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Thank you very much for downloading renal pathophysiology the essentials. Renal Pathophysiology The Essentials 3rd Edition PDF Preface Publisher's Note: . pdf. RENNKE & DENKER - Renal Pathophysiology 4Ed (1). Pages . 1 2 Renal Pathophysiology: The Essentials The kidney performs two major functions: . Get Instant Access to PDF File: #52cfa1 Renal Pathophysiology: The Essentials By Helmut G. Rennke, Bradley M. Denker [PDF EBOOK EPUB KINDLE].
Segmental Sodium Reabsorption The major nephron segments Fig. Schematic representation of the transport mechanisms involved in sodium chloride and calcium reabsorption in the distal tubule. As shown in Figure 2. The increase in extracellular fluid leads to increased urinary sodium excretion. Autoregulation of glomerular filtration rate GFR , expressed as a percentage of control values, as the renal artery pressure is reduced from a base- line level of mmHg in dogs.
Issues of differential diagnosis and therapy are linked to pathophysiologic mechanisms. Short questions interspersed in the text require students to apply their knowledge. SlideShare Explore Search You. Submit Search.
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Upcoming SlideShare. Like this presentation? Why not share! An annual anal Embed Size px. Start on. Show related SlideShares at end. WordPress Shortcode. Published in: Full Name Comment goes here. Are you sure you want to Yes No. Be the first to like this. No Downloads. Views Total views. Proximal Tubule The proximal tubule has two major reabsorptive functions: Filtered sodium enters the proximal tubular cell via a series of transport- ers 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 solute 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.
From a quantitative viewpoint, however, sodium—hydrogen exchange is of greatest importance. 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.
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 sol- utes whose reabsorption is passively linked to that of sodium, such as urea, potassium, and calcium. Sodium-induced water reabsorption raises the tubular fluid concentration of these solutes, thereby allowing them to be pas- sively reabsorbed down a favorable concentration gradient.
In comparison, the tight junctions are relatively impermeable in the more distal segments. As a result, concentration and osmotic gradients that can exceed The Essentials When patients become volume depleted, as with vomiting or diarrhea, the renin—angiotensin and sympathetic nervous systems are activated see Chapter 2.
What will happen to proximal urea reabsorption in this setting? Loop of Henle Thirty-five to forty percent of the filtered sodium and chloride is reabsorbed in the ascending limb of the loop of Henle.
Reabsorption of sodium in the loop occurs in excess of that of water, since the apical membrane of the ascend- ing limb is impermeable to water, lacking the aquaporins water channels present in the proximal tubule. This separation between sodium and water movement is an essential part of the countercurrent mechanism. The major mechanism of active sodium chloride transport in the thick ascending limb is shown in Figure 1.
However, the concentration of potassium in the lumen, and in the extracel- lular fluid, is much lower than that of sodium and chloride. Thus, continued sodium chloride reabsorption requires that the potassium entering the cell be recycled back into the tubular lumen through selective potassium chan- nels in the apical membrane. This movement of potassium is electrogenic, making the lumen electropositive.
Chloride exits the cell through a selec- tive basolateral channel. The lumen positivity generated by potassium recycling is able to drive the passive reabsorption of cations sodium, calcium, and magnesium between the cells across the tight junction.
In fact, the cortical aspect of the thick ascending limb of Henle is the major site within the nephron at which magnesium is reabsorbed. What effect will this have on 2 calcium reabsorption in this segment?
Schematic model of ion transport in the thick ascending limb of the loop of Henle. The lumen-positive potential generated by the recycling of potassium promotes the passive reabsorption of sodium, calcium, and magne- sium between the cells across the tight junction. The Essentials Note that the transport in the thick ascending limb is very different from that in the proximal tubule. Sodium reabsorption is not linked to organic solutes, since almost all of the filtered glucose and amino acids have already been removed.
It is this fall in the concentration of chloride, rather than sodium or the action of hormones, that limits sodium chloride reabsorption in the loop of Henle and the distal tubule. The fall in the luminal chloride concentration has two effects that limit continued transport: Although it is the inward gradient for sodium that appears to pro- vide the energy for these transport processes, the attachment of luminal chloride to its site on the transporter appears to be of primary importance in inducing the conformational change in the transporter that is required for solute movement into the cell.
Thus, the falling concentration within the lumen creates a favorable concentration gradient for the backflux of sodium and chloride into the lumen across the tight junctions. Reabsorption ceases when the rate of sodium entry into the cell equals the rate of backflux. The net effect is that transport in the loop of Henle and the distal tubule is flow dependent. If, for example, more fluid is delivered to the distal tubule because of the administration of a loop diuretic, then more sodium chloride can be reabsorbed.
This distal response reduces the degree to which a loop diuretic can increase sodium excretion. Schematic representation of the transport mechanisms involved in sodium chloride and calcium reabsorption in the distal tubule. The Essentials parathyroid hormone and calcitriol 1,25 dihydroxy vitamin D, the active metabolite of vitamin D. A model for distal calcium reabsorption is shown in Figure 1.
Calcium is able to enter the cell down a favorable electrochem- ical gradient through apical calcium channels and a vitamin D-dependent calcium-binding protein.
Once within the cell, calcium may be bound to a calcitriol-dependent calcium-binding protein. The collecting ducts contain a variety of cell types. The principal cells in the cortical collecting duct and the cells in the inner medullary collecting duct play an impor- tant role in sodium and water reabsorption and in potassium secretion. In comparison, the intercalated cells in the cortex and the cells in the outer medulla are primarily involved in the regulation of acid—base balance see Chapter 5.
Sodium entry in the collecting ducts occurs through selective sodium channels in the apical membrane Fig. This movement of sodium with- out chloride is electrogenic, creating a lumen-negative gradient that pro- motes the reabsorption of chloride between the cells and the secretion of potassium through selective potassium channels.
The number of open sodium channels is under hormonal control, being affected by aldosterone and by atrial natriuretic peptide ANP. ANP, on the other hand, acts primarily in the inner medulla, decreasing sodium reabsorption by reducing the number of open sodium channels. The interaction between these opposing hormones—aldosterone and ANP—in the regulation of sodium balance is reviewed in Chapter 2.
Aldosterone-induced entry of sodium into the cell also promotes the secretion of potassium from the cell into the lumen. Two factors con- tribute to this response: Schematic model of the transport pathways and hormonal factors—aldosterone, atrial natriuretic peptide ANP , and antidiuretic hormone ADH —involved in sodium, potassium, and water handling in the collecting ducts.
Aquaporin AQP , vasopressin V2 , protein kinase A PKA , different cells, such as the intercalated cells in the cortical collecting duct, are involved in the regulation of acid—base balance see Chapter 5.
The Essentials Water Transport As described above, the proximal tubule and descending limb are water per- meable while the thick ascending limb and distal tubule are not. As such, the reabsorption of sodium without water results in a dilute fluid leaving these segments. Under basal conditions, the collecting ducts are relatively imper- meable to water since there are few aquaporins in the apical membrane.
Water reabsorption, however, is under the control of antidiuretic hormone ADH. When ADH release is increased, a sequence of events is initiated that includes attachment to the V2 vasopressin receptor in the basolateral mem- brane, activation of adenylyl cyclase by heterotrimeric G protein Gs , Gs, and insertion of cytosolic vesicles containing preformed aquaporin-2 water channels into the apical membrane. Water entering the cell readily reaches the circulation through constitutively expressed basolateral aquaporin-3 and -4 water channels Fig.
Countercurrent Mechanism Although the glomerular filtrate has the 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 after a period of water restriction. The excretion of dilute or concentrated urine is achieved via the coun- tercurrent 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 the major steps involved. The role of ADH in the maintenance of water balance is presented in Chapter 2.
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. The factors resulting in countercurrent multipli- cation countercurrent refers to the opposite direction of urine flow in the ascending and descending limbs are the different water permeabilities and solute transport characteristics in the two limbs.
The descending limb is permeable to water but not to ions, whereas the ascending limb both thin and thick is permeable to ions but not to water. In contrast, only passive solute transport occurs in the descending and thin ascending limbs. For the sake of simplicity, it will be assumed that both the thin and thick ascending limbs function in a homogeneous manner. Relationship of vasa recta to tubule segments and counter current mechanism depicting the events in the renal medulla involved in the excretion of concentrated urine.
The transport of sodium chloride without water from the ascending limb of the loop of Henle makes the tubular fluid dilute and the med- ullary interstitium and descending limb of the loop of Henle concentrated.
The key points are as follows: The ascending limb and distal tubule; not shown are impermeable to water. As a result, the fluid returning to the medulla in the medullary collecting duct is isosmotic to plasma. However, the osmolality of urine gradually rises in the collecting duct in the presence of ADH as the tubular fluid equilibrates with the medullary interstitium.
The Essentials of Henle, so those nephrons with long loops that descend into the inner medulla are the most effective at generating a wide osmolar gradient. The process starts in the thick ascending limb with active removal of NaCl out of the urine and into the interstitium. Therefore, the interstitium becomes hypersomolar resulting in water diffusion out of the descending limb.
This process concentrates the urine in the descending limb and the resulting water removal tends to lower the intersitital osmolality. This process is summarized in Figure 1.
The excretion of concentrated urine begins with generation of the inter- stitial osmotic gradient as described above. The configuration of the tubule results in the collecting duct descending into the medulla in parallel with the loop of Henle Fig.
As a result, the increasing osmolality gradient through the cortex and medulla generated by the countercurrent mechanism in the loop of Henle is also in equilibrium with the collecting duct. Unlike any other nephron segment, the collecting duct is dramatically responsive to ADH permitting it to be highly permeable to water in the presence of ADH, but impermeable in the absence of ADH.
In the presence of ADH, urinary concentration within the collecting duct can reach levels approaching the interstitial concentrations at the papilla bottom of the loop of Henle. The increase in urine osmolality varies with the circulat- ing concentration of ADH.
The role of the cortical collecting duct is essential to the production of concentrated urine. If the only processes were sodium chloride reabsorption without water in the medullary ascending limb and water reabsorption without sodium chloride in the medullary collecting duct, the excreted urine would essentially be isosmotic to plasma.
This does not occur because most of the water is removed in the cortex. This marked reduction in water delivery to the medullary collecting duct allows osmotic water reabsorption to take place in the medulla without substantial washout of the interstitial osmotic gradient.
In the absence of ADH, the collecting duct is not permeable to water, allowing excretion of dilute urine without affecting medullary osmolality. In addition to these basic steps, the hairpin or loop configuration of the vasa recta capillaries plays an important contributory role by minimiz- ing removal of the excess medullary interstitial solute.
The descending vasa recta enters the medulla at the corticomedullary junction and flows down to the tip of the papilla; it then turns around and becomes the ascending limb, which returns to the cortex. Although this does occur in the descending limb of the vasa recta, these processes are reversed as the direction of flow is reversed in the ascending limb.
The net effect is that the fluid leaving the medulla is only slightly hyperosmotic to plasma and medullary tonicity is maintained. SUMMARY Although the preceding discussion has considered each nephron segment sepa- rately, it is important to appreciate that the different segments act in concert to maintain fluid and electrolyte balance.
This can be illustrated by two examples that will be discussed in detail in Chapter 2. First, if the extracellular volume is reduced because of fluid losses as with diarrhea or vomiting , the kidney attempts to compensate by minimizing sodium excretion to prevent a further fall in volume. Neurohumoral and hemodynamic mechanisms are activated that can increase sodium reabsorption in almost every segment: Angiotensin II and norepinephrine act in the proximal tubule; a volume depletion-induced fall in blood pressure acts in the loop of Henle via the phenomenon of pressure natri- uresis; and aldosterone acts in the collecting ducts.
These compensatory mechanisms also come into play if urinary fluid loss is induced by the administration of a loop diuretic, which diminishes sodium chloride reabsorption in the thick ascending limb of the loop of Henle see Chapter 4. This fluid loss again activates the renin—angiotensin—aldosterone and sympathetic nervous systems.
As a result, the net increase in sodium excre- tion resulting from decreased loop reabsorption is at first minimized and even- tually abolished by enhanced sodium reabsorption in other tubule segments. The total kidney GFR is equal to the sum of the filtra- tion rates in all of the functioning nephrons and there are approximately one million nephrons per kidney; as a result, total GFR is an index of the functioning renal mass. Thus, estimation of GFR can be used to evaluate the severity and the course of renal disease.
For example, a fall in GFR means that the disease is progressing, whereas a rise in GFR is indicative of at least partial recovery. In normal subjects, however, GFR is primarily regulated by alterations in Pgc that are mediated by changes in glomerular arteriolar resistance.
The Pgc also plays a role in renal disease. For example, the initial fall in glomerular permeability in glomerular disease does not nec- essarily lead to reduction in GFR. In this setting, changes in arteriolar resis- tance can increase the Pgc, thereby raising the gradient favoring filtration and at least in part overcoming the effect of decreased permeability.
Arteriolar Resistance and Glomerular Filtration Rate The glomerular capillaries are interposed between two arterioles: As a result, the Pgc is governed by the interplay between three factors: Arteriolar resistance is not only partially under intrinsic myogenic control but can also be influenced by other factors, including tubuloglo- merular feedback, angiotensin II, norepinephrine, and other hormones Chapter 2.
In view of the importance of Pgc, it might be assumed that small variations in arterial pressure could produce large changes in glomeru- lar filtration. However, GFR and renal plasma flow is almost constant over a relatively wide range of renal arterial pressures Fig.
This phenom- enon, which is also present in other capillaries, is called autoregulation. Autoregulation in most capillaries is mediated by changes in precapillary resistance. Constriction of the afferent arteriole increases renal vascular resistance thereby reducing RPF and decreases the intraglomerular pressure and GFR, since less of the arterial pressure is trans- mitted to the glomerulus A. Arteriolar dilation has the opposite effects. Autoregulation of glomerular filtration rate GFR , expressed as a percentage of control values, as the renal artery pressure is reduced from a base- line level of mmHg in dogs.
The squares represent control animals in which GFR was maintained until renal perfusion pressure was markedly reduced. The circles represent animals given an intrarenal infusion of an angiotensin II antago- nist. In this setting, GFR is less well maintained. Although not shown, autoregula- tion also applies when renal artery pressure is initially raised. Conversely, GFR can be preserved by afferent dilation when renal perfusion pressure falls.
However, the mechanism of autoregulation of GFR is more complex. Angiotensin II makes an important contribution when renal perfusion pres- sure falls, a situation in which the renin—angiotensin system is activated.
Angiotensin II preferentially increases the resistance at the efferent arteriole, thereby preventing the Pgc from declining in the presence of hypotension.
The contribution of angiotensin II to autoregulation can be seen in Figure 1. In normal animals, GFR begins to fall only when there is a marked reduction in renal perfusion pressure; this limitation presumably is due in part to maximal dilation of the afferent arteriole. In comparison, GFR begins to fall at a higher perfusion pressure in animals pretreated with an angioten- sin II antagonist.
Even in this situation, however, the ability to autoregulate is maintained with the initial reduction in renal perfusion pressure. This auto- regulation at mild reductions in perfusion pressure is mediated by tubuloglo- merular feedback see next section and the stretch receptors. Narrowing of the renal arteries renal artery stenosis is a relatively common cause of severe or refractory hypertension, and is usually due to atherosclerotic lesions in older patients.
What 3 should happen to GFR in a stenotic kidney as BP is lowered with antihypertensive agents that act independently of angiotensin II?
Would the response be different if any angiotensin-converting enzyme inhibitor, which decreases the formation of angiotensin II, were given? Tubuloglomerular Feedback. GFR is in part autoregulated by the rate of fluid delivery to the specialized cells in the macula densa, which begins at the end of the cortical thick ascending limb of the loop of Henle. This restores macula densa flow hence the name tubuloglomerular feedback.
Conversely, the afferent arteriole will constrict and GFR will fall in the pres- ence of a rise in renal perfusion pressure that increases GFR.
These observations suggest that a major function of autoregulation is not only to maintain GFR but also to maintain distal flow at a relatively constant rate. As described above, the bulk of the filtrate is reabsorbed in the proximal tubule and loop of Henle, while the final qualitative changes sodium and water reabsorption, potassium secretion are made in the col- lecting ducts.
However, the collecting ducts have a relatively limited total reabsorptive capacity. Juxtaglomerular apparatus and macula densa in tubuloglomeru- lar feedback. The juxtaglomerular apparatus and macula densa cells at the begin- ning of the distal tubule are in close proximity. Renin release is also regulated at this site see Chapter 2.
It is important to recognize that the macula densa cells have at least two different functions: The Essentials by tubuloglomerular feedback and increased secretion of renin, leading to efferent constriction.
Both of these changes will tend to increase GFR, thereby raising macula densa flow toward normal. The intrarenal effects of autoregulation and tubuloglomerular feedback are important in the day-to-day regulation of renal hemodynamics in nor- mal subjects.
These processes also help prevent a rise in GFR with systemic hypertension or a reduction in GFR with selective renal ischemia due to renal artery stenosis. A primary glomerular disease will tend to lower GFR by decreasing the surface area available for filtration. What will be the autoregulatory response to this change? A reduction in renal perfusion pressure in patients is most often due to effective circulating volume depletion as with gastrointestinal fluid losses or congestive heart failure; see Chapter 2 , rather than to selective renal ischemia.
In these disorders, systemic hypoperfusion leads to increased release of the vasoconstrictors angiotensin II and norepi- nephrine. The former increases resistance at the efferent arteriole more than at the afferent arteriole, whereas norepinephrine affects both the arterioles to a similar degree. The net effect is renal vasoconstriction not vasodilata- tion as with pure autoregulation , a potentially marked reduction in renal plasma flow, and a slight fall or even no change in GFR due to the effect of efferent constriction.
This is a physiologically appropriate adaptation since it preferentially shunts blood to the critical coronary and cerebral circulations, while maintaining GFR and therefore excretory capacity. These vasoconstrictive effects are antagonized by renal vasodilator prostaglandins.
Angiotensin II and norepinephrine stimulate glomerular prostaglandin production. The ensuing prostaglandin-induced decrease in arteriolar tone prevents excessive renal ischemia.
This adaptation is important clinically because of the widespread use of nonsteroidal anti-inflammatory drugs to treat arthritis and other conditions.
These drugs inhibit prosta- glandin production and can produce an acute decline in GFR acute renal failure in susceptible subjects who are volume depleted and who therefore have relatively high levels of angiotensin II and norepinephrine. On the other hand, normal subjects are at little risk since, in the absence of high levels of vasoconstrictors, the rate of renal prostaglandin production is relatively low.
Clinical Estimation of Glomerular Filtration Rate As described above, the estimation of GFR is used clinically to assess the severity and course of renal disease. Measurement of GFR relies on the concept of clearance. If, for example, 1. Creatinine Clearance Although accurate, performance of the inulin or radioisotopic clearance is too cumbersome and expensive for routine clinical use. The most com- mon method used to obtain an estimate of measured GFR is the endogenous creatinine clearance: Like an inulin infusion, it has a relatively stable plasma concentration, it is freely filtered at the glomerulus, and it is not reabsorbed, synthesized, or metabolized by the kidney.
However, a variable quantity of creatinine is secreted into the urine in the proximal tubule. Creatinine clearance is usually determined by using venous blood for the plasma creati- nine concentration and a hour urine specimen for the urine volume and urine creatinine concentration. The Essentials Limitations.
Two errors can occur with creatinine clearance. The first is underestimation of the true GFR due to an incomplete urine collection by the patient. The relative constancy of creatinine production and therefore of creatinine excretion in the steady state can be used to assess patient compli- ance. Creatinine production varies directly with muscle mass which falls with age and to a lesser degree with meat intake which is a source of creati- nine. From the ages of 50 to 90, there is a progressive decline in creatinine excretion, due primarily to a fall in muscle mass.
Values much below expected levels suggest an incomplete collection or severe malnutrition leading to a loss of muscle mass. A year-old woman weighing 65 kg is being evaluated for possible renal disease.
Plasma creatinine concentration is 1. Does the rate of creatinine excretion suggest that this is a complete urine collection? As mentioned, a second frequent error is overestimation of GFR due to cre- atinine secretion. In this situation, creatinine clearance can markedly overestimate the true GFR, masking the severity and perhaps even the presence of a decline in renal function.
It has been suggested that, in patients with moderate to advanced dis- ease, a more accurate estimate of GFR can be obtained by averaging creat- inine and urea clearances. Thus, urea clearance will under- estimate GFR, a change that will counteract overestimation by creatinine clearance when the two values are averaged. Plasma levels of some drugs normally excreted by the kidneys can be monitored for potentially toxic effects such as digoxin or an aminoglycoside antibiotic.
As a result, newly produced creatinine will accumu- late in the plasma until the filtered load again equals the rate of production. This will occur when plasma creatinine concentration has increased twofold, excluding the contribution from creatinine secretion: Creatinine production can also be influenced by the intake of meat, which contains creatine, the precursor of creatinine.
The idealized reciprocal relationship between GFR and plasma creati- nine concentration is shown by the solid curve in Figure 1. There are three points to note about this relationship: If, for example, GFR suddenly ceases, plasma cre- atinine concentration will still be normal for the first few hours because there has not been time for nonexcreted creatinine to accumulate. An apparently minor elevation in plasma creatinine concentration from 1. The Essentials 9.
Relationship between true GFR as measured by inulin clear- ance and plasma creatinine concentration in patients with glomerular disease. The latter becomes saturated at a plasma creatinine concentration above 1. Since creatinine production is assumed to be constant, the relationship between plasma creatinine concentration and GFR can be used to estimate the GFR at a new steady state creatinine concentration. The horizontal dashed line in Figure 1.
A serum creatinine of 1. The following formula has been used to account for the effects of body weight and age on muscle mass and therefore on the relationship between plasma creatinine concentration and GFR: Using this formula, which correlates fairly closely with a simultaneously measured creatinine clearance, we can see that a seemingly normal plasma creatinine concentration of 1.
Similar findings can be dem- onstrated in malnourished patients, such as those with advanced hepatic cirrhosis. These include www. However, this equation was derived from white patients with nondi- abetic kidney disease and is less precise in obese patients, patients with normal or near-normal GFR, and other ethnic populations.
A year-old man who weighs 70 kg has been unable to urinate for several days due to obstruction of the urethra by an enlarged prostate. Back pressure up the nephron will raise the 6 intratubular pressure and cause GFR to fall to very low levels.
A catheter is placed in the bladder to relieve the obstruction. What accounts for this reduction in plasma creatinine concentration? Three factors can contribute to this problem, two of which prevent or minimize any reduction in GFR and one of which minimizes the rise in plasma creatinine concentration when GFR does fall: Nevertheless, GFR is initially maintained at normal or near-normal levels by a compensatory elevation in intraglomerular pres- sure that may be mediated by tubuloglomerular feedback.
The potential effect of enhanced creatinine secretion is illustrated in Figure 1. Thus, a stable value within the normal or high-normal range does not necessarily reflect stable disease. Like plasma cre- atinine concentration, BUN is excreted by glomerular filtration and tends to vary inversely with GFR. However, this relationship is less predictable, since two factors can affect BUN without a change in GFR or plasma creatinine concentration.
First, urea production is not constant. Urea is formed from the hepatic metabolism of amino acids that are not utilized for protein synthesis.
Amino acid deami- nation leads to the generation of ammonia NH3 , which is then converted into urea in a reaction that can be summarized by the following reaction: Thus, increased proximal reabsorption as appropriately occurs in hypovolemic states will raise BUN out of proportion to any change in GFR or plasma creatinine concentration see Chapter 11 for a discussion of how this relationship can be useful in the differential diagno- sis of acute renal failure.
Answers to Questions Increased reabsorption of sodium and water will raise the tubular fluid urea 1 concentration, resulting in enhanced passive urea reabsorption. This will reduce urea excretion, thereby increasing the BUN concentration.
This selective elevation in BUN is, in the appropriate clinical setting, suggestive of volume depletion and decreased renal perfusion as the cause of renal dysfunction, rather than intrinsic renal disease see Chapter This ability to increase calcium excretion makes a loop diuretic a key component of therapy for hypercalcemia. The intrarenal pressure distal to the stenosis should be lower than the arte- 3 rial pressure.
As a result, lowering systemic blood pressure will further reduce intrarenal pressure to below normal. Nevertheless, autoregulation will maintain GFR unless the stenosis is so severe or the systemic pressure is lowered so much that intraglomerular pressure falls below the autoregulatory range.
The administration of an angiotensin-converting enzyme inhibitor will tend to lower GFR by blocking angiotensin II—mediated regulation at the efferent arteriole. Therefore, the combination of reduced afferent flow distal to the stenosis and inhibition of normal efferent regulatory mechanisms by angiotensin-converting enzyme inhibitor can lead to acute renal failure if bilateral renal artery stenoses or unilateral stenosis in a solitary kidney.
The fall in GFR will lead sequentially to decreased fluid delivery to the mac- 4 ula densa, activation of tubuloglomerular feedback, afferent arteriolar dila- tation, and a rise in intraglomerular pressure that will return GFR and macula densa flow toward normal. Thus, estimation of GFR will underestimate the severity of glomerular disease, since substantial damage can occur without any significant fall in GFR.
In addition, the compensatory elevation in intraglomerular pressure may be maladaptive over the long term, since intraglomerular hypertension can pro- duce progressive glomerular injury independent of the activity of the underlying disease see Chapter The Essentials which is about one-half the expected value.
The very low GFR during the period of almost complete urinary tract 6 obstruction caused creatinine to accumulate in the plasma. Relief of the obstruction allowed GFR to return to near-normal levels. However, a normal GFR at a plasma creatinine concentration that is more than four times greater than normal 6 vs. As a result, plasma creatinine concentration will fall toward normal.
The aquaporin family of water channels in kidney. Kidney Int ; Performance of the modification of diet in renal disease and Cockcroft—Gault equations in the estimation of GFR in health and in chronic kidney disease.
J Am Soc Nephrol ; Rose BD. New York: McGraw-Hill, , Chapters 2—5. Limitations of a creatinine as a filtration marker in glomerulopathic patients.
She is started on a salt-restricted diet, but little antihypertensive effect is noted. As a result, 25 mg of hydrochlorothiazide—a thiazide-type diuretic that inhibits sodium chloride reabsorption in the distal tubule—is added. Five days later, she is noted to be lethargic and feeling very weak. Physical examination reveals a tired woman in no acute distress. The remainder of the examination is unremarkable; there are no focal neurologic findings.
Initial laboratory data reveal the following: The Essentials Objectives By the end of this chapter, you should have an understanding of each of the following issues: Introduction Water and sodium balance are regulated independently by specific pathways that are designed to prevent large changes in the plasma osmolality which is primarily determined by the plasma sodium concentration and the effective circulating volume.
The differences between these pathways can be appreci- ated by considering the clinical manifestations of impaired regulation: The plasma sodium concentration is regulated by changes in water balance and not by changes in sodium or volume balance. Physiologic Role of Osmotic Pressure An approach to the regulation of water balance begins with the processes of osmosis and osmotic pressure, which can be easily understood from the simple experiment in Figure 2.
Distilled water in a beaker is separated into two compartments by a membrane that is freely permeable to water but not to sodium chloride NaCl. Water molecules exhibit random motion and can diffuse across a membrane by a mechanism that is similar to that for diffu- sion of solutes. Effect of adding sodium chloride on fluid distribution in a rigid beaker separated into two compartments by a semipermeable membrane, which is permeable to water but not to sodium chloride.
The addition of sol- ute decreases the random movement of water, resulting in water diffusion into the solute-containing compartment at a faster rate than diffusion in the opposite direction. In a rigid compartment as in this experiment, the net force promoting water movement can be measured as the osmotic pressure.
Since water will move from an area of high activity to the area of low activity, water will flow into the solute- containing compartment.
This increase in volume in the solute-containing compartment will raise the pressure within this compartment; this hydrostatic pressure can be mea- sured by the height of the fluid column above the compartment. Equilibrium will be reached when the hydrostatic pressure, which tends to push water back into the solute-free compartment, is equal to the osmotic forces gener- ated by the addition of NaCl, which tends to cause water movement in the opposite direction.
This equilibrium pressure is called the osmotic pressure. The osmotic pressure generated by a solute is proportional to the num- ber of solute particles, not to the size, weight, or valence of the particles.
Since 1 mol of any nondissociable substance has the same number of par- ticles 6. The unit of measurement of osmotic pressure is osmole Osm. One osmole is defined as one gram molecular weight or 1 mol of any nondis- sociable substance. The Essentials one-thousandth of a mol. For example, glucose has a molecular weight of ; thus, mg is equal to 1 mmol and can potentially generate 1 mOsm of osmotic pressure. In comparison, 1 mmol of NaCl will generate approxi- mately 2 mOsm due to its dissociation into sodium and chloride ions.
Solutes generate an osmotic pressure by their inability to cross mem- branes. Some solutes like urea are lipid-soluble and can freely cross mem- branes. As a result, the addition of urea to one compartment will lead to a new equilibrium that is reached by urea entry into the solute-free compart- ment, rather than by water movement in the opposite direction.
Thus, no osmotic pressure is generated at equilibrium and there is no water move- ment. Therefore, urea is an example of an ineffective osmole. The same prin- ciples apply to other lipid-soluble solutes such as ethanol. Plasma ethanol levels can reach relatively high levels in a patient who is drunk, but there will be little change in the effective plasma osmotic pressure or therefore in water distribution.
Osmotic Pressure and Distribution of Body Water Osmotic pressure is important physiologically because it determines the distribution of the body water between the different fluid compartments.
Adipose tissue contains no water and is not included in this calculation. The body water is primarily contained in two compart- ments that are separated by the cell membrane: The extracellular fluid is further divided into two compartments: These extracellular fluid spaces are separated by the capillary wall.
Since virtually all cell membranes and peripheral capillaries are per- meable to water, the distribution of water between these compartments is entirely determined by osmotic pressure. Each compartment has one sol- ute that is primarily limited to that compartment and therefore acts to pull water into that compartment: In comparison, sodium is able to freely cross the capillary wall and therefore acts as an ineffective osmole at the site separating the intersti- tial from intravascular compartments.
The development of edema in a vol- ume sodium expanded patient reflects the accumulation of sodium in the interstitial compartment see Chapter 4. The much larger plasma proteins, however, cannot easily diffuse across the capillary. Schematic representation of the osmotic factors that determine the distribution of the body water among its three major compartments: It might be suspected that water would continually move from the interstitium into the vascular space down this favorable osmotic gradient.
However, this does not occur because the plasma oncotic pressure is coun- terbalanced by the capillary hydraulic pressure generated by cardiac con- traction that tends to cause water movement in the opposite direction. This relationship is described in detail in Chapter 4 and Figure 4. Relationship between Plasma Osmolality and Sodium Concentration Since the osmolality in all the fluid compartments is essentially equal, we can estimate the osmolality of the body water simply by measuring the plasma osmolality.
The latter can be estimated from the following formula: These observations illustrate an important difference between osmo- lality, which is measured in the laboratory and reflects the total number of particles in solution, and the osmotic pressure, which determines fluid distri- bution and reflects the number of osmotically active particles in each com- partment. It is important to note the following: However, albumin mol. Osmoregulation and Volume Regulation The relationship between plasma osmolality and plasma sodium concentra- tion is often thought to reflect the importance of sodium balance in osmo- regulation.
However, these are separate processes since the plasma osmolal- ity is regulated by changes in water intake and water excretion, while sodium balance is regulated by changes in sodium excretion. The different characteristics of osmoregulation and sodium regulation can be illustrated by evaluating the effects of adding NaCl alone as with eating salted potato chips , water alone as with drinking but not excret- ing water , or isotonic salt and water as with an infusion of isotonic saline, which has a sodium concentration similar to that in the plasma water.
The results of these experiments are summarized in Table 2. The increase in osmolality will, as in Figure 2. Note that the osmotic effect of the added sodium is distributed through the total body water even though the sodium is restricted to the extracellular fluid. As a result, some of the excess water will move into the cells until osmotic equilibrium is achieved.
The net result is hyponatremia a low plasma sodium concentration , hypo- osmolality, and an increase in both the extracellular and intracellular fluid volumes. The increase in extracellular fluid leads to increased urinary sodium excretion.
All of the excess salt and water will remain in the extracellular fluid, producing extracellular volume expansion but no alteration in the plasma sodium concentration. A number of important observations can be appreciated when we sum- marize these experiments Table 2.
The latter is increased in all three experiments, whereas the plasma sodium concentration rises, falls, and is unchanged.
As will be reviewed below, the extracellular fluid volume is regulated by changes in sodium excretion. Since volume expansion occurred in all three experiments, there will be an appropriate increase in sodium excretion in an attempt to lower the extracellular fluid volume toward normal , even though the plasma sodium concentration may vary widely.
Hyponatremia and hypo-osmolality induce fluid movement into the cells, whereas hypernatremia and hyperosmolality induce fluid move- ment out of the cells. These changes in volume within the brain are largely responsible for the symptoms associated with hyponatremia and hyperna- tremia see Chapter 3. Suppose that you exercised on a hot day, leading to the loss of sweat, which is a relatively dilute fluid containing low concentrations of sodium and potassium.
What will happen to 1 the plasma sodium concentration, extracellular fluid volume, and urinary sodium excretion? Hormonal Role in Water and Sodium Balance The lack of predictable relationship between the plasma sodium concen- tration and extracellular fluid volume means that these parameters must be regulated independently. Table 2.
Osmoregulation Plasma osmolality is regulated by osmoreceptors in the hypothalamus that influence the release of antidiuretic hormone ADH and thirst. ADH reduces water excretion while thirst increases water intake. The combined effects result in water retention, which will tend to lower plasma osmolality and plasma sodium concentration by dilution.
These include the juxtaglomerular cells of the afferent arteriole Fig. As will be described below, these systems affect urinary sodium excretion and, via angiotensin II and norepinephrine, systemic vascular resistance. Can you think of a physiologic reason why it is beneficial to have multiple receptors for volume regulation, while only one receptor in the hypothalamus is sufficient for 2 osmoregulation?
Before discussing the basic aspects of these humoral pathways, it is useful to review the changes that will occur in the three experimental conditions sum- marized in Table 2. The Essentials will be activated: Renin release will be suppressed, while ANP secretion will be enhanced. This increase in pronatriuretic forces will appropriately enhance sodium excretion in an attempt to excrete the volume load. The ensuing fall in water reabsorp- tion will allow the excess water to be excreted rapidly in dilute urine.
The rise in plasma osmolality will enhance both ADH release and thirst, thereby reducing water excretion and increasing water intake in an attempt to lower the plasma osmolality toward normal. Volume expansion, on the other hand, will suppress the secretion of renin and increase that of ANP. The net effect will be enhanced excretion of sodium in a relatively small volume of urine, a composition that is similar to intake. In the above example of unreplaced sweat losses in Question 1, what will happen to the osmoregulatory and volume regulatory pathways?
ADH the human form is called arginine vasopressin; AVP is a poly- peptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus Fig. Secretory granules containing AVP migrate down the axons of the supraopticohypophysial tract into the posterior lobe of the pituitary, where they are stored and subsequently released after appropriate stimuli. Actions The absence or presence of ADH is the major physiologic determinant of urinary-free water excretion or retention.
ADH acts on the collecting ducts, to allow water reabsorption independent of sodium down the osmotic gradi- ents created by the countercurrent system see Chapter 1. The ADH-induced increase in collecting duct water permeability occurs primarily in the principal cells, as the adjacent intercalated cells are mostly involved in acid or bicarbonate secretion see Chapter 5. Schematic representation of the mammalian hypothalamus and pituitary gland showing pathways for the secretion of antidiuretic hor- mone ADH.
ADH is synthesized in the supraoptic and paraventricular nuclei, transported in granules along their axons, and then secreted at three sites: Black arrows indicate transport pathways to secretory sites. Activation of the V1 receptors induces vasoconstriction and enhancement of prostaglandin release, whereas the V2 receptors mediate the antidiuretic response. Activation of adenylylcyclase by ADH via the V2 receptor on the baso- lateral membrane initiates a sequence of events in which a protein kinase is activated see Chapter 1 and Fig.
This leads to apical membrane inser- tion of aquaporin-2 water channels from preformed cytoplasmic vesicles that contain aquaporin-2 water channels. Once the water channels span the luminal membrane, water is reabsorbed into the cells, and then rapidly returned to the systemic circulation across aquaporin-3 and -4 water chan- nels in the basolateral membrane. The Essentials even in the absence of ADH and the basolateral membrane has a much greater surface area than the luminal membrane.
When the ADH effect has worn off, the water channels aggregate within clathrin-coated pits and they are removed from the luminal membrane by endocytosis.
A defect in any step in this pathway, such as attachment of ADH to its receptor or the function of the water channel, can cause resistance to the action of ADH and an increase in urine output. This disorder is called nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus can occur through inherited defects in the V2 receptor or the aquaporin-2 gene, or can be acquired most commonly as a side effect of lithium therapy or hypercalcemia.
Vascular Resistance The antidiuretic effects of ADH are mediated by the V2 receptors and adeny- lylcyclase stimulation, while the V1 receptors stimulate phospholipase C and primarily act to increase vascular resistance hence the name vasopressin.
Thus, ADH may contribute to the regulation of vascular resistance, although it is clear that the renin—angiotensin and sympathetic nervous systems are of much greater importance. Renal Prostaglandins ADH stimulates the production of prostaglandins particularly prostaglan- din E2 and prostacyclin in a variety of cells within the kidney, including those in the thick ascending limb, collecting ducts, medullary interstitium, and glomerular mesangium. The prostaglandins that are produced then impair both the antidiuretic and vascular actions of ADH.
These findings have suggested that a short negative feedback loop may be present in which ADH enhances local prostaglandin production, thereby preventing an excessive antidiuretic response.
However, the effect of ADH on prostaglandin synthesis is mediated by the V1, not the antidiuretic V2, recep- tors. Thus, the major function of the ADH—prostaglandin relationship may be to maintain renal perfusion as ADH-induced vasoconstriction is mini- mized by the vasodilator prostaglandins.
Patients often use over-the-counter anti-inflammatory medications that inhibit prostaglandin biosynthesis NSAID or nonsteroidal anti-inflammatory drugs.
What might happen 4 to the serum sodium concentration in a patient taking these medications and drinking large amounts of water? These responses are physiologically appropriate, since the water retention induced by ADH will lower the plasma osmolality and raise the extracellular volume toward normal. Conversely, lowering the plasma osmolality by water loading will diminish ADH release.
The ensuing reduc- tion in collecting duct water reabsorption will decrease the urine osmolality, thereby allowing the excess water to be excreted.
Since the half-life of ADH in the circulation is several minutes, the maximum diuresis after a water load is delayed for 90 to min—the time required for the metabolism of the previously circulating ADH. Osmoreceptors The location of the osmoreceptors governing ADH release was initially dem- onstrated by experiments utilizing local infusions of hypertonic saline, which raised the local but not the systemic plasma osmolality.
ADH secretion was enhanced and the urine output fell following infusion into the carotid artery, but not the femoral artery. These findings indicated that the osmoreceptors were located in the brain hypothalamus , and not in the periphery Fig.
The signal sensed by the hypothalamic osmoreceptors is an effective osmotic gradient between the plasma and the receptor cell, leading to water movement out of or into the cell. The ensuing change in the intracellular osmotic pressure stimulates both ADH secretion and synthesis.
Relationship of the plasma ADH concentration to plasma osmo- lality in normal humans in whom the plasma osmolality was varied by chang- ing the state of hydration and to isosmotic blood volume depletion in the rat.
Although volume depletion produces a more pronounced increase in ADH levels, a relatively large fall in blood volume is required for this to occur. The Essentials The plasma sodium concentration is the major osmotic determinant of ADH release, since sodium salts are the primary effective extracellular sol- utes. In contrast, alterations in the BUN do not affect ADH release, because urea is an ineffective osmole that readily crosses cell membranes.
Above the osmotic threshold, there is a progressive and relatively linear rise in ADH secretion Fig. For example, a large water load will lower the plasma osmolality and essentially shut off the release of ADH. The net effect is the excretion of the excess water within 4 hours.