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Renal Physiology,1 proximal tubule PT histologically 3 segments. i pars convoluta,ii pars recta,2 loop of Henle 3 parts. i descending thin limb,ii ascending thin limb,iii ascending thick limb. 3 macula densa passing between arterioles of own glomerulus. 4 distal tubule DT also termed the late distal tubule. i distal convoluted tubule,ii connecting segment,iii initial collecting tubule. Collecting System,1 cortical collecting tubule,2 medullary collecting tubule.
3 papillary collecting ducts, these drain into a calyx of the renal pelvis then to the ureter bladder. Blood Supply,1 renal artery,2 interlobar arteries,3 arcuate arteries. 4 interlobular arteries, 5 afferent arterioles parallel series from each interlobular artery. 6 glomerular capillaries,7 efferent arterioles,8 peritubular capillaries nonspecific. NB interlobular arcuate interlobar and renal veins parallel arteries. Renal Physiology,Regional Differences, nephrons are not homogeneous and vary according to the location of the glomerulus in the.
a superficial cortical nephrons all short looped,b midcortical nephrons mixture. c juxtamedullary nephrons all long looped, the efferent arterioles of the juxtamedullary glomeruli are long and form vascular bundles. extending and branching into the medulla, the descending vasa recta extend to the inner medulla networking and forming a countercurrent. exchanger with the ascending vasa recta, the interstitial cells increase in size and number from cortex to papilla. Juxtaglomerular Apparatus,Def n an aggregation of three cell types.
1 granular cells, differentiated smooth muscle cells of afferent arterioles. secretory vesicles contain renin, 2 extraglomerular mesangial cells continuous with the mesangium. 3 macula densa cells,terminal part of thick ascending limb LOH. probably control both renin secretion and GFR,NB JGA has a rich sympathetic nerve supply. Intrarenal Hormone Synthesis,a angiotensin II intrarenally generated.
b prostaglandins esp PGE2 and prostacyclin,c kinins lysyl bradykinin bradykinin. d erythropoeitin,e Vit D hormone not a vitamin,not synthesized but biotransformed. Renal Physiology,GLOMERULAR FILTRATION,average values for mythical 70 kg male. a GFR 180 l d 125 ml min, this represents 20 of plasma entering the glomerular capillaries. b total plasma volume 3 0 l filtered 60 times day, c urine production 1 2 l d 99 of filtrate is reabsorbed.
Composition of Filtrate, the filtration barrier is freely permeable to water and crystalloids MW 30 000. however is virtually impermeable to colloids,small quantities mainly of albumin escape 50 mg l. as proteins are not filtered the filtrate electrolyte concentrations vary slightly from plasma water. due to the Donnan effect, further any crystalloid protein bound is only partially filterable. small proteins are filterable eg myoglobin Hb light chains etc. there is no hindrance to molecules of MW 7 000 4 8 m. Filtration Barrier,1 endothelial fenestrae,2 basement membrane. 3 slit diaphragms and,the entire path is extracellular.
the greatest restriction is at the basement membrane through the hydrated spaces between. glycoprotein chains, some high MW molecules traverse the basement membrane and lodge in the slit diaphragms. these are possibly taken up by endocytosis and broken down. in addition to steric hindrance electric charge is important. the cell coats of the endothelium basement membrane and cell coats of the podocytes are all. polyanions at any MW anions are selectively restricted. this is not critical for plasma crystalloids, the leaky glomeruli of certain disease states results from loss of the polyanion coat. Renal Physiology,Net Filtration Pressure, Def n algebraic sum of opposing hydraulic and osmotic forces Starling. NFP P GC BC P BC GC, NB as there is virtually no protein BC 0 therefore. NFP PGC PBC GC, both hydraulic and oncotic pressures change along the length of the glomerular capillary.
Arteriolar Afferent Efferent,PGC mmHg 60 58,PBC mmHg 15 15. GC mmHg 21 33,NFP mmHg 24 10, the above figures are for dogs but are probably similar for man. in all mammals other than the dog PGC 60 mmHg and the NFP may reach filtration pressure. equilibrium, this likely to occur if the GC hydrostatic pressure is low eg hypovolaemia. increases in GC are greater than predicted from the filtration fraction due to the non linear. osmotic activity of albumin, GFR is also dependent on hydraulic H2O permeability and surface area. GFR hydraulic permeability x SA x NFP, the first two combined to give the filtration coefficient KF.
GFR KF x NFP, as the NFP 10 24 mmHg and GFR 180 l d so KF is very high. KF GFR NFP 125 ml min 17mmHg,7 4 ml min mmHg, this is due in part to the large SA but mainly to the high permeability which is 10 100 times. greater than non renal capillaries,Renal Physiology. Direct Determinants of GFR,GFR KF x PGC PBC GC, KF 1 contraction relaxation of mesangial cells alters SA KF. proportional changes in GFR,PGC increase renal a pressure.
decrease afferent aa resistance increase GFR,increase efferent aa resistance. PBC increase intratubular pressure decrease GFR,GC increase plasma oncotic pressure. sets initial,decrease total renal plasma flow decrease GFR. determines rate of rise of, effects of changes in KF may be greatly reduced where NFP reaches filtration pressure. equilibrium as GFR results from only a part of available SA anyway. Renal Physiology,Tubular Reabsorption, qualitatively a different process from GF the later being bulk flow.
relatively little bulk flow occurs across the tubular epithelium due to. 1 small filtration pressures and,2 low hydraulic permeability. Transport Mechanisms,1 simple diffusion SD, the result of an appropriate electrochemical gradient EC. as this occurs through cell membranes,lipid solubility is a major determinant. 2 simple facilitated diffusion SFD, this also down an EC gradient but is dependent upon interactions with specific. membrane proteins either channels or carriers,most important for non lipid soluble molecules.
displays the characteristics of specificity saturability and competition. 3 secondary active transport SAT, two or more molecules interact with specific membrane proteins and are. translocated across the cell membrane, the substance undergoing SAT is transported against its EC gradient. the energy for this is derived from the simultaneous movement downhill of the. other molecule usually Na in the PT, may represent either co transport or countertransport depending on the direction. of movement of the respective moieties,4 primary active transport PAT. transport via interaction with specific membrane proteins but requiring energy from. membrane bound ATP ase which forms part of carrier protein. this also displays the characteristics of specificity saturability and competition. 5 endocytosis,important for uptake of macromolecules.
requires ATP for the splitting off of the membrane therefore technically is a form. Renal Physiology,Mechanisms in Reabsorption, except for a few substances which follow simple diffusion through the tight junctions between. cells all other reabsorbed substances must cross two plasma membranes. a the luminal or apical membrane and,b the basolateral membrane. the basement membrane must also be traversed but this is functionally inert. bulk flow or simple diffusion into the peritubular capillaries is the final common step for all. reabsorbed substances, intracellular Na i is maintained low by the basal Na K ATPase Na being reabsorbed from the. lumen by simple facilitated diffusion, the continued net movement of Na depends entirely on basolateral transport. a large number of solutes are transported with Na via the following mechanisms. a Na entry per se by SFD,b cotransport with glucose or organic acids SAT.
c countertransport with intracellular H SAT,d cotransport with Cl SAT. e Na following Cl diffusing through tight junctions. NB for glucose amino acids phosphate etc transport is a secondary active process. the energy being derived from the basal Na K ATPase. Transport Maximum, where reabsorption requires specific membrane proteins these display saturability. the maximal tubular transport capacity TMax,for glucose T Max. a male 375 mg min,b female 300 mg min, the former being equivalent to a Gluc pl 180 200 mg 100 ml 10 0 11 1 mmol l. glucose or any similar solute is excreted before the T Max is reached splay. this is due to,a system kinetics are the same as enzyme systems.
ie maximal activity is substrate dependent TMax is not seen until the Gluc T Max. b the nephron population is non homogeneous,Renal Physiology. Tubular Secretion, as for reabsorption the initial step is simple diffusion bulk flow from the peritubular capillaries to. the interstitial fluid, from there solute gains entry to the tubule either by SD through tight junctions or by active. transport through the cells, in contrast to glomerular filtration SD from capillaries is an equilibrium process. therefore protein bound substances inc drugs may undergo secretion. removal from proteins being by mass action, there are several low specificity systems for organic anions and cations.
these are analogous to the reabsorptive systems being. a active ie TMax limited,b competitive,Bidirectional Transport. rarely if ever does purely unidirectional movement occur the net transport of solute being the. sum of opposing fluxes, the epithelium is not completely impermeable to crystalloids therefore bidirectional diffusion. always occurs, active reabsorptive processes create a concentration gradient for passive secretion. active secretory processes create concentration gradient for passive reabsorption. NB since back diffusion is solely the result of the gradient created by the active. pumping the net flux is always in the active direction. the leak component of epithelial pump leak systems is the major determinant of maximal. EC achievable, for most mineral ions organic molecules the major path of leak is paracellular not. transcellular depending on the characteristics of the junctional complexes. 1 PT leaky,high water permeability,actively transports large quantities of solute.
low maximal EC,2 DT CT tight,low water permeability. slow rates of transport of solute,high maximal EC,Tubular Metabolism. traditionally glomerular filtration tubular reabsorption and tubular secretion are considered as the. basic renal processes however metabolism is also important for many substances. eg synthesis of HCO3 and ammonia from glutamine,Renal Physiology. RENAL CLEARANCE, Def n the clearance of a substance is the volume of plasma from which the substance. was completely cleared by the kidneys per unit time units vol plasma time. NB clearance of x CX GFR when the substance x meets the following criteria. i freely filterable at the glomerulus,ii not reabsorbed by tubules.
iii not secreted by tubules,iv not synthesised by tubules. v not broken down by tubules, these are met by the polysaccharide inulin so CIN GFR. however inulin does not occur naturally in the body and requires several hours of infusion to. reach steady state concentration,therefore creatinine is used to estimate GFR. creatinine is formed from muscle creatine and is released at approximately a constant rate. therefore blood Cr changes little per 24 hrs, however Cr is secreted by the tubules and overestimates GFR by small amount. for freely filterable substances when,a CX CIN net tubular reabsorption.
b CX CIN net tubular secretion, if x is significantly protein bound in order to compare CX with CIN the freely filterable fraction. of x must be used not the total x pl, para aminohippurate PAH undergoes tubular secretion and is freely filterable. at low PAH pl virtually all PAH escaping filtration is secreted by the tubules therefore all. plasma supplying nephrons is cleared of PAH, about 10 15 of total renal plasma flow TRPF supplies non secreting portions of the kidney. thus CPAH actually measures effective renal plasma flow ERPF and this is 85 90 of TRPF. NB this only applies at a low PAH pl at higher levels the TMax is exceeded. the radiographic contrast Diodrast is handled similarly to PAH. urea is freely filterable but 50 is reabsorbed R 40 60. therefore is less accurate than creatinine as an estimate of GFR. Renal Physiology,Fractional Excretion, Def n fractional excretion FE X is the mass of x excreted as a fraction of the total. mass filtered where,FE X GFRX P X,1 FEX 1 0 net tubular reabsorption.
2 FEX 1 0 net tubular secretion, also when CIN is used to calculate GFR FE X becomes CX CIN. FE X U IN V P IN, although creatinine clearance is a good estimate of GFR the plasma creatinine is often used as. a clinical indicator of GFR, as most excreted Cr gains entry to tubule by filtration and a negligible amount is secreted there is. an inverse relationship between Cr pl and GFR,this is not completely accurate because. a some Cr is secreted by the tubules,b Cr pl at normal GFR varies between individuals.
c Cr production may not remain constant, urea also serves as indicator but is less accurate due to variable reabsorption. Renal Physiology,Handling of Organic Substances,Reabsorption of Organic Nutrients. these include,ii amino acids,iii Krebs cycle intermediates. iv water soluble vitamins,v lactate acetate hydroxybutyrate etc. main site is the proximal tubule,they share the following characteristics.
a reabsorption is an active process against a EC, b the uphill step is across the luminal membrane usually via cotransport with Na. c they cross the basolateral membrane by simple facilitated diffusion. d the manifest TMax s which are well above the amounts normally filtered. e manifest specificity, ie there are a large number of different carriers though closely related solutes may. share carriers eg AA s allowing for competition, f transport is inhibited by various drugs and disease processes. Proteins and Peptides, the main site is the proximal tubule but the mechanisms are significantly different. the amounts filtered are very small 0 02 of Alb pl 10 mg l in urine. a normal GFR loss of 1 8 g day in the absence of reabsorption normal loss 100 mg d. the reabsorptive process is easily saturated when the filtered load is increased in disease states. the initial step is attachment to specific binding proteins on the luminal membrane followed by. endocytosis, endocytosed vesicles merge with lysosomes and proteins are broken down to low MW fragments.
the later are released from the basolateral membrane to the interstitium. many other plasma proteins though their plasma concentrations are lower are filtered to a far. greater degree due to a lower MW eg GH MW 20 000 is 60 filterable. relatively large fractions of these smaller proteins are filtered and degraded in tubular cells. the kidneys are a major site of protein catabolism. even smaller linear polypeptides such as angiotensin are completely filterable and are catabolised. into AA s within the tubular lumen by peptidases on the luminal membrane. fragments and AA s are then reabsorbed,Renal Physiology. highly permeable and crosses most biological membranes with ease. freely filterable so urea BC urea pl, as water and solute are reabsorbed in the PT so the luminal urea increases. this creates a concentration gradient and urea diffuses from the lumen to the interstitium and. peritubular capillaries, NB this is a passive process totally driven by the reabsorption of water. urea is actively secreted into the straight PT and loop so that the urea at the start of the DT is. increased to 2x the initial urea BC, the source of this secreted urea is reabsorption from the collecting ducts not the peritubular. capillaries, urea continues to be reabsorbed in the DT and cortical collecting tubule but only small amounts.
due to the low permeability further increased urea. most of the urea entering DT reaches the medullary CTs which because of their high. permeability to urea and extensive water reabsorption reabsorb large amounts of urea which then. enters interstitium, this is the source of the urea entering the loops above. the net overall handling of urea reabsorption 60,a 50 due to PT reabsorption. b 10 by the remainder of the nephron during cyclic travel. this figure decreases to 40 when urine flow is high ie water reabsorption is low. the reabsorption range is constant irrespective of urea pl ie there is no effective TMax. Proximal Secretion of Organic Anions, the PT secretes large numbers both exogenous and endogenous anions. many are freely filterable others are extensively protein bound. for the later PT secretion constitutes the only significant path for excretion. active PT secretory path s exhibit low specificity therefore are able to eliminate a wide range of. the PT handles glucuronate and sulphate conjugates from liver metabolism. the mechanism for secretion of PAH active transport into the PT cell then facilitated diffusion. at the luminal membrane, NB not known if basal entry is primary active transport or secondary process. as many ions share the same carriers there is competition for transport. transport is also saturable with respective T Max s for anions. most anions cf PAH undergo no net reabsorption anywhere along the nephron. Renal Physiology, a few select anions undergo active tubular absorption distal to the PT eg urate.
plasma urate is mainly ionised therefore not protein bound and is freely filterable. it undergoes both active tubular secretion and reabsorption both in the PT. usually tubular secretion reabsorption so the net effect reabsorption. the secretory rate is regulated to maintain a normal plasma urate. most subjects with a high urate pl excrete less for any given plasma urate. elevation is rarely caused by decreased GFR or excessive reabsorption. Proximal Secretion of Organic Cations,the system is analogous to that for anions. a relatively non specific,b exhibit TMax s,c exhibit competitive inhibition. these systems are essential for the excretion of cations extensively bound to plasma proteins and. not filterable at the glomerulus,Passive Diffusion of Weak Organic Acids Bases. many organic ions are ionised forms of weak acids and bases. the non ionised fraction undergoes passive diffusion along a EC the major determinants for. which are the luminal pH and the pK A of the acid base. 1 acidification of the lumen by mass action, reabsorption of weak acids secretion of weak bases. 2 alkalinisation of the lumen by mass action, reabsorption of weak bases secretion of weak acids.
NB as the major H occurs in distal tubule segments. these are the main site for pH dependent passive diffusion. In Summary, the excretion of a weak acid or base reflects the amount. a filtered at the glomerulus GFR,filterable fraction. b secreted actively in the PT s plasma,c which diffuses passively urine flow. luminal pH,pKa for acid base,Renal Physiology,RENAL HAEMODYNAMICS. 1 total renal blood flow TRBF 1100 ml min,20 25 of CO 5000 ml min.
90 to cortex,2 total renal plasma flow TRPF 605ml min Hct 0 45. 3 the filtration fraction 20 GFR 125 605 ml min, the low medullary flow is due to high resistance of the vasa recta. low flow is required to maintain the medullary concentration gradient. kidney mass 1 of total body weight total flow is well in excess of metabolic needs. Autoregulation and Mean Arterial BP, renal blood flow is virtually constant over the BP range 80 180 mmHg due to autoregulation. this is the case for both RBF and GFR, the afferent arterioles are the major site of regulation of renal vascular resistance. effectively blunting significant changes in glomerular capillary pressure. these effects are seen in both isolated and transplanted kidneys therefore the mechanisms are. totally intrarenal factors including,1 myogenic mechanism.
2 tubulo glomerular feedback,3 sympathetic control. 4 angiotensin II,5 intrarenal baroreceptors,6 macula densa. 7 renal SNS,8 intrarenal prostaglandins,Myogenic Mechanism. smooth muscle contraction in response to stretch tension. one possible mechanism is distortion of the plasma membrane and opening of Ca channels with.

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