renal1 Flashcards
Nephron
the nephron consists of blood supply and an epithelial tube, known as the tubule. The blood supply is remarkable, since it consists of two capillary beds in series; these are known as the glomerular and peritubular capillaries, respectively.
Glomerular Filtration
The first thing the nephron does to is filter the plasma into the initial part of the tubule. This process of filtration allows the free passage of water and solutes into the tubule, but retains larger colloids (i.e. proteins, lipid aggregates, etc.) and circulating blood cells in the blood.
Tubular Reabsorption
Once in the tubule, the kidney can recapture the filtered components that it wishes to regulate by a process generically known as reabsorption, which involves the transport of substances across the epithelia cell layer, and it involves highly selective transporters. Thus as the plasma filtrate flows through the tubule, the kidney can selectively regulate the rate of reabsorption of individual ECF components; these rates of reabsorption are constantly varied so that just enough ECF components are returned to the circulating plasma to achieve ECF constancy.
Excretion
Regulated substances in excess of those required to maintain ECF balance simply pass through the tubule and are excreted as part of the urinary output.
Regulation by tubular secretion
The forgoing description strictly applies to the two most abundant components of the ECF, water and sodium. However, other substances undergo a regulated process of secretion as part of their tubular handling to achieve ECF balance. Secretion is an epithelial transport process that involves the movement of substances from the blood or blood side of the tubule into the tubular lumen. It also often involves specific molecular transporters (channels and/or pumps). It’s also useful to mention that some substances can undergo both reabsorption and secretion within the tubule. As we shall see, the regulation of potassium (K+) involves just such a situation.
Non-ECF functions of the renal system
The kidneys perform a number of other functions not directly related to their role in ECF homeostasis. For example, the kidneys produce erythropoetin (EPO) from its precursor synthesized in the liver. Thus anemia has to be considered as a potential problem in the management of renal failure cases. In addition, the kidneys can contribute to gluconeogenesis, or the production of glucose from other metabolites in the situation of fasting or starvation.
The renin-angiotensin axis
However, the kidneys do play a hormonal role in the regulation of blood pressure by regulating the circulating levels of the potent vasopressor hormone angiotensin.
The Renin-Angiotensin axis
In this pathway, the primary regulatory event occurs when a decrease in blood pressure is sensed by baroreceptors, causing the kidneys to increase their secretion of the renal enzyme renin. The purpose of this enzyme is to cleave the 13 amino acid peptide prohormone angiotensingen to the10 amino acid angiotensin I (AgI), which is biologically inactive. However AgI circulates to the lungs, where it is cleaved by converting enzyme into the active form, angiotensin II (AgII). This hormone then circulates, causing arteriolar smooth muscle to constrict; the increased peripheral resistance thus causes a rise in blood pressure (MAP) back towards normal. The main thing to remember here is that the level of renin is rate-limiting for the production of AgII and thus determines the status of the axis. It’s useful to note that a number of antihypertensive agents are directed at this system, particularly the angiotensin converting enzyme (A.C.E.) inhibitors and angiotensin receptor antagonists.
Structure of the filtration apparatus
Filtration takes place across the capillary loops into Bowman’s capsule of the tubule; here the filtrate starts its journey through the tubule where it is processed into urine. The arterioles on either side of the glomerular capillary bed serve as valves that can control both the flow of plasma (and blood) through the filtration apparatus (and kidney) while regulating the glomerular filtration rate. Finally, the granular cells, a specialized subset of smooth muscle cells of the afferent arteriole, secrete renin, the enzyme that controls angiotensin II production. These cells are part of the juxtaglomerular apparatus (JGA).
Filtration properties of the glomerulus
Here the concentration of a substance in the filtrate formed in Bowman’s capsule relative to its concentration in the plasma, i.e. its filterability, is plotted as a function of the solute’s molecular size. Obviously for a freely filtered substance this value is 1, and for a totally excluded (nonfiltered) substance this number is zero. This molecular sieving process is also called “ultrafiltration”. Note that the dependence of filterability on molecular size is not especially sharp. Thus solutes up to several thousand daltons in size pass freely though the filter and even molecules up to 50,000 daltons have some measurable filterability. However, at around 60,000 daltons, substances do not pass through the filter, thus this value is referred to as the “molecular size cut-off” of the filter. This cut-off value is not accidental, however, since it is just lower than the size of the serum albumins (67,000 daltons). Nonetheless, significant amounts of smaller proteins do get through this filter (about 2 grams per day); these are reabsorbed and catabolized to their constituent amino acids by the tubular epithelial cells.
glomerular capillary endothelium.
The flow of the filtrate first passes through the glomerular capillary endothelium. Note that this endothelium lacks the usual slit membranes, thus it is known as a “fenestrated” epithelium. On a molecular scale, these holes are large, and they do not present much resistance to the movement of the plasma through them; hence they contribute little to the ultrafiltration properties of the glomerulus, except to exclude circulating red blood cells from entering the other layers.
podocytes
On the other side of the filter is a sheet of tubular epithelial cells known as podocytes. Instead of the usual cuboidal/columnar structure of typical epithelial cells, these have rounded cell bodies from which numerous “feet” (pedicels) are projected toward the endothelial cell layer. Feet from adjacent podocytes intimately intertwine; further there appear to be slit membranes that connect the feet. Thus it appears that the podocyte layer has the ability to function as a molecular sieve with the properties. Evidence for this view comes from human genetic diseases in which proteins that form the podocyte feet slits are defective and slits do not form; in these patients the glomerulus is very “leaky” and passes large proteins, suggesting that the slits themselves are molecular sieves.
the basal lamina
However, it also appears that the podocytes help create and support an equally important filtration barrier, the basal lamina. This structure is a thick basement membrane that is secreted by both the endothelial and epithelial cells into the space between them. It is composed of mucoproteins, which are large complexes of acidic sugars attached to protein cores. Similar to the well known nasal mucous (“snot”), on a molecular level this substance appears as a tightly woven mesh-work with holes of the correct dimensions that account for the filtration properties of the glomerulus. Further, the negatively charged basal lamina accounts for the observations that near the molecular size cut-off, highly positively charged macromolecules filter much better than would be predicted, whereas highly negatively charged macromolecules have a much lower than expected filterability. Also, as you will hear in other lectures in this series, a number of pathological conditions selectively affect the integrity of the basal lamina; this invariably results in deleterious changes to GFR. In any case, it seems most likely that both the podocyte feet slit membranes and the basal lamina contribute to the molecular sieving properties in the glomerulus.
Derivation of the Starling equation for filtration
Here we consider the GFR as a bulk flow of fluid across the glomerulus. Normally this flow extracts about 20% of the plasma as it flows along the glomerular capillaries, hence we say that the “normal filtration faction is 0.2”. How does so much fluid get filtered into the tubule? First, we consider that the GFR is just a special example of a transmural flow, i.e. a flow across a resistive boundary. The magnitude of such flows is simply given by the pressure difference across the boundary divided by the hydrodynamic resistance to flow of the boundary. For our case of GFR: GFR =deltaP/R where ΔP is the pressure across the filtration layers, and R is the resistance to flow. Let’s consider that R does not normally vary, hence we can simply give it a constant value “K”, and GFR = KDP
what are the pressures within the glomerulus that drive and resist filtration?
As for any capillary bed, filtration out of the capillary is driven by the value of the blood pressure where filtration occurs, i.e. for GFR the hydrostatic pressure within the glomerular capillary, Pgc. This is the only significant driving force for filtration. However, there are two significant forces that oppose glomerular filtration. The first results from the fact that the filtrate must flow in the narrow confines of the tubule. This results in a “backpressure” at Bowman’s capsule, which we denote by Pt. The second force is less obvious, but as you will see is strong indeed; it’s a net osmotic force that by itself would cause fluid to flow in the reverse direction to the GFR, hence the net osmotic force across the filtration apparatus is an opposing, negative force relative to glomerular capillary pressure.
How does the osmotic force arise?
It isn’t due to the normal tonicity of the plasma associated with dissolved ions and small solutes, since these filter freely across the glomerulus, and thus osmolarity due to freely filterable substances is the same on both sides of the glomerulus. Instead, on the blood side, the large dissolved proteins in the plasma (i.e. serum albumin, immunoglobulins) do not filter, hence as water is extracted from the plasma by filtration, the protein concentration rises, resulting in a net negative osmotic pressure that opposes filtration. We call this pressure the colloid osmotic pressure or COP. Sometimes this pressure is called the oncotic pressure. It is symbolized as πgc.
Net Filtration Pressure or NFP
we can now write the equation for GFR as: GFR=K(Pgc –Pt-piegc. The sum of the forces (Pgc-Pt- πgc) is called the Net Filtration Pressure or NFP. You will also recognize them as the “Starling forces” that describe glomerular capillary filtration.
Actual magnitudes of the forces and the NFP
Pgc=46mm, Pt=10mm, PIEgc=30mm. NFP=6mm
The potential role of changes in filtration area “A” in GFR regulation
The glomerular capillaries are covered by the so-called mesangial cells. It is thought that the mesangial cells can contract, and in doing so can decrease the filtration area, hence GFR. Thus it is possible that GFR to some unknown degree might be regulated or affected by the action of the mesangial cells. However, this principle of GFR regulation has not been fully established. However, an area where changes in filtration area, or indeed specific conductivity ρ are clearly important is in diseases that attack or affect the glomerular apparatus.
GFR is regulated to be relatively constant in normal physiology.
At this point we should discuss whether changes in GFR can be part of the overall regulatory picture for ECF substances under normal circumstances. For example, suppose a person drank a large excess of water; wouldn’t it make sense to simply increase the GFR while holding water reabsorption constant? This would certainly increase urinary excretion of water. The problem with this approach lies in the fact that the filtration process is nonspecific. Thus when one increases GFR with the aim of putting more water in the tubule, the other regulated solutes are also increasingly filtered; hence to stay in balance for all other regulated substances, one would have to increase the reabsorption (or decrease the secretion) for all of these other ECF components. Naturally this would result in a highly complex and energetically costly way of doing business. Instead, it appears that the renal system tries very hard to keep the GFR constant and then varies the rates of tubular handling of each regulated substance as necessary. For the example above, what happens is that GFR stays relatively unchanged but the rate of water reabsorption is decreased, resulting in the required increased urine output to stay in water balance.
The necessity for Pgc regulation
Note that under normal circumstances that Pgc is about half of the MAP found in major arteries. Naturally all capillary blood pressures are fairly low compared with MAP since the blood must flow some distance from the major arteries through ever narrowing blood vessels before reaching the capillary beds. Changes to MAP do not cause proportionate changes in glomerular capillary pressure. Instead, Pgc is very tightly regulated by the process of autoregulation.
GFR constancy
is maintained under normal conditions by glomerular capillary autoregulation. The phenomenon of autoregulation maintains blood flow in capillary beds very constantly in the face of a wide range of changes in arterial blood pressure (MAP). This is done via a myogenic mechanism, i.e. when MAP changes smooth muscle cells of the arteriole very precisely constrict or dilate in order to keep the downstream capillary blood flow constant. The very same mechanism applies to the kidney. Here it is the afferent arteriole that serves as a regulating valve to keep renal blood flow constant. However, the additional aspect of this regulation for the kidney is that with this mechanism Pgc and hence GFR are also maintained constant. This is just a consequence of the simple hydrodynamics of this system. Thus the significant changes in MAP in the renal artery can in theory be exactly compensated by the action of the afferent arteriolar valve, leaving all of the flow and pressures downstream of the valve unchanged.
Problems in autoregulation
In reality, autoregulation operates over a range of pressure changes and is not entirely “perfect”. Over a fairly wide range of MAP values (generally 75 to 150mm Hg in the human), RBF, Pgc, and GFR all remain fairly constant. However, there is some residual error in the autoregulatory mechanism, resulting in an upward creep of all three regulated variables as MAP increases. Outside the range of regulation, these variables do change rather dramatically. In particular, note how Pgc rises rapidly when MAP exceeds its autoregulatory range. This situation, such as occurs in malignant hypertension, can have grave consequences for the integrity of the delicate glomerular capillaries.
Response of the kidneys to severe hypovolemia
The autoregulatory mechanisms operate constantly during our normal daily lives, and they are intrinsic to the kidneys. However, we also have a built-in emergency response of the renal system in the rare event that our ECF volume decreases significantly, posing a threat to the function of the circulatory system. One of the vital circulatory responses to hypovolemia is to increase the resistance of the peripheral circulation, thus effectively shunting the remaining cardiac output to the organs essential for short term survival, namely the heart, brain, and lungs. In this scheme the kidneys are called upon to make their own blood flow reduction; this is especially important since the RBF is usually such a high proportion of the cardiac output. On the other hand, it is also important to viability that the kidneys not shut down markedly, but rather continue to process the plasma at a level as close to normal as possible. This is because both the primary pathological event (e.g. K+ release from tissues in muscle trauma or burns) and the recovery phase (e.g. drinking lots of pure water after severe dehydration) can involve threats to ECF homeostasis. However, complete filtration shutdown could easily occur if the volume loss leads to hypotension and a MAP drop below the autoregulatory range. Thus the kidneys have an alternative mechanism that preserves GFR at a reasonable level while also decreasing RBF.
The renal solution to hypovolemia
GFR is maintained by co-ordinate constriction of the afferent and efferent arterioles. The afferent and efferent arterioles represent a sophisticated valve system that can independently control RBF and GFR. In response to a prolonged and severe hypotension, both the afferent and efferent arterioles constrict, and they do so to about the same degree. First, afferent arteriolar constriction will increase resistance to renal blood flow, hence will have the desired effect of decreasing RBF. However, this will also have the effect of significantly decreasing Pgc and according to the principles discussed above, even more dramatically decreases GFR, perhaps even stopping it. Thus the second constriction of the efferent arteriole has a beneficial effect, for its constriction serves as a flow diverter in which Pgc is restored to its normal value, and GFR resumes a normal flow (to understand this effect better, imagine what would happen if extreme efferent constriction completely shut off blood flow through this arteriole: In this case the only pathway for plasma to flow would be to filter through the glomerulus into the tubule). In addition, the constriction of the efferent arteriole also serves to further increase renal vascular resistance, thus causing RBF to decrease even further, additionally aiding perfusion of the central organs.
Affects of renal compensation to hypovolemia
In actual practice GFR will decrease somewhat, the degree depending on the severity of the hypovolemia. However, its proportional decrease will always be less than that of the RBF. The reason for the decline of GFR under these conditions relates to the fact that by decreasing RBF, hence RPF, the filtration fraction will rise and thus πgc increases. According to the GFR equation this will tend to reduce GFR even if Pgc is held constant by the coordinate constriction of the flanking arterioles. Note that this doesn’t happen in autoregulation, since RPF is maintained constant, thus filtration fraction stays constant, and πgc is thus unchanged as well. Note also the differences in how the arterioles are affected in autoregulation versus hypovolemia. In particular, for a drop in MAP the autoregulatory response is to dilate the afferent arteriole, whereas the baroreceptor response in hypovolemia causes a constriction of this very same vessel. Naturally, for the hypovolemic response to be effective at some point it has to overwhelm the action of the autoregulatory myogenic response. Such is the case when the hypotension resulting from a loss of volume becomes sufficiently severe and chronic.
Regulation of coordinated constriction of arterioles during hypovolemia
The coordinate constriction of arterioles during hypovolemia is mediated by external and renal baroreceptors. First, the usual baroreceptors in the main arteries sense a decline in MAP. If this decrease is significant and long-lasting, a baroreceptor reflex occurs in which the activity of the renal sympathetic nerve increases. This nerve forms neuromuscular synapses on the afferent and efferent arterioles, and as with any such activity, causes the arteriolar muscle to contract, thus constricting the arterioles together. This has the desired effects of decreasing RBF while resulting in either an unchanged or more modestly decreased GFR. Second, the external baroreceptor reflex results in a hormonally-mediated constriction of the arterioles, since neural stimulation of the afferent arteriole also causes the increased release of renin from the granular cells of the JG apparatus. This automatically increases the levels of the powerful vasopressor, angiotensin II, which circulates and acts directly to constrict the arterioles of the kidney. Thirdly, the renin/angiotensin axis is stimulated by detection of reduced arteriolar pressure by intrarenal baroreceptors thought to reside on the granular cells themselves.
Filtration equilibrium
As complex as this may all seem to you, we have still employed the simplifying condition that all filtration takes place at the same point in a glomerulus. In reality, the glomerular capillaries have significant length, and as the plasma travels down this vessel it is constantly losing water to filtration and losing blood pressure due to the resistance of the capillary. Thus, according to equation, the NFP for filtration is constantly decreasing along the capillary length. In fact, under certain circumstances of low RPF, it is possible that NFP will reach 0 at some point before the plasma exits the capillary! This point is known as “filtration equilibrium” and from here on until the end of the glomerular capillary, no further filtration takes place. In effect, in this situation the GFR takes a “double hit”, since not only does filtration start off with a lowered NFP due to hypotension, but the effective area for filtration is reduced since there is now a part of the glomerulus under which there is no filtration. At present it is uncertain whether filtration equilibrium occurs in humans pathologically, but has been shown to occur in certain animals.
Role of renal prostaglandins
These prostaglandins are produced by the renal interstitial cells that are mainly located in the kidney medulla between the renal pyramids. These prostaglandins are secreted in response to angiotensin II and have a local dilatory effect on the renal arterioles. However, since the role of AgII in the hypovolemic response is to constrict these same arterioles, for what purpose does AgII produce a hormone that antagonizes its own actions? The current thinking is that two important things are accomplished by dilatory renal prostaglandins. The first is that the prostaglandins maintain an adequate renal blood flow by blunting the affect of AgII on renal arteriolar constriction. This is thought to be important since renal tubular cells are highly sensitive to ischemic hypoxia (i.e. lack of oxygen caused by reduced blood flow); thus the prostaglandins provide a measure of protection against acute renal failure in hypovolemia (refer to your pathophysiology lectures for further details). Second, it is believed that the dilatory effect of prostaglandins is somewhat selective for the afferent arteriole. This will tend to restore GFR back toward normal. However, it should be stressed that renal dilatory prostaglandins do not eliminate the hypovolemic mechanisms described above but merely blunt them a bit so that RBF and GFR reductions will not be as severe as they would with the purely vasoconstrictive effects of the baroreceptor and AgII mechanisms.
General Anatomy of the kidney
A longitudinal section of the kidney shows several regions. It is surrounded by an outer fibrous capsule that has the cortex immediately beneath it. Under the cortex are the medullary pyramids which are arranged as conical functional units that consist of a series of tubular elements of nephrons and their associated collecting ducts. Collecting ducts empty urine at the tip of each cone or pyramid (papilla) into a calyx. Calices are essentially urinary drainage conduits that connect various sections of the kidney together at the renal pelvis. Urine leaves the kidney as the ureter in a central region called the hilum. The hilar region is also the site for entry of the renal artery and vein.
Vasculature
The renal arteries branch from the abdominal aorta, one supplying each kidney. Within the hilar region they branch into anterior and posterior segments that in turn branch into the interlobar arteries that run between the medullary pyramids. Near the medullary-cortical junction they branch into arcuate arteries that run roughly parallel to the outer capsule. They branch further into smaller arteries (interlobular arteries) that course through the cortex toward the capsule. These branch further to form the afferent arterioles that supply blood to the fundamental blood filtration sites, the glomeruli of individual nephrons. The glomeruli are capillary units from which some of the plasma contents are filtered, the remaining blood volume passing into the efferent arterioles that leave the glomeruli. For the glomeruli located in the outer part of the cortex, the efferent arterioles form a capillary plexus that initially surrounds tubules of the nephron within the cortex and can enter the medulla as a capillary plexus called the vasa recta. For the glomeruli that are near the medulla (they form part of the juxtamedullary nephrons), efferent arterioles directly enter the medullary region. Blood from the capillaries drain into radially-oriented interlobular veins, to arcuate veins near the cortical-medullary junction and to interlobar veins that connect to the renal vein leaving the kidney. Blood flow is regulated within the kidney, and the kidney is also involved in regulation of blood pressure.
The Nephron
The nephron is the basic functioning unit of the kidney, and the two main functions (blood filtration and selective resorption) are carried out by the Renal corpuscles and Renal tubules, respectively. The renal corpuscles are all located in the cortex. A tubule is associated with each corpuscle, and usually courses for at least part of its length into the medullary region where it forms a hairpin bend in a region of the tubule called the loop of Henle. Renal tubules of juxtamedullary nephrons extend into the deepest regions of the medulla, and play a key role in establishing a medullary salt gradient. Tubules of cortical nephrons can extend to different distances in the medulla, but do not extend to the depths of juxtamedullary nephrons.
The Renal Corpuscle
The renal corpuscle is where filtration of blood occurs. It consists of a condensed capillary network (the glomerulus) surrounded by an epithelial capsule (Bowman’s capsule). Single afferent and efferent arterioles enter and leave the anastomosing glomerular capillaries. In the interior of the capillary bed is the connective tissue of the mesangium containing mesangial cells. On the outside of the capillaries is a special layer of cells called podocytes, which comprise the visceral epithelium of Bowman’s capsule. Between the endothelial cell of the capillary and the podocytes is a crucial basal lamina called the filtration barrier. It has properties unique to the kidney that enable it to selectively filter the blood. The outer layer of Bowman’s capsule (the parietal epithelium) is continous with the visceral epithelium at the base of the glomerulus. However, the outer layer is a simple squamous epithelium and is entirely different in structure from the layer immediately surrounding the glomerulus comprised of podocytes, as will be discussed below. The space in Bowman’s capsule represents the beginning of the urinary space. It is continuous with lumen of the proximal tubule that will ultimately drain urine to a minor calyx.
The Filtration Barrier
This is the barrier immediately surrounding the blood flowing in the glomerulus, and is comprised of 1) The fenestrated endothelium of the capillary itself, 2) The complex, thick basal lamina and 3) The filtration slits between podocytes. Filtration though this barrier is driven by hydrostatic pressure of the blood. The fenestrated endothelium of the glomerular capillaries themselves prevents formed elements of the blood, including cells and platelets, from coming in contact with the basal lamina. However, all components of the plasma can come in contact with the basal lamina.
The basal lamina
is thinner where capillaries con- tact the mesangium, which is itself comprised of connective tissue of similar density. The thickness of the lamina is markedly increased in certain dis- eases such as diabetes mellitus, and autoimmune disorders such as lupus. The basal lamina is a barrier to molecules approximately 60-70,000 MW in size, which includes albumin in the plasma, but this barrier is not an absolute number. Negatively-charged molecules of somewhat smaller size will often not penetrate the barrier, although most very small molecules (
The function of podocyte filtration slits
is unclear, but filtrate must pass through these 25-30 nm slits which have thin diaphragms of about 4-7 nm thickness, and they may be involved in part in the filtration process. The loss of foot processes in certain renal diseases results in excessive plasma protein in the filtrate, but it is not known whether this is a direct result of podocyte absence or reflects an effect of the maintenance of the integrity of the basal lamina.
Mesangial cells and the mesangium
Within the more central regions of the glomerulus is the connective tissue of the mesangium which supports the glomerular structure. Mesangial cells secrete the matrix that is continuous with the basal lamina in the inner part of the glomerulus where the mesangium meets the endothelial cells of the capillaries. The mesangial cells are phagocytic and are thought to play a role in maintenance of the filtration lamina in the inner portion of the glomeruli. These cells are also contractile, although a potential role for them in contraction of the glomerular cap- illary loops is not clear.
The Renal Tubules
Most of the urinary filtrate (over 99%) is returned to the blood during the meandering trip from Bowman’s capsule to the renal pelvis. The job of selective resorption of water and many of the solutes of the filtrate occurs as the filtrate passes through the tubules and collecting ducts. Regions of the tubular portion of the nephron carry out specialized resorption functions, and include:
1. The proximal convoluted and straight tubule.
2. The thin descending loop of Henle.
3. The thin ascending loop of Henle.
4. The ascending thick loop of Henle.
5. The distal convoluted tubule
, 6. The collecting tubule. The collecting tubules of several
nephrons join the collecting ducts which also have specialized water-resorption functions. The specialized functions and control of resorptive processes will only be briefly covered here, but will be covered in greater detail in physiology lectures. Details of the cell structures of the tubular endothelial layers en route to the renal papillae are clearly indicative of the types of functions they participate in.
The Proximal tubule
This portion of the renal tubule is specialized in having a cuboidal epithelium with an extensive brush border of tall microvilli on the luminal side, as is typical of epithelia undergoing major absorptive transport processes. Cells are connected near the luminal surface by a band of tight junctions. The basolateral side has extensive basal and lateral infolds that are highly enriched in Na+K+ ATPase, for pumping sodium out the basolateral side. This drives the uptake of sodium, glucose, and amino acids by facilitated diffusion at the microvillar lu minal side. These cells are packed with numerous mitochondria for ATP production to sup- port the extensive uptake of sol utes in this portion of the tubule. Roughly 75-85% of the volume of the filtrate is absorbed by the time it enters the thin portion of the loop of Henle.
The loop of Henle
An abrupt transition occurs between the thick descending portion of the proximal tubule and the thin portion of the loop of Henle. Cells in the thin loops are simple squamous epithelium, with the thin descending and thin ascending portions having different permeabilites to NaCl and water. This permits an osmotic salt gradient to be maintained in the medulla, from the cortical junction to the medullary papilla, which will be discussed in physiology. Cells of the thick ascending loop are cuboidal and active transporters of sodium, and contain numerous mitochondria similar to the cells of the proximal tubule, with extensive basolateral infolds.
The Distal tubule
The distal tubule is a continuation of the thick ascending loop of Henle after it enters the cortex. This epithelium is similar in appearance throughout.
Cells are cuboidal, with short micromilli
on the luminal side which are not as abundant as in proximal tubule cells. Distal tubules play a major role in acid base balance. They respond to aldosterone and antidiuretic hormone (ADH) in their more terminal regions. Like the cells of the proximal tubule, they have numerous mitochondria, and basolateral infolds. The basolateral regions also contain Na+K+ ATPase to drive the active transport of sodium across the basolateral membrane.
Collecting Tubules and Ducts
Collecting tubules join the distal tubule to the collecting ducts. Two major cell types are present, the more abundant principal (clear) cells and intercalated cells (which tend to stain more darkly). Cells of the tubule are cuboidal, with very short microvilli, becoming increasingly more columnar as they reach the collecting duct, where the cells are columnar. Principal cells are active transporters, and couple sodium uptake to potassium secretion into the lumen of the tubules. Intercalated cells function to secrete H+ and reabsorb bicarbonate; hence their main function is to regulate acid-base balance. Water resorption is regulated in the collecting tubules and ducts through the action of antidiuretic hormone, which increases the permeability to water of the collecting ducts and tubules through an increase in aquaphores (specific proteins permitting water passage) in the membrane. This results in a more concentrated urine. Collecting ducts join with other collecting ducts that run vertically through the medulla to form large papillary ducts that drain urine into the minor calices.
The Juxtaglomerular Complex or Apparatus
The juxtaglomerular complex is a specialization of cells located at the vascular pole of the renal corpuscle. The distal convoluted tubule is physically connected to the region near the vascular pole through the macula densa. This is comprised of a specialized set of cells of the distal convoluted tubule that are taller and have larger nuclei. Juxtaglomerular cells are modified smooth muscle cells in the wall of the afferent arteriole. These cells can secrete renin. Lacis cells are found in direct contact with the macula densa and juxtaglomerular cells. They have numerous processes and continuity with the mesangium. Juxtaglomerular cells contain granules of renin, an enzyme that cleaves a plasma protein angiotensinogen to angiotensin I. Angiotensin I is primarily converted to Angiotensin II by the lung. It is a potent vasoconstrictor. So juxtaglomerular (JG) cells control both systemic and local blood pressure through renin release. This topic of blood pressure control will be discussed in greater detail in physiology lectures.
the cells of the macula densa
Another control mechanism is that the cells of the macula densa are thought to respond to the concentration of chloride ions (referred to quite often in texts as responding to sodium ions or osmolarity) in the urinary filtrate pre- sent in the distal tubules. Some of the cells of the macula densa are in close contact with JG cells. Lacis cells are located between the macula densa and cells of the mesangium. Although no clear role has been demonstrated for them, they have been suggested to participate in some way in a feedback signaling event between cells of the macula densa and intraglomerular mesangial cells.
Interstitial cells
Other cells are present outside of the tubules in the medulla and to a lesser extent, in the cortex. Wandering macrophages are present, as well as fibroblast-like cells. Stellate cells containing lipid droplets are pre- sent. Some interstitial cells and some tubule cells have been found to contain mRNA for erythropoietin, which, as you may recall, is produced in the kidney in response to hypoxia.
Gross anatomy of the kidney
Blood vessels and the ureter enter through a zone called the hilus. A renal pyramid contains a group of nephrons that drain into a minor calyx as urine proceeds to the ureter. Minor calices connect to form major calices of the renal pelvis. The cortex and medulla are indicated.
components of the nephron
Blood flows via the afferent arteriole into the glomerulus of the kidney. Urinary filtrate enters the urinary space of the renal corpuscle, and then into the proximal convoluted tubule. Components of the filtrate are reabsorbed with specialization along the route to the ureter, first in the proximal tubule, the straight descending segment of proximal tubule, the descending and ascending thin segments (the loop of Henle) the straight segment of the distal tubule, and the distal convoluted tubule. Note that more than one distal tubule joins with the collecting tubule, which drains concentrated urine into the minor calyx of the kidney. In some juxtamedullary nephrons a short arched duct is interposed between the distal tubule and the straight collecting duct. The tubular portion of the nephron begins as the parietal layer of Bowman’s capsule and terminates at the end of the distal tubule.
Cortical and juxtamedullary nephrons
In each human kidney there are an estimated one million or more nephrons. About 1/7th of these are juxtamedullary nephrons; the renal corpuscles of these nephrons lie deep in the cortex, adjacent to the medulla. Juxtamedullary nephrons have long loops of Henle. Cortical nephrons have short loops of Henle or none at all. The functional significance of the loop of Henle is that the length of the medullary component is related to their ability to generate more concentrated urine
The two primary constituents of the ECF
water and sodium chloride. The maximal excretion of either salt and water is only a small fraction of the filtered load. In other words, under normal circumstances most of the filtered load of water and salt is obligatorily reabsorbed, with only a small fraction under homeostatic control. In percentage terms, at least 86% of the filtered water and 98% of the filtered NaCl must be reabsorbed. Thus the regulatory mechanisms that we will describe affect only 14% of the filtered water and 2% of the filtered NaCl.
Physiological implications of water and NaCl filtration, excretion, and reabsorption
nearly all of the obligatory recapture of water and salt occurs in the “proximal segments” (i.e. proximal tubule and loop of Henle), while the homeostatically varied reabsorption primarily takes place in the so-called “fine tuning” segments, namely the distal tubule and collecting duct. This spatial separation and arrangement of obligatory reabsorption occurring first with regulated reabsorption later is necessary for the efficient handling of water and salt.
Pathological implications of water and NaCl filtration, excretion, and reabsorption
We might briefly consider whether these ranges, in particular the maximum excretion rates, are adequate to defend the ECF against pathological gains in water or salt due to over-ingestion. Water ingestion in normal folks generally presents no problem, for it is behaviorally (and anatomically) very difficult to ingest a large volume of water sufficient to overwhelm the excretory abilities of the kidneys in maintaining water balance. However, in certain pathological conditions, for example impaired GFR or inappropriately elevated water reabsorption as might occur with use of the drug “ecstasy”, retention of excess ingested water can occur, leading to the dangerous condition of water intoxication. On the other hand, for salt intake in the normal individual, the regulated component is so small, that it is indeed possible for dietary intake to exceed excretory limits. Thus the average daily salt intake in the U.S. is about 9-10 grams, and given the prevalence of high salt foods in our diet it is likely that some individuals regularly exceed the upper excretory limit. This has suggested to some researchers a partial explanation for the epidemiologic link between high salt and essential hypertension. As we will discuss later, the addition of salt to the ECF has a volume-expanding effect, which in itself would increase blood pressure. However, the actual pathology must be more complex, for the hypertension tends to persist even when the salt-induced volume overload is corrected. No doubt you will hear more about this subject in your clinical lectures on hypertension.
Energy-requiring transport of sodium
Na+ transport is the process that drives nearly all other transport phenomena in the tubule. The primary energetic event occurs when Na+ is actively extruded from the interior of the tubular epithelium by the basolateral Na+/K+-ATPase ion pump. As you will recall, in all living cells the effect of this pump is to greatly reduce the sodium concentration inside the cell by moving it to the extracellular fluid. In the renal tubular epithelial cell, since these pumps are located on the basolateral membrane, sodium is moved to the serosal side of the epithelium. Also remember that this pump also enriches the cell interior in potassium, which selectively leaks out of the cell to establish the cell interior at a negative electrical potential. In the tubular epithelial cells, this creates a large driving force for Na+ entry into the cell; this happens when sodium passes from the lumen into the cell through sodium channels in the apical membrane. Thus in the overall reabsorption scheme for Na+ there is first passive lumenal movement of the ion down its electrochemical gradient into the cell followed by basolateral pumping of the ion into the serosa.
Reabsorption of chloride, water, and other solutes
are coupled to the active reabsorption of sodium. Since sodium is a cation, its primary movement requires the associated co-transport of an anion or the counter-transport of a cation to maintain electrical neutrality. Mostly this is accomplished by the reabsorption of chloride. The most common mechanism for this chloride movement is paracellular, i.e. through the tight junctions. Now both sodium and chloride accumulating on the serosal side of the membrane. This creates an osmotic gradient across the epithelium. Thus, if a pathway for water is provided, water will then also move from the lumen into the serosal interstitium. In the renal epithelium, such movement may be either paracellular or transcellular or both, depending on the tubular segment. Finally, the primary electrochemical gradient for lumenal sodium entry can be utilized by other solutes in a coupled-transport scheme. Here we note that glucose can be reabsorbed in a “secondary” active transport scheme in which the movement of glucose from lumen into the cell is driven by coupling it to the energetically downhill movement of Na+ via the Na+ /glucose co-transporter. The utilization of energy from the Na+ gradient in this process actually allows glucose to be concentrated in the cell relative to its serosal and lumenal values, hence it can then passively move from the cell to the serosa via a passive carrier mechanism. Such a reabsorptive process is essential for the recapture of nonspecifically filtered glucose as well as filtered amino acids. In summary, the primary, energy-requiring basolateral movement of Na+ allows the coupled movements of most other reabsorbed ECF components.
The role of the proximal tubule
Taking an obligatory “big bite” of the filtered load of water and NaCl, and the recapture of important metabolites in the filtrate. In the proximal tubule 65% of the filtered water and NaCl is obligatorily reabsorbed. Thus this segment always reabsorbs the majority of the filtered load for these two substances, regardless of homeostatic requirements. The water “pores” in the transcellular pathway are actually proteins known as “aquaporins”. The proximal tubule also plays an essential role in the recapture of metabolites that have been incidentally filtered into the tubule because of their small size. Thus essentially all of the filtered glucose and amino acids are reabsorbed here, using Na+ - driven co-transporters described above. Most of the filtered bicarbonate, which is essential for the buffering of metabolic acid, is also reabsorbed here, again involving Na+ as a cofactor. Thus much of the obligatory Na+ reabsorption in the proximal tubule occurs in conjunction with small organic molecule recapture. Thus it seems that the kidney is no procrastinator, but has evolved to recapture these vital metabolites at the first opportunity. This is an important point, since due to the high rate of filtration the failure to recapture even a small fraction of the filtered amount of any metabolite would result in the excretion of a large mass of it over the course of a day.
Transport maximum
since recapture is mediated by discrete transporters, the capacity for reabsorption of these metabolites in the proximal tubule is finite. This maximal absorption rate is often referred to as the transport maximum for a substance. For glucose, the transport maximum for reabsorption can be exceeded if the plasma concentration of glucose becomes abnormally high, as in diabetes mellitus. In this case, the rate of filtration can indeed exceed the transport maximum, and thus some glucose escapes reabsorption to appear abnormally in the urine. Thus “glucosuria” is one of the diagnostic indicators of diabetes mellitus. In any case, since equivalent proportions of NaCl and water are reabsorbed in this segment, the tubular fluid remains approximately isotonic during its journey through the proximal tubule. This is because the reabsorptive pathway for water is very permeable and close to the pathways of sodium chloride and metabolite reabsorption, thus water flows freely and essentially achieves osmotic equilibrium across the epithelium of this segment. This is not the case for the loop of Henle, the next segment encountered buy the filtrate.
The loop of Henle
creation of a hypertonic interstitium. As noted above, a greatly reduced but still isotonic filtrate enters the loop of Henle. Here, however, the processes for NaCl reabsorption are quite different than in the proximal tubule and they are spatially separated from water reabsorption in this segment. The primary event of NaCl reabsorption occurs in the ascending limb of the loop; this reabsorption is robust in that it transports 25% of the original filtered load from the lumen into the surrounding interstitium. Naturally this movement of solute into this space makes the interstitium highly hypertonic, creating a significant osmotic gradient for water reabsorption.
the water permeability of the ascending limb
is quite low, so water does not follow salt from the lumen in this segment. Instead, note that the descending limb of the loop has high water permeability and no permeability to NaCl; thus water flows fairly readily from this segment into the interstitium in response to the osmotic gradient set up in the ascending limb. However, the relative water permeability and tubular flow rate of the descending limb is such that osmotic equilibrium does not occur in this segment, but rather only 15% of the original filtered load of water is reabsorbed. Since overall more NaCl than water is reabsorbed, a hypertonic interstitium and a hypotonic tubular fluid are created. Further, as in the proximal tubule, these processes are largely obligatory. The hypertonic interstitium is a crucial component of regulated water reabsorption in the fine tuning segments.
The cellular mechanisms for NaCl reabsorption in the ascending limb
are a bit different than those of the proximal tubule. The main difference lies in the apical membrane transport of NaCl, which involves a Na/K/2Cl co- transporter (actually these are in the thick part of the ascending limb, but we’ll not bother with this distinction further). As with glucose transport, this co-transporter secondarily couples the energy in the sodium gradient to drive the uphill reabsorption of potassium and chloride. As such it is a significant mechanism also for the reabsorption of filtered potassium, a fact that will assume more importance when you learn about the potassium wasting side effects of so-called loop diuretics.
Reabsorption of water and NaCl in the distal tubule and collecting duct (“fine tuning” segments)
the combined obligatory reabsorption in the proximal tubule and loop accounts for nearly all of the required unregulated reabsorption. Thus only 20% of filtered water and 10% of filtered NaCl remain to enter the distal tubule at this point. While there is still some obligatory reabsorption that occurs in these segments (i.e. 6% of filtered water, 8% of filtered NaCl), we’ll concentrate on the regulatory mechanisms. On the surface, these seem very similar to the basic mechanism of tubular epithelium that applies to the proximal tubule. However, there are several critical differences that allow the reabsorption of salt and water to be homeostatically varied here. First, the tight junctions in these segments are indeed “tight”, i.e. the majority of reabsorption must use the transcellular pathway that involves selective transporters. Second, although there is a high basal rate of reabsorption, the rate of transport can be varied by circulating hormones.
NaCl handling
The basic pathway for sodium reabsorption here is upregulated by the mineralocorticoid hormone aldosterone. Aldosterone effect is to increase the number of apical sodium channels and basolateral sodium pumps, thus the cellular rate of sodium transport increases. In addition, these is also evidence that aldosterone increases ATP synthesis, the primary fuel for the process. How does aldosterone do this? The fundamental mechanism occurs when aldosterone enters the cell (it is a lipid soluble hormone and easily crosses the cell membrane from the blood) and binds to an intracellular receptor. The hormone/receptor complex then diffuses to the nucleus, where it turns on genes that increase the synthesis of transporter proteins. Naturally this is not an instantaneous process, but rather takes place on the scale of an hour or more. However, there is some indication of a faster increase in reabsorption caused by aldosterone that occurs in tens of minutes. This is thought to involve the rapid insertion of pre-existing pools of transporters that reside in small vesicles near the cell membrane.
Water reabsorption
Overall, both the obligatory basal reabsorption of salt (8% of the original filtered load) and the aldosterone-controlled variable transport (up to 2% of the original filtered load) add more solute to the interstitium surrounding the fine tuning segments. Since this interstitium was already made hypertonic by the action of the ascending loop, it becomes even more so, thus increasing the osmotic gradient between the lumen of the fine tuning segments and the interstitium. Thus there is a high driving force for water reabsorption. In the basal state these segments are fairly water impermeant, so relatively little water will flow across them. However, the water permeability of these segments can be dramatically increased by the actions of the peptide antidiuretic hormone (ADH) (also known as “vasopressin”). In the presence of ADH, small vesicles containing aquaporins are fused into the apical membrane of the epithelial cells. Since there are pre-existing, unregulated aquaporins in the basolateral membranes, this completes a potent transcellular pathway for the osmotic flow of water from the lumen to the serosa. The intracellular signaling pathways for ADH action have been well worked out and involve the initiation of an intracellular phosphorylation cascade when ADH binds to a receptor on the basolateral membrane. This pathway also initiates the de novo synthesis of aquaporins. The response to ADH is very rapid indeed, and similarly the lifetime of the aquaporins in the apical membrane is very short due to rapid turnover. Thus unlike the response to aldosterone, the regulation of water reabsorption is a very acute and fast responding system.
A basic integrated description of the nephron handling of water and NaCl
While in the proximal tubule most of the filtered load is obligatorily reabsorbed in an isotonic fashion, in the loop of Henle the spatial separation of NaCl and water reabsorption results in the creation of a hypertonic interstitium and a large osmotic gradient across the tubular epithelium of the fine tuning segments. In the fine tuning segments further NaCl reabsorption occurs both obligatorily and homeostatically in response to the hormone aldosterone. Either of these processes will further increase the trans-tubular osmotic gradient. Finally, ADH controls the water permeability of the fine tuning segments and in this way regulates the reabsorption of water using the interstitial osmotic gradient.
How reabsorbed water and NaCl flows from the renal interstitium to the peritubular capillaries
Starling forces for bulk recapture flow. There is one additional aspect of basic nephron function to be considered, namely how does the huge amount of water and NaCl pumped across the tubular epithelium actually re-enter the capillaries to be returned to the ECF? In actuality, this process involves a bulk flow of interstitial fluid into the peritubular capillaries, and as such it is governed by the same Starling principles for the other capillaries flows that you have learned about (e.g. the GFR). As discussed for GFR previously, this is another transmural flow, and the Starling equation for it (which we’ll simply designate as Fic) is as follows: Fic = K’ (Pint + πcap– Pcap - πint) where K’ is again a constant representing the hydraulic conductivity of the pathway over which flow occurs. What we are interested in here is knowing what forces actually drive this flow.
The flow dependence of tubular processing and it implications
Protecting the fine tuning segments. Up to this point we have described a highly simplified scheme in which filtration of water and its dissolved NaCl is held constant, followed by constant reabsorption of most of the filtered load in the early tubule, and then is“fine-tuned” by a variable reabsorption/excretion of these substances to achieve overall ECF balance. However, there are circumstances, particularly in pathological situations, where this scheme is upset. Many of these have to do with changes in tubular flow, so we need to explain why this can have a profound effect on the tubular processing and renal excretion of salt and water.
The reabsorption and excretion of NaCl and water can be affected by tubular flow changes
To understand how flow rate affects the urinary excretion rate of a reabsorbed substance, we should view the tubular journey of the filtrate as one in which filtered salt and water stream past a gauntlet of reabsorptive mechanisms in an attempt to move to the outside world in the urine. Thus the faster fluid flows in the tubule the less time it has to interact with the epithelial transporters that reabsorb it; thus increased tubular flow tends to allow a greater proportion of tubular substances to escape reabsorption, thus their excretion rate will tend to increase with tubular flow. Naturally the opposite is true for reduced tubular flow rates, i.e. exposure time of tubular substances to their transporters is increased, hence a greater proportion of them is reabsorbed, thus their urinary excretion rate decreases. Tubular flow also dramatically affects the excretion of secreted substances such as potassium, although the reasons for this are somewhat different.
Diuretics
increase tubular flow and excretion of most substances. Diuretic substances are those that increase urine output, and all do so in large part by decreasing water reabsorption in some part of the tubule. This results in a larger volume of water staying in the tubule, hence an increased tubular flow results. A consequence of this is that all solutes in the tubular fluid from this point on flow faster past their transporters, hence their excretion will tend to increase also. Thus most diuretics tend to increase the urinary excretion rate of sodium, potassium, and chloride indirectly due to this flow effect.
Consequences of filtration changes for the regulation of NaCl and water
In the above discussion, we have assumed that filtration is being held constant by autoregulatory mechanisms described in lecture #2. Now we consider that imperfections in the autoregulatory control of GFR as well as a number of pathological conditions can indeed result in changes to the filtration of the plasma outside of the normal range. Naturally such changes will change tubular flow from at the very start of the tubular stream. As such, unregulated variations in GFR will then tend to cause unregulated changes in the excretion of salt and water. But how serious can such an effect be? What might happen if, for example, imperfect autoregulation resulted in a very small, 1mm increase in Pgc at the glomerulus? This would raise the NFP from 6 to 7mm, hence GFR would be expected to rise by about 17%. While significant, one might assume that since this change is a small fraction of the original GFR that it wouldn’t pose much of a problem for the tubular system to compensate for. The same arguments can be made for NaCl, hence the most modest of regulatory increases in glomerular capillary pressure will tend to completely swamp tubular regulatory reabsorption and cause disastrous increases in urinary excretion.
Finally, one can also consider the effects of decreased GFR in the same way. Here, if obligatory reabsorption remains constant a 1mm decrease in Pgc would result in complete obligatory reabsorption of the filtered load of NaCl and water, hence no excretion of these substances could occur to achieve ECF balance!
Defending the “fine tuning segments” against changes in tubular load due to GFR changes
In fact, in the circumstances above, there indeed are other compensatory mechanisms within the tubule that greatly blunt the effects of GFR changes to maintain the delivery of water and NaCl to the fine tuning segments very constant. These mechanisms are known respectively as glomerulotubular balance and tubuloglomerular feedback (these very different processes are unfortunately similarly named).
Glomerulotubular balance
refers to the ability of the obligatory reabsorption mechanisms in the proximal tubule to compensate for changes in filtered load. This compensation is conceptually simple, i.e. proximal tubule reabsorption readjusts to filtration changes so that a fixed proportion of the filtered load of water and NaCl is always reabsorbed. This proportion is 65%. Thus in the example of increased filtration above, nearly two thirds (i.e. 22 liters) of the additional 32 liters of filtrate formed daily would be reabsorbed in the proximal tubule. Naturally this also applies to reduced filtration rates.
Tubuloglomerular Feedback (TGF)
However, while this glomerulotubular balance mechanism greatly reduces the difference in the filtrate volume from normal, there will still be a surplus or deficit in the tubular filtrate as it flows out of the proximal tubule. This remaining difference from normal filtrate is then dealt with by the process of Tubuloglomerular Feedback (TGF). This mechanism actually directly regulates the GFR of each nephron in response to changes in NaCl concentration at a specialized group of epithelial cells called the macula densa. These cells are in direct contact with cells of the afferent arteriole and they can cause the arteriole to constrict or dilate. In addition, the macula densa cells are placed at the start of the distal tubule. Thus they are perfectly placed to monitor the status of obligatory reabsorption just before the tubular fluid enters the fine tuning segments.
the way TGF works
A rise in GFR causes an initial rise in tubular fluid flow in the initial segments. Although part of this will be compensated for by glomerular tubular balance in the proximal tubule, the uncompensated part causes fluid to move faster in the loop of Henle. As discussed above, the resultant flow effect causes a reduction in the proportion of NaCl reabsorbed in the ascending limb, hence NaCl concentration increases in the lumen of the ascending limb. As this fluid exits the loop, it immediately encounters the macula densa; the macula densa cells have a special mechanism that senses the rise in NaCl concentration, and through a series of intracellular and paracrine steps they signal the afferent arteriole to contract. This drops Pgc just enough to return GFR to its normal level. Naturally this feedback loop works in the opposite way for an initial decrease in GFR.
GFR changes can be significant in abnormal physiology
The above discussion demonstrates that in normal circumstances GFR is very tightly regulated and most of the regulation of NaCl and water takes place in the fine tuning segments under hormonal control. However, in a number of pathological circumstances GFR will be altered and be an important part of the pathophysiology.
Regulation of ECF sodium levels via aldosterone
Naturally, as a cation Na+ must exist with an anion, which is mostly chloride (Cl-). However, a significant amount (~25mM) of this balancing anion is bicarbonate (HCO3-), with lesser amounts of nonvolatile acid and protein anions. In any case, when we talk about aldosterone-mediated Na+ reabsorption, we are really describing a process that mostly co-transports Cl- .
Nature of the ECF sensors for Na+ levels
The concentration of sodium changes relatively little when sodium is lost or gained from the ECF. This is because sodium is the major osmotic substance in the ECF, and because the ECF is in osmotic equilibrium with a much larger compartment, the cells. Thus losses or gains in ECF sodium actually cause greater changes in ECF volume than they do in sodium concentration. For example, an increase in total ECF sodium mass of 10% is caused by the ingestion of salty food. It might be thought that this would raise sodium concentration in the ECF, but it also raises ECF osmolarity. Since the membranes of most cells are freely permeable to water, water flows rapidly from the cells to the ECF in response to this sodium gain to quickly balance the osmolarity between the two compartments. In a closed system such as this (i.e. fixed volumes of the cellular and ECF compartments), such water flow not only decreases the osmolarity of the ECF but also increases the osmolarity of the cellular compartment as water leaves it; thus equilibrium is reached when the osmolarity of these two compartments converge and become equal. The trick here is to understand that since the cellular compartment is nearly twice as large as the ECF, the flow of water from the cells changes the osmolarity of the ECF more rapidly than that of the cells. To understand this better, it’s useful to think theoretically of the extreme situation in which the cellular compartment is infinitely large; here the flow of water from the cells won’t change cellular osmolarity at all, so all of the change must take place in the ECF. In our example with a 10% addition of salt, this means that ECF volume must increase by 10%, and in the end there in no change in sodium concentration, just a pure increase in ECF volume. In our “real” example, the cell volume is not infinitely large, but “only” twice that of the ECF volume. Thus water flow into the ECF changes its osmolarity twice as fast as water leaving the cells does, hence the osmolarities become equal when the ECF volume has increased proportionally twice as much as the cell volume has. For the specific example of starting addition of 10% of the total salt mass to the ECF, final osmotic equilibrium is reached when the ECF volume has increased 6.7% and the cell volume decreased 3.3%. In addition, note that at this equilibrium the final ECF sodium concentration will only have risen 3.3%, or only half the change in the volume!
Effect of two fold greater volume of cellular over the ECF compartment
Due to the two-fold greater volume of the cellular over the ECF compartment, gains (or losses) of sodium from the ECF result in two-fold greater changes in ECF volume than they do in ECF sodium concentration. Thus it make sense that the sensors of sodium regulation monitors changes to ECF volume, not sodium concentration. Naturally the convenient volume sensors that we have in the ECF are those for blood pressure, and for sodium they are those that monitor the mean arterial pressure (MAP of the major arteries. The reasoning for the same principle as applied for sodium losses from the ECF is simply the reverse of that given for our example of sodium gains.
The feedback loop for sodium regulation
For example, with ECF sodium loss, the resultant decrease in ECF osmolarity causes a water shift into the cells, hence ECF volume and MAP decrease. We now want increase sodium reabsorption to increase to prevent undue urinary loss of sodium, i.e. to conserve the remaining sodium in the ECF. Working backwards, we know that we thus need to increase aldosterone secretion, so we need to describe how one gets from a decrease in MAP to an increase in aldosterone plasma levels. First, as we already know, a decrease in MAP activates the renin/angiotensin axis, i.e. external and intrarenal baroreceptor mechanisms cause increased renin release from the JGA/granular cells which then results in elevated levels of angiotensin II. In a function apart from its vasoconstrictive role, AgII acts on aldosterone-secreting cells of the adrenal cortex and causes them to increase aldosterone synthesis (since aldosterone is very membrane permeant, increased synthesis automatically causes increased aldosterone secretion into the blood). Finally, aldosterone then circulates to the epithelial cells of the fine tuning segments and up-regulates the reabsorbed of sodium.
ECF sensors for water
As for sodium, we start by describing how water levels are physiologically detected. Actually, here we’ll simply state the obvious, that since water is the most abundant component of the ECF, its relative abundance determines ECF volume directly, and it determines ECF osmolarity in partnership with sodium and its anions. Thus it is no surprise that the regulation of ECF water levels involves monitoring of both ECF volume and osmolarity.
Feedback loops for volume and osmolarity-mediated control of water reabsorption
Since we already know that ADH controls water reabsorption, our object here is to describe the pathways that control the secretion of ADH into the blood. First, ADH is a peptide hormone that is synthesized in neurons located in the hypothalamus of the brain. However, the synthesized hormone is packaged into vesicles and transported down the axons of these neurons which terminate in the posterior aspect of the pituitary gland. It is from the posterior pituitary that the peptide is secreted into the circulation. As one might expect, the reduction in ECF volume in severe sweating is monitored by changes in blood pressure, which to a lesser extent is done by the usual arterial high pressure baroreceptors. However, filling pressure in the left atrium of the heart is considered more important, since atrial distension is a rather sensitive indication of circulating volume (i.e. preload). Thus baroreceptors mainly residing in the auricle (a.k.a. “left atrial appendage”) sense a decreased filling of the left atrium. Then, through a baroreceptor reflex involving neural circuitry that you will learn about next year, the ADH-synthesizing hypothalamic neurons are activated to release ADH from their terminals in the posterior pituitary. The hormone then flows through the circulation to the kidney, where as we’ve described it induces the insertion of aquaporins into the apical membrane of epithelial cells of the late distal tubule and collecting duct, causing enhanced water reabsorption. How about the effect of severe sweating on ECF osmolarity? Here it might be a surprise to learn that normal sweat in actually about 80mM NaCl, and is thus hypotonic. Thus severe sweating remove hypotonic fluid from the ECF, which will become hypertonic. The increased osmolarity of the ECF directly activates brain osmoreceptors on neurons in the hypothalamus; these neurons in turn activate the same ADH-synthesizing neurons in the volume-regulated pathway, with the same result of increased ADH secretion and increased water reabsorption.
Volume versus Osmolarity
Insights into the true nature of ECF water control. The example of water regulation is relatively straightforward and was chosen to illustrate the cooperative interaction of both the volume and osmolarity- monitoring feedback loops. However, there are circumstances where these separate loops are in opposition to one another. Diarrhea represents an isotonic loss of ECF via pathological secretion into the gut. Here the sufferer loses 3 liters during the acute stage of the disease. 3 liters represents a very severe volume loss for an average individual, and one that would cause the enhanced secretion of ADH according to the left atrial filling pressure pathway in Figure 3. On the other hand, since the fluid loss is isotonic, the osmotic pathway is not activated or inhibited at this stage. In this example we consider first the dehydration of a patient suffering from severe diarrhea. As you will learn in your G.I. lectures diarrhea represents an isotonic loss of ECF via pathological secretion into the gut. Here the sufferer loses 3 liters during the acute stage of the disease. 3 liters represents a very severe volume loss for an average individual, and one that would cause the enhanced secretion of ADH according to the left atrial filling pressure pathway. On the other hand, since the fluid loss is isotonic, the osmotic pathway is not activated or inhibited at this stage. As the patient recovers, he drinks 2 liters of water as he feels a bit better. Since 3 liters of ECF volume were originally lost and only 2 liters have been ingested, the ECF volume will still be decreased by 1 liter. Hence one might expect that there will still be a volume stimulus for ADH secretion. However, our patient has replaced 3 liters of isotonic fluid with 2 liters of pure water, hence the overall osmolarity of the ECF will fall significantly. This should cause an inhibition of the osmotic pathway for ADH secretion, hence ADH levels should fall.
how the secretion of ADH varies with changes in either volume or osmolarity.
it is apparent that if ECF volume is held constant at its normal value (e.g. 15 liters for our normal human), that changes in ECF osmolarity cause monotonic, roughly linear changes in ADH levels in the plasma for osmolarity values both above and below normal. On the other hand, for normal osmolarity, it seems that changes in ECF volume have little effect on ADH levels, except when ECF volume falls severely. For the initial acute condition of loss of 3 liters of isotonic diarrhea, it is clear that the proportional ECF volume reduction (i.e. 20% loss of ECF volume) is severe enough to trigger massive ADH secretion (see red arrow in figure 5), and since the osmolarity pathway is not activated, a net rise in ADH levels occurs at this point. However, after drinking 2 liters of water during recovery, the volume change is now much more modest (about a 7% decrease, green arrow), and the volume curve predicts that as far as volume goes there will be no stimulus to ADH secretion. But what about the osmolarity input? An ECF in which 2 liters of water were added to 12 liters of isotonic fluid would be reduced in osmolarity by about 15% below normal, hence would be strongly inhibitory to the osmotic pathway. Overall, then, in this example the osmolarity effect “wins” and ADH would be suppressed to very low levels (i.e. near zero), and urinary water excretion would be at a maximum.
ECF water regulation
is primarily an osmoregulatory system with an emergency low-volume override. Thus, in relatively normal, day-to-day physiology, water is regulated almost entirely to achieve osmotic constancy with little regard for even fairly moderate volume losses. However, when volume loss starts to become severe (.e.g >10% volume reduction), then the volume input rapidly dominates osmotic effects on ADH levels. This low volume dominance of ADH secretion ensures that the circulation is defended at all costs during severe hypovolemia. This important principle is fundamental to understanding disease mechanisms in a number of situations where the circulation is compromised. As opposed to the volume effects, it should be mentioned that the osmoregulatory loop is exceptionally sensitive to very small changes in osmolarity from normal. Thus changes in ADH levels can be detected for osmolarity changes of
Regulation of volume overload by atrial natriuretic peptide (ANP)
There is no suppression of ADH if volume increases above normal. However, inappropriate ECF volume expansion is potentially a very unhealthy situation, causing hypertension and an increased risk of stroke. For many years after the role of ADH in water conservation was understood, researchers wondered whether a natural diuretic hormone existed that could deal with the opposite limb of water regulation, namely too much ECF water. We now know that such a diuretic hormone does exist and it plays an essential role in the big picture of water regulation. It was initially discovered in prominent granules of atrial cardiocytes; its diuretic role was suggested when these granules disappeared in volume-expanded animals. The hormone was then purified from isolated cardiocyte granules and shown be a potent diuretic peptide that also increased sodium excretion. Hence it has been called atrial natriuretic peptide (ANP; a.k.a. atrial natrituretic factor (ANF); atriopeptin).
The pathway and site of action of ANP
First, increased ECF volume results in an increased distention of the atria, and this causes release of the ANP granule contents from the atrial cardiocytes. In fact, the granules contain the 52 amino acid pro-ANP form, which is then cleaved by peptidases in the blood to the active 28 amino acid ANP. Active ANP then reaches it targets throughout the body, all of which aid in the increased production of urine. Note how widespread and comprehensive the action of ANP is in antagonizing the normal tubular mechanisms of water reabsorption. Thus ANP acts to increase filtration by selectively dilating both the afferent and efferent arteriole (why will this increase GFR?), placing more fluid in the tubule and increasing excretion of water and sodium through flow effects. At the same time, ANP acts to decrease the sodium and water reabsorption mechanisms that we discussed in lecture #3. First, through a direct action on the brain, it decreases the secretion of ADH. Second, it inhibits renin secretion, hence AgII formation, thus ultimately decreasing aldosterone synthesis. So both hormones that stimulate water and salt reabsorption are inhibited. Further, ANP also prevents the effects of remaining levels of ADH and aldosterone on the tubular epithelium. Both of these actions on hormones will further increase the diuretic effect since they increase tubular fluid flow while they decrease the osmotic gradient for water reabsorption and the water permeability in the fine tuning segments. The result is a massive diuresis with an accompanying increase in sodium excretion, i.e. natriuresis.
pathways for water and sodium
We have greatly simplified the descriptions of how water and sodium are regulated, for we have treated each substance as if it were regulated independently. This is clearly NOT what happens in real life physiology, as it should be obvious that many of the stimuli and pathways for water and sodium are interdependent. For example, in the severe sweating example discussed above, the individual has also lost a significant amount of sodium, and ultimately the sodium homeostasis pathways must be activated to allow increased the increased reabsorption of sodium over time to replenish what has been lost. This is accomplished in part by the hypovolemically-induced decrease in MAP that turns on aldosterone-mediated Na+ reabsorption. This in turn will allow the retention of dietary sodium in the ECF, which will keep osmolarity high, which then keeps ADH levels up; thus salt and water are restored in proportion to the ECF until the osmotic and volume stimuli attenuate due to return to normal of ECF parameters. In addition, as you will learn in the neuroscience block, AgII acts on the brain to increase thirst, hence motivating the patient to add fluid to the ECF via ingestion.
Chronic renal disease and mental illness
The burden of physical illness is an important risk factor for suicide independent of mental illness. Increased risk of suicide in patients with chronic renal disease is similar in magnitude to suicide risk with other chronic illnesses such as chronic pulmonary disease and stroke, and patients with end-stage renal disease have an 84% higher rate of suicide compared to the U.S. population. Patients with kidney transplants have a 75% highe rrate of suicide compared to national rates. Patients with self-reported kidney disease attempt suicide at three times the rate of the U.S. population. Depression among dialysis patients may adversely affect mortality, possibly independent of dialysis adequacy. The risk of suicide is highest in the first 3 months of dialysis, which suggests that suicideis prompted by failure to cope with stress rather than declining health status. With drawal from dialysis before death is common and occurs approximately 100 times more often than suicide. Studies suggest poorer survival among depressed dialysis patients. Psychiatric illness is common among patients with chronic medical disorders, particularly in
those with end-stage renal disease (ESRD): Patients with end-stage renal disease have a high prevalence of depression, especially at dialysis initiation. In renal patients, exclude uremia and assure adequate dialysis before diagnosing depression; since symptoms of depression and those originating from a metabolic disorder are similar: under-dialysis, including anorexia and failure to thrive, may mirror depression; correction of fluctuating blood pressure, nausea, or other gastrointestinal complaints may improve quality of life and may effectively treat psychosocial markers suggesting depression; common complaints in the dialysis patient, such as chronic fatigue, weakness, and constipation, may reflect a psychosocial disturbance. There quest to with draw from dialysis may suggest depression. In patients who appearto have intact decision-making capacity, exclude the subtle presence of factors such as situational depression, mild dementia, and uremic or toxic encephalopathy. The diagnosis of depression can be confounded by patients who do not realize - or deny - they are clinically depressed due to suicidal intent or the stigma associated with mental
illness.
Why are potential problems sometimes missed in medical practice?
- Physicians receive inadequate training. You would not learn CPR at your first cardiac arrest. You need to learn the principles of emergency psychiatry before a suicidal patient comes into your office. Unfortunately, most residencies spend very little, if any, time on psychiatric matters although surgeons will see a lot of trauma; family physicians, internists and pediatricians see the whole panoply of abuse, incest, suicide and so forth. 2. Same-class bias and other counter-transference issues may prevent you from asking patients - especially those who you feel you are like - tough questions about lethality (suicide, homicide, child and spouse abuse, incest, and drug abuse). It is said that physicians will diagnose alcoholism only in those who drink more than they do. 3. Inadequate mental health backup. Physicians are less likely to identify tough psychiatric problems in their patients unless they feel they have someone to back them up and to whom they can send their patients.
DANGEROUS BEHAVIORS = MALADAPTIVE RESPONSE TO STRESS
Psychiatric emergencies may be thought of as resulting from maladaptive responses to stress. For example, a stressor (e.g. loss) leads first to denial then may precipitate disorganization and symptom formation, then maladaptive responses (e.g. suicide, abuse) and then re-equilibration. Even normal life events can precipitate dangerous behaviors in susceptible persons. For example, pregnancy is a high-risk time for spousal violence and incest in susceptible men. Patients come – or are brought – to us only in the phases of Disorganization /Symptom Formation or when they have resorted to a maladaptive behavior such as suicide or abuse. According to this model, a vulnerable patient is first stressed and then resorts to dangerous behaviors. The healthier the patient, the more profound the stress has to be to precipitate problems. The KEY question for us is to figure out what the patient is trying to accomplish and fix, albeit in this destructive way, when they resort to abuse, suicide and so forth. For example, suicide may be a way of reuniting with someone who is dead or punishing someone who is alive. Finally, according to this model, the period of highest lethality typically does not last long. Either the problem is solved – e.g. the spouse returns – or the patient makes a suicide attempt. This fact, that the period of highest lethality is short, is why brief hospitalizations can be life-saving.
COMMON PRESENTATIONS OF PSYCHIATRIC EMERGENCIES IN MEDICAL PRACTICE
None are pathognomonic and the only way to really find out what is going on with your patients is to ASK. HOW YOU ASK IS LESS IMPORTANT THAN THAT YOU ASK. Patients with vague somatic complaints, aches, and pains or multiple visits to physicians: patients may be labeled as crocks, WADAOs (weak and dizzy all over), hypochondriacs, somatizers, etc., which is fine. You can make such pejorative diagnoses to yourself; what really matters is what you do next, how you evaluate and treat these people. Symptoms and signs of depression, anxiety, drug and alcohol abuse e.g. insomnia or hypersomnia, fatigue, worry, weight gain or loss, irritability, difficulty with concentration, problems at home, work or school. Remember that studies have found that 70% of depressions are missed in medical practice. Accidents, multiple or unexplained trauma (child/spouse abuse), GU complaints or early pregnancy (incest), GI complaints (alcoholism), problem pregnancies (abuse), school problems (child abuse, incest) and so forth. Symptoms and signs of family disruption, school problems, truancy all may be indications of spousal violence, child abuse or incest. Sexual promiscuity, running away and suicidal activity is known as the “incest triad” and indicates a very high risk of incest. One psychiatric emergency may mask another. Emergencies come in bunches and often overlap. For instance, alcoholism may coexist with abuse or suicide; spousal violence may co- exist with child abuse. Therefore, if you find one, look for the others.
The neurochemistry of violence
Serotonin has been implicated in the control of violent behaviors – both suicide and violence directed towards others. There is a remarkably consistent association between low cerebrospinal fluid concentrations of the Serotonin metabolite 5- HIAA and suicidal behavior. This association is found not only in depressive disorders but has been found in schizophrenia, some personality disorders, and in certain impulse disorders but not in bipolar disorder. Low concentrations of CSF 5-HIAA is associated with a real increase in suicide risk. Studies in violent criminals in non-human primates suggest that aggression dyscontrol may partly explain this association. There is a lot of evidence that supports the association between aggression and alcohol consumption as well. Alcohol consumption has a major effect on Serotonin metabolism. The “Serotonin deficiency hypothesis” of alcohol-induced aggressive behavior postulates that people susceptible to aggression after consuming alcohol exhibit a marked depletion of their brain Serotonin. This makes them prone to aggressive outbursts in response to environmental or psychological stimuli or situations. In addition, a significant association has been found between low cholesterol levels and violence – towards self and others – across many studies. It is postulated that lowered cholesterol levels may lead to lowered brain Serotonin activity; this may in turn, lead to increased violence.
Suicide Assessment: changeable states and immutable traits
- The Patient’s History and Demographics: traits. History of suicide attempt or impulsive, violent behavior? Family history of suicide, male, Caucasian, single, recent loss, divorced, widowed? Chronic illness? History of major depression, schizophrenia, bipolar mood disorder, drug or alcohol problems, cognitive disorder, anorexia nervosa, personality disorder with axis I co-morbidity all push people into a higher risk category. In people with Anorexia Nervosa, for instance, suicide occurs in 5-10% of patients within 10 years and almost 20% of patients within 20 years of onset of the disease. Suicide also occurs in approximately 15% of patients diagnosed with alcohol abuse or dependency, patients with depression, and patients diagnosed as schizophrenic. 2. The Acute Clinical Picture: changeable state. Passive death wishes? Active suicide desire? Death wishes in family and friends? Hopelessness and lack of future plans, lethal suicide plan, suicide note, intoxicated, psychotic, weapons, etc…
the work up of sucide
Developing a differential depends on your “snapshot” of the patient now and your assessment of your patient’s symptoms over time, i.e. the clinical course of your patient.
I structure my work-up around the following Seven Diagnostic Questions. Information about these questions should be gleaned from as many sources as possible:Why is the patient here now? What does the patient want and expect to accomplish? Is a general medical illness contributing to the patient’s difficulties? How lethal – suicide, abuse, incest, violence – do you judge the situation to be? Are family and friends part of the problem or part of the solution? What are the patient’s cultural expectations/explanations/treatments for their illness? What is the patient’s psychiatric diagnosis? Lethality and medical issues must be answered first and constitute the core of the first-line of the emergency evaluation.
ERRORS MADE IN THE EVALUATION OF SUICIDE IN PSYCHIATRIC PATIENTS
Not corroborating the patient’s story with family and friends. This is the number one mistake made by psychiatrists and non-psychiatrists alike. Failing to review old records. Failing to seek consultation: collegial, medical or psychiatric. Share your worry about tough patients and do not assume that you have to know and do everything. Avoiding specific questions about guns, plans, fantasies and so forth. Ignoring risk enhancing factors such as the presence of a psychotic disorder (i.e. command hallucinations, paranoia), drug/alcohol abuse, feelings of hopelessness, a prior history of abuse, suicide, etc. Such factors always raise the risks of lethality.
TREATMENT Of Suicidal ideation
Treatment clearly depends on your diagnostic assessment of dangerousness but it is better
safe than sorry. Remember that you can hold a patient against their will if you judge them mentally ill and
to be a potential harm to themselves and others or gravely disabled. You also have a duty to warn potential victims as well as care for your patient. You have a duty to report suspected child abuse and incest as well as domestic violence.
Before Sending a Patient Home from suicide watch
Following the evaluation of the specific emergency (at the very least lethality and medical issues), there are four issues the practitioner might examine in order to judge the adequacy of the immediate treatment plan. Do I understand the seriousness of the patient’s problem or am I going along with the patient’s or family’s denial? Two notions have helped me: A false alarm is better than no alarm at all and the last person to see the patient gets to make the last mistake. What was the patient attempting to accomplish with their destructive behavior and did they accomplish it? In other words, has the crisis passed or is the patient still overwhelmed with whatever stressed them in the first place? Do I dare let the patient go home or is the patient going back into the pathogenic environment which contributed to his/her difficulties in the first place? Will the patient follow the treatment plan? What contingency plans have I made if the patient does not follow through? Do I know how to reach the patient and have the correct address and telephone number? Do I have a friend, relative or neighbor I can call? A good follow-up plan – and close follow-up makes up for any mistakes in clinical judgment.
Normal plasma value of Na
140 ± 3 mEq/L (Tells you about the relative amount of water in the ECF compared with Na. It tells you nothing about total body Na; best considered as an indirect but readily available assessment of plasma osmolality that is accurate under most (but not all) circumstances).
Normal plasma value of K
4.5 ± 0.6 mEq/L (Tells you about plasma K; relatively poor indicator of total body K).
Normal plasma value of Cl
104 ± 3 mEq/L (Generally considered a passive anion; used in the anion gap calculation as described below).
Normal plasma value of Total CO2 (tCO2)
27 ± 2 mEq/L (Total CO2 content of blood; about 3 mEq/L higher than the arterial HCO3- because of dissolved CO2. Used for calculation of anion gap).
Normal plasma value of Glucose (Fasting)
90 ± 30 mg/dL
Normal plasma value of Creatinine
1.0 ± 0.3 mg/dL (Used to estimate renal function; reciprocal (1/cr)
directly proportional to CrCl and, indirectly, to GFR).
Normal plasma value of BUN
12 ± 4 mg/dL
Normal plasma value of Phosphorus
4.0 ± 1.0 mg/dL
Normal plasma value of Calcium
9.5 ± 1.0 mg/dL
Normal plasma value of Cholesterol
140-200 mg/dL
Normal plasma value of Osmolality
285 ± 3 mosm/kg H2O (Direct measurement of plasma osmolality;
difficult to obtain in a short time from a clinical lab).
Normal plasma value of Plasma Anion Gap
Na–(Cl+tCO2)=9±2mEq/L
Normal urine value of Na
low suggests avid tubular sodium reabsorption ( 40 mEq/L)
Normal urine value of K
must be considered in light of plasma potassium.
Normal urine value of Creatinine
usually viewed in concert with plasma creatinine; a UCr/PCr value
greater than 20 suggests avid tubular water reabsorption, a value less than 10
suggests less avid water reabsorption.
Normal urine value of Osmolality
(again, no “normal range) 285 is isotonic -normally can dilute to less
than 50-100 mosm/kg H2O, -normally can concentrate to greater than 1000 mosm/
kg H2O
Normal urine value of Specific gravity
1.010 is isotonic ( this is concentrated)
Normal Blood Gas Value of pH
7.42 ± 0.02
Normal Blood Gas Value of pO2
94 + 8 (remember, we’re assuming sea level)
Normal Blood Gas Value of pCO2
38 ± 2 (remember, we’re assuming sea level)
Normal Blood Gas Value of HCO3-
24 ± 2 (remember, we’re assuming sea level). Note that both venous tCO2
and arterial HCO3- are calculated from the Henderson-Hasselbach equation and are equally accurate.
Acute kidney injury (AKI)
defined as a rapid reduction in glomerular filtration rate manifested by a rise in plasma creatinine (Pcr) concentration, urea and other nitrogenous waste products. AKI results in reduced clearance of nitrogenous waste products to produce a state called azotemia (Azote is the French word for nitrogen, hence azote-emia or increased nitrogen in blood). Three broad types of disorders can cause AKI: Pre-renal acotemia, post renal axotemia or obstructive neuropathy, or intrinsic renal disease
Pre-renal azotemia
a decrease in GFR due to decreases in renal plasma flow and/or renal perfusion pressure.
Post-renal azotemia or obstructive nephropathy
a decrease in GFR due to obstruction of urine flow.
Intrinsic renal disease
a decrease in GFR due to direct injury to the kidneys (may be due to a variety of insults).
Uremia refers to the constellation of signs and symptoms of multiple organ dysfunction caused by retention of “uremic toxins” and lack of renal hormones due to acute or chronic kidney injury. Such symptoms include nausea, vomiting, abdominal pain, diarrhea, weakness and fatigue.
Azotemia
Buildup of nitrogenous wastes in the blood; i.e. Blood Urea Nitrogen
(BUN) and serum creatinine are increased.
Prerenal azotemia
Normal renal function is dependent on adequate renal perfusion. The kidneys receive up to 25% of the cardiac output resulting in more than 1 liter of blood flow per minute. This high rate of renal blood flow (RBF) is required not only to maintain GFR, but also to maintain renal oxygen supply required for ion transport. A substantial reduction in renal perfusion may be sufficient to diminish effective filtration pressure and thus lower GFR. Prerenal azotemia is the most common cause of an abrupt fall in GFR in a hospitalized patient. In general, prompt restoration of intravascular volume restores RBF and GFR and prevents structural ischemic renal injury. Prolonged pre-renal azotemia, however, may result in acute tubular necrosis. Be careful not to associate pre-renal azotemia with only hypovolemia because there are certain hypervolemic states that can cause a pre-renal picture, e.g. congestive heart failure (CHF) and cirrhosis. People with CHF have poor cardiac output and therefore reduced blood flow to the kidneys. If CHF is severe enough, blood ‘backs-up’ into the pulmonary circuit resulting in pulmonary edema and a hypervolemic state. CHF and cirrhosis are characterized by a low effective arterial blood volume (EABV) and reduced renal perfusion. Therefore, these conditions are classified as pre-renal even though they may cause hypervolemia. The renal tubules function normally in prerenal azotemia and will concentrate the urine and reabsorb sodium avidly. Thus, urine sodium concentration will be low (less than 20 mEq/L) and urine creatinine concentration will be high (Ucr/Pcr ratio > 20).
The ratio of the clearance of sodium to creatinine (also called the fractional excretion of sodium or FENa)
is calculated as follows: FENa = (UNa/PNa) ÷ (UCr/Pcr ) X 100 (expressed in %) This equation takes both of these features into account and is useful in separating prerenal azotemia from other causes of AKI. In general, the FENa is 2% when AKI is caused by other pathologies. There are exceptions to this rule, i.e. radiocontrast and rhabdomyolysis (severe muscle breakdown) can cause FENa
Postrenal azotemia (obstruction)
Obstruction to urine flow is another potentially treatable form of AKI. With urinary tract obstruction, increases in intratubular pressure typically cause the low GFR acutely but if obstruction is prolonged, an intense renal vasoconstriction usually develops and results in a persistent decrease in GFR. Except in patients with single kidneys or with pre-existing bilateral parenchymal disease and reduction in renal function, obstruction must be bilateral to produce significant kidney injury. Obstructive uropathy will be encountered in 2 to 15% of all patients with AKI. Obstructive uropathy often presents as no urine flow (anuria) or intermittent urine flow, but may also present as nonoliguric AKI. Obstruction is the most common cause of anuria.
Causes of Postrenal Azotemia
Obstruction of ureters: Extraureteral (e.g. carcinoma of the cervix, endometriosis, retroperitoneal fibrosis, ureteral ligation). Intraureteral (e.g. stones, blood clots, sloughed papilla). Bladder outlet obstruction (e.g. bladder carcinoma, urinary infection, neuropathy). Urethral obstruction (e.g. posterior urethral valves, prostatic hypertrophy or carcinoma).
Urinary obstruction
generally results in derangement of tubular function that affects sodium and water handling. In general there is an impairment of tubular sodium reabsorption that is reflected by high urinary sodium concentrations (> 40 mEq/L) and an impairment of water reabsorption that results in low urine creatinine concentrations (Ucr/Pcr, ratio 2% in urinary obstruction.
The most sensitive test for the diagnosis of obstruction
the renal ultrasound evaluation (US). An US will demonstrate obstruction as an expansion of the collecting system (hydronephrosis) in as many as 98% of cases. For obstruction at the level of the urethra, placement of a bladder catheter following voiding may confirm the diagnosis. If there is still considerable urine present, obstruction to flow of this urine has occurred. This volume of urine is called the ‘post-void residual’. A bladder catheter will also bypass the obstruction and provide treatment. Prompt relief of acute obstruction is usually associated with complete return of renal function, but prolonged obstruction is often accompanied by incomplete return of renal function after relief of the obstruction.
Intrinsic renal disease
Intrinsic renal disease (i.e. disease that affects the renal parenchyma) is divided into four types based on the four structures found in the kidney: vessels, glomeruli, interstitium and tubules. The most commom injury is acute tubular necrosis (ATN) that is caused by either ischemia or nephrotoxins (which are typically medications). It should be noted that the term ATN may be somewhat of a misnomer as histologic studies have not consistently demonstrated tubular necrosis.
Intrinsic Renal Diseases Causing AKI
Vascular diseases: e.g. cholesterol emboli, renal vein thrombosis. Glomerular diseases: e.g. acute glomerulonephritis, hemolytic uremic
syndrome
Interstitial diseases
Acute interstitial nephritis (e.g. allergic interstitial
nephritis (AIN)), infection, myeloma kidney.
Tubular diseases
Ischemic or nephrotoxic acute tubular necrosis (ATN).
Mechanisms of decreased gfr in atn
The pathophysiology of human ATN is still uncertain, although considerable work has been performed on this topic. In experimental ATN, it appears that different physiologic factors may mediate the initiation and maintenance of the decreases in GFR that is the hallmark of ATN. The physiologic factors are usually subdivided into vascular and tubular. The vascular factors include decreases in renal blood flow and decreases in glomerular permeability (Kf), whereas the tubular factors include tubular obstruction (by cellular debris) and backleak of glomerular filtrate (across an incompetent tubular basement membrane). Animal data suggests that most ischemic human ATN involves a reduction in renal blood flow as the primary event. This causes ischemia and consequently, injury to the proximal tubular epithelial cells. The injured (or sometimes necrotic) cells break away from their tubular basement membrane exposing bare sections of tubule through which ‘backleak’ is thought to occur. The cells clog up the proximal tubule causing tubular obstruction and maintain the low GFR. More recent studies addressing renal vascular reactivity suggest that ischemic injury may also produce a failure of autoregulation of renal blood flow. This may contribute to the maintenance of ATN allowing recurrent ischemic insults to result from relatively mild episodes of systemic hypotension. Patients with ATN may be oliguric or nonoliguric.
Oliguric vs Nonoliguric patients with ATN
Nonoliguric patients have a lower mortality rate (about 20% as compared to 60-80% for oliguric ATN) perhaps because: Nonoliguric ATN is a less severe injury or Management of fluid and electrolyte status is easier.
Infections due to decreased leukocyte function and gastrointestinal tract hemorrhage due to increased acid secretion (stress, ulcers) are two serious complications associated with ATN. Ischemic AKI with ATN is typically characterized by an oliguric phase of about 7- 14 days, followed by a nonoliguric phase of 10-14 days. However, this is not always the rule in clinical practice where prolonged oliguric phases as well as initial nonoliguric presentations are both common.
History and physical examination of AKI
Look for evidence that will help you decide if your patient has pre-, renal, or post-renal AKI. Some important signs and symptoms are: Intravascular volume depletion is suggested by a decrease in weight, flat neck veins, and postural changes in blood pressure and/or pulse. The presence of these signs and symptoms would suggest a pre-renal etiology of AKI. Cardiac dysfunction is suggested by edema, pulmonary rales, and a S3 gallop. Again the presence of these signs and symptoms would suggest a pre-renal etiology of AKI. Note that in these instances, the patients demonstrate signs of hypervolemia (see section on Pre-renal Azotemia). A history of exposure to renal insults associated with ATN, i.e. hypotension, surgery involving large blood loss, transfusion reactions, or exposure to radiocontrast dye used for CT scans and cardiac catheterization. Evidence of urinary obstruction e.g. anuria, intermittent anuria or large swings in urine flow rate. Evidence of other causes of AKI, e.g. rash and fever after exposure to ampicillin (antibiotic) suggests AIN (allergic interstitial nephritis)
Urinalysis and sediment examination of AKI
This represents an important extension of the basic History and Physical, and must be performed on all patients with AKI. The urinalysis provides useful information including the tonicity of the urine as well as the presence or absence of heme pigments. For example, high tonicity occurs when the kidney retains water due to increased antidiuretic hormone (ADH). These include pre- renal states and SIADH (more in the hyponatremia and water chapter). The presence of heme pigments (detected by a positive blood test on the urine dipstick) without microscopic evidence of RBCs in the urine would suggests rhabdomyolysis or hemolysis. Rhabdomyolysis is a syndrome characterized by muscle necrosis and release of intracellular muscle constituents (including myoglobin) into the circulation. It is a common cause of AKI, especially in trauma patients.
Three main components of urine analysis
Macroscopic or gross exam, Dipstick chemical analysis, and Microscopic exam
Macroscopic exam
This is a direct, visual observation of collected urine. Fresh urine from a normal patient is clear and pale to dark yellow in color. Patients who are ill may have cloudy or turbid urine. RBCs in the urine may cause the color to appear red or reddish brown (“cola colored”).
Dipstick analysis
Dipsticks are long thin strips of inert plastic that have square reaction pads that provide color readouts based on biochemical reactions with the urine. Reaction pads include: glucose, protein, heme, bilirubin, ketones, and leukocyte (esterase and nitrite).
Microscopic exam
This is for identifying formed elements. These include cells, casts, and crystals. Cells include WBCs, RBCs, bacterial and epithelial cells. RBCs in the urine can have a variety of shapes and appearances depending on their origins within the genitourinary system (glomerular versus non-glomerular origin). The renal tubules secrete mucoproteins and when these proteins “gel” in the tubules, they form casts. (see figure 6) They are cylindrical in shape, just like the lumen of a tubule. Anything present in the tubules when these casts are formed will be trapped in the casts. Hyaline casts have no cells within them and they are normal findings in healthy individuals. RBC and WBC casts reflect pathology since RBCs and WBCs are normally not in the tubules. They are associated with glomerulonephritis and AIN, respectively. To perform a microscopic exam, you centrifuge ten to 15 mL of fresh urine at 400-450 g for 5 minutes (procedure may vary). The supernatant urine is decanted and the sediment is resuspended in a small volume of remaining urine. You then place a drop on a slide for microscopic examination.
Urinary casts
are typically formed in the distal convoluted tubule (DCT) or the collecting duct (distal nephron). The proximal convoluted tubule (PCT) and loop of Henle are not locations for cast formation. Hyaline casts are composed primarily of a mucoprotein (Tamm-Horsfall protein) secreted by tubule cells. The Tamm-Horsfall protein secretion (dots) is illustrated in the diagram, forming a hyaline cast in the collecting duct.
Prerenal azotemia UA Pattern
Relatively high specific gravity, no heme pigment, normal sediment (i.e. any casts are waxy or finely granular).
Glomerulonephritis UA Pattern
Variable tonicity, + heme pigment, sediment exam reveals RBC and RBC casts.
AIN
Isotonic urine, +/- heme pigment, white blood cell casts, eosinophils (with allergic interstitial nephritis)
Vascular UA Pattern
Variable tonicity, ± hematuria
ATN UA Pattern
Typically isotonic, variable heme pigment (+ if from hemolysis or rhabdomyolysis). Sediment exam will show pigmented coarsely granular casts and renal tubular epithelial cells (RTEs).
