proximal tubule are the same as that in plasma. This is also true of the concentration of solutes whose reabsorption is passively linked to that of sodium, such as urea, potassium, and calcium. Sodium-induced water re-absorption raises the tubular fluid concentration of these solutes, thereby
8. Renal pathophysiology : the essentials
Allowing them to be passively reabsorbed down a favorable concentration gradient.
In comparison, the tight junction are relatively impermeable in the more distal segments. As a result, concentration and osmotic gradients that can exceed 50:1 for sodium (Urine sodium concentration _ when adh release is increased, a sequence of events is initiated that includes attachment to the v2 vasopressin receptor in the basolateral membrance, activation of adenylyl cyclase by gs, and the insertion of cytosolic vesicles containing performed aquaporin-2 water channels into apical membrane. Water entering the cell readily reaches circulation through constitutively expressed basolateral aquporin-3 and aquaporin-4 water channels (Fig. 1.5).
Countercurrent mechanism
Although the glomerular filtrate has same osmolality as that of the plasma, water intake is so variable that the excretion of isosmotic urine is usually not desirable. After a water load, for example, water must be excreted in excess of solute in dilute urine that is hypo-osmotic to plasma. On the other hand, water must be retained and a hyperosmotic or concentrated urine must be excreted urine is achieved via the countercurrent mechanism, which includes the loop of henle, the cortical and medullary collecting ducts, and the blood supply to these segments. Although a complete discussion of this process is beyond the scope of this chapter, it is useful to review briefly balance is presented in chapter 2.
The excretion of concentrated urine (Osmolality relative to plasma; can approach and maintenance of a hypertonic medullary interstitium (Up to 1200 mosm/kg). The hairpin configuration of the loop of henle and the unique microcirculation of the vasa recta that parallels the loop are essential for this process (Fig. 1.6). The factors resulting in countercurrent multiplication (Countercurrent refers to the opposite direction of
15. Review of renal physiology
Figure 1.6. Relationship of vasa recta to tubule segments and depiction of the events in the renal medulla involved in the excretion of concentrated urine. The transport of sodium chloride without water from the asce nding limb of the loop of henle makes the tubular fluid dilute and the medullary interstitium and descending limb of the loop of henle concentrated. The key points are as follows: (1) the descending limb is freely permeable to water and therefore able to equilibrate osmotically with the interstitium. (2) active sodium chloride transport in the ascending limb maintains a gradient of approximately 200 mosm/kg at each level. As urine flows doen the descending limb, the urine concentrates and the interstitium maintains this 200 mosm/kg gradient. The fluid leaving the medulla in the ascending limb has an osmolality of 200 mosm/kg (Less than plasma due to the active nacl transport).In the presence of antidiuretic hormone (Adh), water is then reabsorbed in the cortical collecting ductby osmotic equilibration with the cortical interstitium, which has an osmolality similar to plasma (285 mosm/kg). As a result, the fluid returning to the medulla in the medullary collecting duct (In the presence of adh) as the tubular fluid equilibrates with the medullary interstitium.
16. Review of renal physiology: the essentials
Urine flow in the ascending and descending limbs) are the different water permeabilities and solute transport characteristics in the two limbs.
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