Review of Normal Renal PhysiologySyed I. A. Zaidi, Ph.D.Assistant ProfessorDepartment of Physiology & BiophysicsPhone (202) 806-9867sizaidi@howard.edu

Anatomy of the excretory systemHow the kidney is organizedHow the nephron works to filter blood, recycle, secrete, and excreteHow filtration is regulatedUrination reflexReview of Normal Renal Physiology

Homeostatic regulation: ECF volume, osmolarity, ion & pH balanceExcretion: Metabolic wastes & foreign moleculesRegulating hormones & enzymesBlood pressure regulationGluconeogenisisErythropoises (erythropoitin)Vitamin D activation (Calcitriol ---- reabsorption of Ca++)

Kidney Functions: Overview

Regulation of body fluid osmolarity and volmue

Regulation of electrolyte balance

Regulation of acid-base balance

Excretion of metabolic products

Excretion of foreign substances (pesticides, chemicals etc.)

Gluconeogenisis

Blood pressure regulation

Erythropoises (erythropoitin)

Vitamin D activation (Calcitriol reabsorption of Ca++)

CorticalJuxtaglomerular

Regulation of GFRFigure 19-9: The juxtaglomerular apparatus

Vesa recta (1%)

Blood flow in kidneys and other organsFilterablility of plasma constituents vs. water

OrganApprox. blood flow(mg/min/g of tissue)A-V O2 difference(ml/L)Kidney4.0012-15(depends on reabsorption of Na+ )Heart0.8096Brain0.5048Skeletal muscle (rest)0.05-Skeletal muscle (max. exercise)1.00-

ConstituentMol. Wt.Filteration ratioUrea601.00Glucose1801.00Inulin5,5001.00Myoglobin17,0000.75Hemoglobin64,0000.03Serum albumin69,0000.01

Nephron Functions: Filtration, secretion and excretion

Filtration pressure in the renal corpuscle

GFR 125 ml/min (180L/day)(about 1% is excreted)

Regulation of GFRAutoregulationMyogenic stretchTubuloglomerular feedbackMacula densaJ G cellsANS-SympatheticArteriole vasoconstrictionHormones/paracrinesAngiotensin IIProstaglandinsCatecholamineSerotoninVasopressinExtrinsic factors influencing renal flowStress (exercise, cold, heat)Vasomotor activityPyrogensGeneral anesthesia

Autoregulation of GFRTubuloglomeruar feedbacke.g. response to increased arterial pressureMyogenic mechanismeg. Local infusion of cyanide

Qualities of agents to measure GFRInulin: (Polysaccharide from Dahalia plant)Freely filterable at glomerulusDoes not bind to plasma proteinsBiologically inertNon-toxic, neither synthesized nor metabolized in kidneyNeither absorbed nor secretedDoes not alter renal functionCan be accurately quantifiedLow concentrations are enough (10-20 mg/100 ml plasma)Creatinine:End product of muscle creatine metabolismUsed in clinical setting to measure GFR but less accurate than inulin methodSmall amount secrete from the tubuleHigh readings because of non-specific chromagens in plasmaPara-aminohippurate (PAH): An organic anion not present in bodyFreely filtered, secreted but not reabsorbed by nephronNon-toxic, neither synthesized nor metabolized in kidneyLow concentrations are enough (10 mg/100 ml plasma)

Solute Clearance: Rate of removal from the BloodFigure 19-16: Inulin clearance

Concept of clearanceAPAH = arterial plasma PAH

Cx < 1 means reabsorptionCx > 1 means secretionNet reabsorption rate:Tx = (GFR . Px) (Ux . V) Filtration - ExcretionNet secretion rate rate:Tx = (Ux . V) (GFR . Px) Excretion - FiltrationGFR = Cx = Clearance of inuline (mg/min)Ux = Urine concentration of X (mg/ml)Px = Plasma concentration of X (mg/ml)V = Urine flow rate of X (ml/min)

Reabsorption: Passive Transport & TrancytosisPassive reabsorption of urea in the proximal tubule

Reabsorption: 10 Active Transport(Passive diffusion in)Active Transport Na+ to ECF K+ into cell ATP-aseUses energyNa+ ECF peritubular capillariesReabsorption blood

Reabsorption: Secondary Active TransportFigure 19-12: Sodium-linked glucose reabsorption in the proximal tubuleNa+ linked 20 transportSymportGlucoseIonsAmino acidsProximal tubule, key site

Reabsorption: Passive Transport & TrancytosisPassive Transport of ureaNa+ pumped outH2O followsPassive [urea][urea] higher than ECFpassive diffusion to ECFTrancytosis of proteins

Reabsorption: Receptors can LimitTransport maximumSaturation (# of receptors)CompetitionSpecificityRenal ThresholdExample: glucosuria

Reabsorption: Receptors can LimitFigure 19-15: Glucose handling by the nephron

Active Transport into nephron tubulesExample: K+ & H+ (more on this next unit)Secretion: From Peritubular Blood vessels & ECF

Secretion: From Peritubular Blood vessels & ECFFigure 19-2 : Filtration, reabsorption, secretion, and excretion

Excretion: All Filtration Products that are not reabsorbedFigure 19-5: The filtration fraction

Urination: Micturation reflexFigure 19-18: The micturition reflexDetrusorHypogastic nerves (L1, L2, L3)SympatheticRugae foldsa-Adrenergicreceptors SacralParasympathetic(S1, S2, S3)Pelvic nerveVisceral afferent pathwaySacralPudential nervesSkeletal muscleFundus

Formation of Water Pores: Mechanism of Vasopressin Action

Kidney Hydrogen Ion Balancing: Proximal Tubule

****-kidney can only conduct fluid it cannot restore lost volume. If volume drops too low the GFR will stop-kidney is a retroperitoneal organ, it is behind the peritoneal membrane. ***Blood flow in the kidney-above 100mmhg is the starting blood flow, at the end it is only 8mmhg. The distribution of the blood flow is divided into two beds, one being high pressure the other being low pressure-there is a shunt in which about 1% of blood will go (vasa recta shunt), this will go around the henle loop. There is minimal pressure in this area. The vasa recta are responsible for the countercurrent mechanism. -you need a slow moving fluid and low pressure so that ion transport can occur *-Kidney receives most of the blood but it is only for filtration purposes. -Consumption of O2 in the kidney depends on reabsorption of sodium. Maximum oxygen is being used to provide ATP for the Na/K+ pump. -The filtration ratio shows that there is no restriction if the ratio is one, and if it is smaller this, indicates higher resistance-In the Bowmans capsule, negatively charged glycoproteins and a small pore size regulate materials that pass through. The normal pore size is about 42A. When the membrane loose its charge you will see a lot of albumin and other proteins in the urine. This is common in certain disease states*There are four processes that occur in the nephron-excretion- about 1% of the ultra filtrate is excreted-secretion- means from the peritublar capillaries and vasa recta some products are secreted back into the distal tubule.-most reabsorption takes place in the proximal tubule (water and sodium). Some drugs can pass through the capillary system to be secreted back into the proximal tubule.-the remaining water and sodium reabsorption will take place in the loop of henle

*Pressure at the afferent end is 55mmhg, inside it is only 10mmhg. There is a negative pressure colloid that will absorb water back, EXAM SLIDE*80% of the blood goes back, only 20% of the volume is filtered. Of this 20%, only 19% will be reabsorbed. -total volume that is filtered is only about 180L/day, and 1% of this will excreted. *Auto regulation is controlled by two mechanisms-Myogenic stretch- a local mechanism-Tubuloglomerular feedback- macula densa cells and JG cells play a critical role*Plateau in the graph means that in a wide range of BP the kidney will try to regulate the GFR (from 80mmhg to about 180mmhg). When you infuse cyanide locally the Myogenic control is lost, there is no Autoregulation and you wont see the plateau. This is proof of this mechanism. -When you decrease the GFR and RBF by constriction of the afferent end, there will be less supply to the bowman's capsule. -You can increase the GFR by constricting the efferent end. -by dilating the efferent end you will decrease the GFR. This will reduce the pressure in the bowman capsule and because of the low pressure there is decreased GFR-by dilating afferent there will be increase in pressure, more blood will come in to the renal system, this will cause an increase in GFR. -you can increase renal blood flow by dilation, or decrease the renal blood flow by constriction. -remember that GRF is pressure and flow dependent-THE MYOGENIC MECHANISM WILL BE AN EXAM QUESTIONTubuloglomerular when the BP is increased, there will be a response, so this means that there is a feed back mechanism going on. BP increase in detected by the macula densa, and vasoactive substance will be secreted to increase afferent arteriole vasoconstriction. *There are different types of hormones that can vasodilate or vasoconstrict. Endothilin and ATII cause vasoconstrictionAch, ATP, Histamine, Bardykinin, shear stress all contribute to N.O. being given off and this will lead to vasodilatation. *GFR is a direct correlation to kidney function. If kidneys are jacked up the GFR will decrease. If there is toxicity from any source this will also effect the GFR. When new drugs are being made, measurement of clearance rate and absorption can be measured by these agents. INULIUN and INULIN LIKE DRUGS-if there is a charge in a drug (like dextran which is positively charge) this will effect the extent of its reabsorption. If they are negatively charged they will be filtered less, and if they are positively charged they will be filtered more. -If drug binds to plasma protein this will reduce secretion-drug should be inert and should not be of a hormonal nature-if they are made or metabolized in the kidney this will change the quantity of the drug in the kidney-drug should not be a vasoconstrictor, or vasodilator-inulin is not made in our bodies, but it is infused. Low concentrations are sufficient enough to measure and quantify GFR. In clinical setting most of the time creatinine is used.-inulin will give the total GFR value CREATININE-90% of creatinine will be filtered into the kidney and excreted, the remaining 10% will go into the peritubular capillary system and will later be secreted into the collecting ducts. -there are non specific chromagens in the plasma that can give off readings similar to that of creatinine (As far as color change when you are looking at optic properties) PAH- will give the total plasma value-there is a limitation on the kidney. IF there is an overload on the system it cannot filter all of the substance. CONCENRATIONS WILL BE ON EXAM*Under 10 mg condition. When 10mg/ml of inulin is passed thru the bowmans capsule, it will be filtered. What ever amount is filtered none will be reabsorbed, and none will be secreted. You can measure the GFR with this because whatever is filtered in will be excreted out. *THERE WILL BE A QUESTION ON THIS SLIDE AS WELLGlucose most of the substance that is secreted will be reabsorbed, none will be excreted. PAH, or Penicillin a certain amount goes in the capsule and is filtered, the amount left over will go into the capillaries. It is not desirable to be in the body so the body will secrete it so that eventually all of it will be excreted out into the urine-when injection is given of penicillin, all of the penicillin will be secreted. It is not given IV on a constant basis, you only get one injection or one tablet each day. Once the blood goes into the kidney it will all be secreted. -penicillin is designed so that it will be bound to proteins in the blood, to be able to have a bigger effect. Urea 4 molecules are secreted and 2 are reabsorbed. Urea is a toxic substance to the body. Urea is used in the system to maintain osmolarity. The osmolarity is higher as you go deeper into the kidney. Urea will help to maintain this concentration gradient. *EXAM SLIDE-GFR can be calculated using inulin or creatinine. -ERPF can be calculated using PAH-Penicillin, urea, and Glucose cannot give a good measurement of GFR

*EXAM SLIDE

*-this will be covered in later lectures. -once plasma is filtered most of the NaCl will be reabsorbed (Some in the soluble form and some in the ionic form)-Na in the interstitium space will increase the osmolarity-water will follow the flow of the ions.-these three molecules are passively reabsorbed (urea, water, and sodium)***Most of the NaCl is reabsorbed in the proximal tubule EXAM QUESTION. In the early distal tubule almost water is reabsorbed, in the late distal tubule and CT there is 8-17% reabsorption. If there is any disturbance in the hormones, urine will get concentrated or too diluted this will lead crystal formation (if the concentration is outside of this 8-17% regulation range). -below pH 6.8 death will occur. With kidney failure there will be a change in pH, the kidney is an important regulator of pH-In acidosis- hyperventilation will occur to adjust pH, and the kidney will excrete more acidic urine. ***Renal threshold of the plasma- past this point the kidney cannot reabsorb any longer and substance will be secreted (ie: too much glucose). ****There is a higher CNS input to excrete urine. Urine is secreted and held in the bladder. From the lumbar region the hypo gastric sympathetic nerves will supply the motor neurons. Normally in a filling phase the ruggae folds will be relaxed, and the sphincters are closed due to firing of the neurons to contract the internal sphincter. This is a passive processes-when urine is collected, it will stretch the stretch receptors, sensory neurons will bring the message to the CNS, the sacral parasympathetic fibers send the message to contract the bladder. The sacral pudential fibers will cause the external sphincter to relax and allow for urine to come out. Tonic discharge will be inhibited by the sensory neurons-the body is naturally designed for urine to be collected and excreted out without any control. Kids are trained to use their higher CNS input to control urine excretion. -Bed wetting at night is related to this pathway. It is related to sphincter control. There is medicine that can be spread at night in the nose. Vasopressin is in this combination and it will eliminate excess secretion to keep them from urinating in their sleep. *