THE KIDNEY AND THE CONCEPT OF CLEARANCE*

Transcription

1 THE KIDNEY AND THE CONCEPT OF CLEARANCE* I. The Antomy of the Mmmlin Kidney A. Gross ntomy: 1. The outer region of the kidney = the CORTEX 2. Inner region = the MEDULLA 3. The re where ll of the urine collects is clled the PELVIS OF THE KIDNEY. The urine leves the kidney's pelvis vi the URETERS b. The pelvis is lso where the blood supply enters nd leves the kidney vi the RENAL ARTERY AND RENAL VEIN. Incidentlly, bout 25% of the crdic output flows through these vessels. cortex medull "renl pelvis" ureter B. Histology 1. The functionl units of the kidney re clled NEPHRONS. Of these, there re two types:. CORTICAL (SUPERFICIAL) NEPHRONS: The entire nephron is locted in the outer region, the cortex. These function primrily in secretion nd rebsorption of different substnces. b. JUXTAMEDULLARY NEPHRONS: these nephrons strt in the Cortex nd extend down into the medull, in some cses to ner the pelvis of the kidney. Besides being involved in secretion nd rebsorption of mterils, their unique role is in concentrting the urine. c. Morphologiclly, the difference between corticl nd juxtmedullry nephrons besides their size nd loction is the size of their LOOPS OF HENLE (see below) - - Corticl nephrons essentilly lck long loop of Henle. d. The Rtio of Corticl to Juxtmedullry nephrons is n index of the bility of n niml to concentrte its urine. The more juxtmedullry nephrons, the more the urine cn be concentrted. We will tke this up in more detil in the next clss. 2. Histology of Juxtmedullry Nephron. GLOMERULUS: The filter of the nephron. Essentilly, it consists of two prts: 1. A cpillry tuft tht is highly convoluted; it is surrounded by: * Copyright 2015, Kenneth N. Prestwich, Holy Cross College, Worcester, MA kprestwi@holycross.edu Excretion by the vertebrte kidney: Clernce 1

2 2. A cup- like lyer of epithelil cells clled Bowmn's Cpsule. Notice in the digrm below tht the cpsule cn be seen s hollow bll tht hs been pushed in with fist where the fist is mostly surrounded by the bll. The fist represents the cpillry tuft: fferent rteriole cpillry tuft (glomerulus) filtrtion filtrte proxml convoluted tubule efferent rteriole Bowmn's Cpsule 3. The ction of the cpsule will be reviewed lter in detil, but suffice it to sy tht wter nd solutes re filtered through the cpillry wlls nd the wlls of the cpsule nd end up in the CAVITY OF THE BOWMAN'S CAPSULE s Glomerulr FILTRATE or simply FILTRATE. b. PROXIMAL TUBULE: This is n re where mterils re pssively nd/or ctively secreted nd re- bsorbed. Most of the wter nd solutes (67%) tht were filtered re pssively n ctively rebsorbed here. c. LOOP OF HENLE: This is very long in the juxtmedullry nephron. It hs very complex function tht will be reviewed lter. It consists of: 1. Two thin tubules tht re linked together. The cells lining these tubules re very thin nd lck lrge numbers of mitochondri; they re not involved in ctive trnsport.. The DESCENDING THIN LIMB which crries filtrte towrds the pelvis of the kidney where it mkes HAIRPIN TURN nd becomes the scending thin limb (see below). No significnt solute rebsorption occurs here; however this section of the loop of Henle is permeble to wter. For resons tht will be explined lter, bout 17% of the filtered wter is rebsorbed here. b. the ASCENDING THIN LIMB which crries filtrte bck towrds the cortex nd the thick scending limb (see below). No significnt trnsport occurs here. It is wter impermeble. 3. THICK ASCENDING LIMB: n re where much ctive trnsport of solutes occurs. For instnce, bout 25% of the filtered N + is rebsorbed here. This section is lso wter impermeble nd s result of the fct tht wter cnnot move while solutes re pumped out, the osmolrity of the fluid leving this section is extremely low (bout 150 mosm). Excretion by the vertebrte kidney: Clernce 2

3 d. DISTAL CONVOLUTED TUBULE (DCT): this section is the lst region of the nephron nd is primrily concerned with the regultion of N +, K + nd H + vi secretion nd rebsorption. Its ctions re under the control of the steroid hormone ALDOSTERONE. More bout ldosterone in the next clss. Together with the collecting duct, bout 12% of the filtered N +, Cl - nd 15% of the filtered wter re rebsorbed in the DCT. e. Not relly prt of the Nephron, but connected to it is the COLLECTING DUCT, tube tht tkes filtrte from the distl convoluted tubule nd moves it to the pelvis of the kidney. In the process, depending on the levels of the hormone VASOPRESSIN (lso clled VASOTOCIN nd ANTI- DIURETIC HORMONE or ADH), wter my be removed from the filtrte nd the urine mde more concentrted. The endocrine system hs n extensive role in regulting the secretion nd rebsorption processes of the kidney. Below is tble tht summrizes the hormones nd their trgets nd effects. We will look t some of these in detil lter: Segment Hormone Effects Prox. Conv. Tubule Thick Ascending Loop Distl Tubule nd Collecting duct Prthyroid Hormone Angiotensin Aldosterone, Clcitonin, Glucgon, Vsopressin, Prthyroid Hormone Clcitonin Vsopressin Aldosterone Prostglndins Brdykinin NCl nd wter rebsorption NCl nd wter NCl rebsorption NCl rebsorption Permebility to wter nd NCl rebsorption NCl rebsorption NCl rebsorption NCl rebsorption 3. CIRCULATION:. Blood enters the kidney vi the RENAL ARTERY b. This eventully splits into lrge number of smll ARTERIOLES, mny of which serve s the blood supplies of the glomeruli. Thus, their blood will be filtered. c. The ctul rteriole tht enters the glomerulus is clled the AFFERENT ARTERIOLE. d. The blood then moves through the glomerulr cpillries nd is filtered. e. The blood leves the region of the Bowmn's cpsule vi the EFFERENT ARTERIOLES f. Most of this blood now enters the PERITUBULAR CIRCULATION, group of vessels tht surround the convoluted tubules nd the loop of Henle nd collect the mterils Excretion by the vertebrte kidney: Clernce 3

4 tht come out nd lso ct s the source for mterils tht will be secreted. They lso supply oxygen nd other substnces nd removes wstes from these tissues. g. In juxtmedullry nephrons, bout 0.7% of the blood circultes through series of scending nd descending vessels clled the VASA RECTA. These re ssocited with the loops of Henle, these vessels re rrnged s counter- current exchnger (see digrm on the next pge). They perform n importnt tsk in helping to concentrte the urine. (This will be mentioned in more detil in the next lecture). II. FORMATION OF THE GLOMERULAR FILTRATE: A. Formtion of the filtrte is simple physicl process identicl to the formtion of interstitil fluid nd lymph tht we discussed erlier with the circultion. The min difference is tht the pores in the filtering cpillry (glomerulus) re bit lrger thn in regulr cpillries nd the "other side of the filter", the lumen of the Bowmn's cpsule, cn be through of s hving reltively low hydrosttic pressure s compred to the interstitil fluid. In ny cse, s with the other cpillries, filtrtion is governed by: hydrosttic nd colloidl osmotic pressures nd by the size of the filtered molecules reltive to the pore size in the filter nd by the chrge of the filtered prticles. Here we will focus primrily on the filtrtion of wter; relize tht other mterils tht re smll enough to pss the membrne will come long for the ride. Most of this will be review, with the exceptions being more explicit discussion of chrged prticle size nd more on regultion of blood flow. B. The influence of prticle size nd chrge on filterbility cn be illustrted with n experiment where dextrns (hrmless, non- metbolizble crbohydrtes of different moleculr weights) with vrious mounts of ionic groups ttched re dded to blood nd their concentrtion in the Bowmn's spce is mesured. Here is tble tht summrizes the bility of mterils to pss through the glomerulr filter. The figure below shows the rtio of the concentrtions of given mteril tht is in the filtrte (C f ) to tht in the plsm of the tubule (C p ). Thus rtio of C f / C p tht is ner unity implies tht the substnce is freely permeble, if it is less thn one the mteril is only prtilly permeble or is impermeble (C f /C p = 0). wter NCl 1.0 myoglobin C f / C p 0.5 glucose inulin fter Fig. 45-5, Berne nd Levy, Physiology, Mosby 1983 hemoglobin lbumin Moleculr Rdius (10-10 m) Excretion by the vertebrte kidney: Clernce 4

5 C. Assuming tht mteril is filterble, the rte tht mteril psses through the filter, s we lerned previously, is described by the STARLING HYPOTHESIS: 1. Filtrtion Rte = k * (P GC + Π BS ) - (P BS + Π GC ) where k is fudge fctor coefficient tht describes how fst fluid moves cross the glomerulus t given filtrtion pressure, P GC is the hydrosttic pressure of the glomerulr cpillry, P BS is the hydrosttic pressure in the Bowmn's spce (Bowmn's cpsule), Π GC is the glomerulr cpillry colloidl osmotic pressure nd Π BS is the sme mesure for Bowmn's spce. 1. Let's look t this eqution in detil. IF EVERYTHING ELSE REMAINS CONSTANT: 2. if the cpillry hydrosttic pressure (P GC ) increses or the tubulr hydrosttic pressure decreses, there will be greter pressure tending to drive mterils cross the membrne nd the filtrtion rte will increse. 3. By contrst, reltively higher Bowmn's spce osmotic pressure (Π BS ) will tend to encourge fluid to leve the cpillry s will reltive lower tubule osmotic pressure. 4. We cn envision the net forces of ech of the hydrosttic nd osmotic pressures s: Hydrosttic Filtrtion Vectors To Tubule Osmotic Grdient Net Rte of Filtrtion To Cpillry Distnce Along Glomerulus (sme s bove) NOTE: By n exctly nlogous mechnism, the blood forms lymph in the tissues of the body. IN SUMMARY, REALIZE THAT THE GLOMERULUS- BOWMAN'S CAPSULE ACTS AS A SIMPLE PHYSICAL FILTER AND THAT FOR FREELY FILTERABLE MATERIALS, THE CONCENTRATION OF THE MATERIAL IN THE FILTRATE IS EQUAL TO THAT IN THE PLASMA. D. AUTOREGULATION: 1. Most orgns re cpble of regulting their blood flow, independent of ny externl neurl or hormonl controls. This process is referred to s AUTOREGULATION. 2. In the kidney, there re two mechnisms of utoregultion. They generlly work together: Excretion by the vertebrte kidney: Clernce 5

6 . Myogenic mechnism: When rteril pressure rises (such s in the fferent rteriole), vsculr smooth muscle contrcts s it stretches. This increses resistnce of the rteriole thereby lowering the pressure nd flow through the glomerulus. As the renl blood flow (RBF) is lowered, the glomerulr filtrtion rte (GFR) is lso reduced. Thus high pressure will not result in proportiontely high rtes of urine production. Likewise, s pressure drops, rterioles will relx, R will decrese, P is reduced less nd Q remins high. The rte of urine production remins high even while the blood pressure is somewht reduced. b. TUBULOGLOMMERULAR FEEDBACK: Flow of fluid (or some solute in the fluid) through the glomerulus is sensed by cells tht mke up the JUXTAGLOMMERULAR APPARATUS. Their exct identity(ies) re not known. Nor is the exct mens by which they communicte with the smooth muscle cells of the fferent nd efferent glomerulr rterioles. It could be the renin- ngiotensin system (these cells produce renin), brdykinin, ctecholmines, or prostglndins. Nevertheless the results re well known: 1. If the GFR drops, the efferent rteriole dimeter decreses, this increses resistnce nd cuses n increse in the glomerulr cpillry, thereby incresing the GFR. 2. By contrst, if the GFR gets too high, then efferent rteriole pressure decreses nd filtrtion drops. Here is grph of the overll pttern of utoregultion: Flow Rte blood flow filtrtion rte Perfusion Pressure? Wht things re controlled to chieve reltively constnt GFR? Why is reltively constnt GFR desirble? III. TUBULAR SECRETION AND ABSORPTION MECHANISMS A. A lrge number of substnces re bsorbed from the filtrte or secreted into it by the cells lining the Proximl nd Distl Convoluted Tubules. 1. We will not consider (t this point) which substnces re moved t wht rtes nd where. We insted will be concerned with generl mechnisms. 2. In generl, ll mechnisms of re- bsorption nd secretion will involve some sort of protein meditor nd therefore ll of these processes re potentilly SATURABLE.. Therefore, we cn chrcterize ech trnsport protein in terms of its K m nd V mx. Recll tht: Excretion by the vertebrte kidney: Clernce 6

7 b. K m is lrgely mesure of ffinity between the crrier protein nd its substrte nd is set by its prticulr structure nd the physicl- chemicl environment. c. The V mx is lrgely determined by the totl number of trnsport proteins tht re vilble (nd lso their individul kinetics). Obviously, the more trnsport molecules tht re vilble, the higher the potentil rte of trnsport. 3. The ctul crriers themselves cn be divided into different clsses, lrgely ccording to the type of mterils they trnsport nd the mechnism they use. B. PATTERNS OF SECRETION AND RE- ABSORPTION 1. The most bsic grphicl tretment of secretion nd rebsorption is done by plotting the EXCRETORY RATE (usully in mount of mteril/time) vs. the PLASMA CONCENTRATION (in mount/vol.). There re severl other types of useful grphs; we will discuss ech t pproprite times. 2. GRAPHS OF DIFFERENT PROCESSES:. FILTRATION ONLY: If mteril is only filtered, there will be direct reltionship between the plsm concentrtion of the substnce nd the mount removed (lso referred to s the mount CLEARED): Filtrtion Rte Plsm Concentrtion b. Wht will hppen if substnce is being rebsorbed by the tubules? An exmple would be glucose. 1. The substnce (we'll tlk bout glucose) is filtered in wy tht would give curve identicl to the one shown bove. 2. When it enters the proximl convoluted tubule, there re mny glucose trnsport proteins locted on the inner wll of the tubules tht trnsport glucose out of the tubule. Thus, we hve two processes tht re tking plce in the body: one in glomerulus tht results in glucose getting in the filtrte in proportion to its plsm concentrtion nd the other tht trnsports glucose out of the tubule bck into the blood ccording to the K m nd V mx of the trnsport mechnism: Excretion by the vertebrte kidney: Clernce 7

8 Filtrtion Rte Rebsorption Rte Plsm Concentrtion Filtrte Glucose Concentrtion 3. The summed process is shown below. The removl of glucose results in decresed [glucose] in the filtrte. Excretion Rte predicted line, filtrtion only ctul line Plsm Concentrtion (mg glucose / dl). The removl mechnism is so effective tht t low plsm [glucose] (< ~180 mg/dl), no glucose is ctully excreted even though there is bundnt glucose in the filtrte. b. Eventully concentrtion is reched where the mount of glucose in the tubules is so high tht it overwhelms the trnsport mechnisms. 1. The point where this first strts to hppen is clled the RENAL THRESHOLD nd the concentrtion where V mx is reched is clled the TUBULAR MAXIMUM or T m. 2. Above the T m, the rte of excretion chnges the sme s the rte of filtrtion: however there is difference between the filtrtion nd ctul filtrte concentrtion tht equls the mount clered by filtrtion - the mount rebsorbed. Excretion by the vertebrte kidney: Clernce 8

9 3. In the re between the T m nd the renl threshold, the concentrtion of the mteril in the filtrte chnges t different rte thn fter the T m. This is clled SPLAY. The reson for the sply is obvious from n inspection of the re- bsorption grph shown previously. Glucose Excretion Excretion Rte sply Renl Threshold T m Plsm Concentrtion (mg glucose / dl)? If the K m of the trnsporter is gretly incresed wht would it men in terms of glucose remining in the filtrte t vrious concentrtions? Wht if the totl number of trnsporter proteins incresed? Wht would hppen to V mx nd the glucose tht ws being excreted? Drw grphs to explin your nswer. c. Wht hppens when substnce is ctively being SECRETED from the blood into the filtrte? If the substnce is lso being filtered, the process is identicl to tht of rebsorption shown bove EXCEPT tht now the TRANSPORT CURVE IS ADDED TO THE FILTRATION CURVE: Excretion by the vertebrte kidney: Clernce 9

10 filtrtion + secretion Excretion Rte predicted line, filtrtion only Plsm Concentrtion? If the substnce is not filtered nd is only secreted, wht would the excretion curve (mount clered/min vs. plsm conc.) look like? Wht is the bsis for your nswer? IV. THE CONCEPT OF CLEARANCE: A. Clernce cn be thought of s the removl of substnce from the blood (nd the body). Let's first consider the possible things tht cn hppen to some substnce (glucose for exmple) when it rrives t the kidney. 1. There is one venue of entry - - the plsm of the renl rtery nd therefore the mount tht enters will be the product of the renl rteril plsm flow, RPF nd the renl rteril plsm concentrtion of the substnce (let's cll it substnce x), P x. Thus: 1. Rte Substnce rrives t kidney = Px * RPF 2. There re two possible venues of exit from the kidney, the renl vein nd/or the ureter.. Exit through the renl vein cn be clculted in mnner similr to tht which enters vi the renl rtery, it will be the product of the concentrtion of x nd the renl vein plsm flow: 2. Rte substnce leves vi the renl veins = v Px * RPF v Excretion by the vertebrte kidney: Clernce 10

11 b. Exit vi the urine into the ureter will be clculted in similr mnner, in this cse the product of the rte of urine flow, V 1, nd the concentrtion of the substnce in the urine U x. 3. RATE EXCRETED = U x * V Thus: 4. P * RPF P v v x = x * RPF + ( Ux * V) This represents complete description of the hndling of ny substnce by the kidney. B. Renl physiologists use the notion of clernce to men totlly removing something from the blood. If something is completely clered, then ll of it leves the kidney vi the ureter nd none vi the renl veins; RPF v = 0. Rerrnging eq. 4 nd mking this substitution, we find 5. U * V P x = x * RPF -P v x * RPF = Px * RPF -0 * RPF Ux * V = P x * RPF v v this eqution expresses the equlity between the mount of substnce entering the kidneys in the renl rtery plsm nd tht leving in the urine. If we now define the clernce rte s the volume of renl rtery plsm per time needed to ccount for ll of the substnce found in the urine, then, rerrnging eqution #5 we find: 5. Clernce x = RPF = Ux * V Px where clernce hs the sme units s the renl plsm flow (usully ml*min - 1 in humn physiology).? As you know, in norml individuls, no glucose is lost in the urine. Although quite bit goes through the glomerulr filter, 100% is reclimed by trnsport in the proximl convoluted tubule nd therefore RPF = RPF v nd U x = 0. Wht is the clernce of glucose in ml/min? ANS: in norml individul it is zero none of the glucose is removed from the body by the kidney. We will further explore this concept in the next set of notes. Vo 1 This should relly be symbolized s since it is rte, but for resons unknown to be renl physiologists do not use this notion. So in renl phys., V is volume per time! Excretion by the vertebrte kidney: Clernce 11