PGY 300: RENAL PHYSIOLOGY

Glomerulus (Renal Corpuscle)

- Contained within Bowman's capsule, it is what actually filters blood before filtrate passes through the rest of the nephron system - Intermediate point between Afferent and Efferent arterioles - Composed of fenestrate capillaries - Reinforced with podocytes

Volume Depletion Hypovolemia

- Contraction of volume, 1400 mEq Na, 10 L water retained to maintain 140 mEq/L

Plasma Creatinine, Blood Urea Nitrogen (BUN)

- Creatinine is derived from muscle creatine, Urea is derived from nitrogen metabolism - both are measured in blood analysis but plasma creatinine is the better estimate of GFR - BUN is a product of liver function, should be excreted - if either rises it's signaling that the kidney isn't working

Mechanism to alter RBF, GFR

- Dependent on sympathetic nerve activity If Volume is Expanded: If Volume is Depleted: (increase sympathetic) BP changes, RBF/GFR drops so we want Na excretion to drop, Renin secretion to rise

Effective Circulating Blood Volume (ECBV)

- Determined by Cardiac Output, Actual Blood Volume, Peripheral Resistance - Determines blood pressure, which determines optimum tissue perfusion - not a quantitity that can be measured

Counter Current Multiplier

- function of Henle's loop, it is an important generator of the steep osmotic gradient that exists in the inner medullary region of the kidney - the thick ascending limb is responsible for setting up this gradient - the thick ascending limb leads to solute accumulation in the interstitial space

Transepithelial Solute and Water Transport Pathways

- mechanisms to leave and enter nephron 1. Paracellular Pathway - passage through tight junctions 2. Transcellular Pathway - primary active transport through epithelium

Arginine Vasopressin (AVP) and Antidiuretic Hormone (ADH)

- released into circulation in response to an increase of plasma osm of less than 2% - a decrease in blood volume/ pressure greater than 15% - released by the posterior pituitary, causes vasoconstriction of smooth muscles and anti-diuresis at the late distal tubule

Diuresis State

- serves to excrete water - urine will be highly diluted

What percent of Cardiac Output is directed to the kidneys?

25%

Primary determinant of Osmolality

Plasma [Na] - thus this quality barely changes

Vasa Recta

-parallel extension of peritubular capillaries - found in medulla

Bodily Defense to Acid Load

ECF Buffering, ICF Buffering, Respiratory Compensation, Renal Excretion

Determinants of ECBV (Equation)

ECF volume = Quantity Na in ECF/ Plasma [Na] ECF Volume determines ECBV ** so there is an inverse relationship between ECF volume and plamsa [Na], but plasma [Na] barely changes so Na ECF quantitiy is what is determining ECF volume

Plasma Sodium concentration and ECF [Na] are...

Equal

Urinary Excretion Formula

(amount of x filtered) - (amount of x reabsorbed) + (amount of Excreated) Amount of x excreated = Ux*Vu -Some soluted are only filtered, some solutes are filtered and reabsorbed, some solutes are filtered and secreted, some solutes are filtered reabsorbed and secreted

Regulation Mechanisms of RBF

***intrinsic to each nephron (no neural control) 1. Myogenic (Bayless) - mainly acts on afferent arterioles but all respond, activated by changes in arterial blood pressure and causes stretching of vascular smooth muscle 2. Tubuloglomerular Feedback (TGF) - activated by an increase in tubular fluid NaCl flowing past macula densa (which is epithelium bridging arterioles and ascending limb of loop of henle)- adenosine increases resistance of afferent arterioles to decrease filtration, if FR is elevated, TGF increases GFR to fix filtration/reabsorption balance

Normovolemia (Euvolemia

- 1700 milliequivs Na in 12 L of water in ECF (140 mEq/L) - Assume ICF Volume (ICV) is not changing due to osmoregulation

What percent of blood volume is filtered out?

- 20% by volume is removed from blood as filtrate, the 80% remaining is too big to be filtered (blood cells, plasma proteins) -After filtration through nephron, 99% of plasma that enters the kidney is ultimately returned to systemic circulation

Volume Expansion Hypervolemia

- 2000 mEq Na, 14.3 L water now retained to maintain 140 mEq/L

Autoregulation of Renal Blood Flow

- A mechanism to isolate GFR from transient changes in systemic bp so that filter load does not change and overwhelm nephron to cause fluid loss - The idea is to keep kidney function constant so internal pressure doesn't change too much

Angiotensin II

- Arteriolar Vasoconstriction - Stimulates Secretion of Aldosterone - Stimulates thirst - Stiumlates secretion of ADH - Stimulates sympathetic nerve activity - Stimulates Na+ reabsorption

How does GFR remain constant?

- Blood pressure in GC is major determinant of GFR but GRF is constant over a range of blood pressures due to the autoregulation of Renal Blood Flow (RBF)

What determines Glomerular Filtration Rate?

- Determined by Pnet and Kf - Pnet = Hydrostatic Pressure of GC + Osmotic Pressure BS - Hydrostatic Pressure of BS - Osmotic Pressure of GC - Filtration occurs when Hydrostatic Pressure from the capillaries is higher than the oncotic pressure from Bowman's space - Both the oncotic pressure in the glomerular capillaries and the hydrostatic pressure in Bowmans space oppose filtration

Plasma Glucose and Glucose Filtration

- Filtration of glucose is directly proportional to the plasma concentration - Reabsorption rate of glucose is proportional to the plasma concentration until the transport maximum is reached - Glucose excretion is zero until the renal threshold is reached, if glucose is in the urine it will pull water with it and cause dehydration

Kf (Filtration Coefficient)

- Filtration rate constant which is determined by the leakiness of the membrane itself - A low Kf indicates a strong barrier and little filtrate passing through

Inulin Clearance

- Gold standard for measuring GFR - Polyfructose with a MW of 5000, just small enough to be filtered freely but it is not reabsorbed, not secreted and not metabolized (100% excreted) - Not endogenous - put into the body and only able to pass through the fenestrated capillaries of kidneys

Atrial Natriuretic Peptide (ANP)

- Hormone responding to increased volume, opposite of aldosterone - decreases tubular Na+ reabsorption -inhibits renin release -vasodilate afferent arteriole resistance - decrease sympathetic nerve activity

NET Reabsorption and Secretion Based on Inulin Clearance

- If Clearance of x is less than Clearance of inulin, net reabsorption - If Clearance of x is greater than Clearance of inulin, there is net secretion

What is Tm and what are the implications?

- In terms of Renal Transport, Tm is the transport maximum which is the transport rate at saturation - Essentially this means there is a point at which you can keep increasing substrate but at a certain point saturation of transporters occurs and transport rate will not increase regardless of how much substrate you add

Starling Forces in the Glomerulus

- In the glomerular capillaries, hydrostatic pressure is constant, Oncotic pressure rises across glomerulus causing net filtration to occur (Hydrostatic pressure is still higher) - At the end of the glomerular capillaries (at the start of the efferent arterioles), an equilibrium point is reached before hydrostatic pressure sharply drops and Oncotic pressure remains high causing net reabsorption - If filtration stops (for any reason) the nephron dies and kidney failure occurs

Methods for Assessment of Renal Function

- Measurement of Renal Blood Flow and Glomerular Filtration Rate - Research and Clinical Techniques -Clearance Measurements - Plasma creatinine (tells us about GFR) - Blood Urea Nitrogen (tells us about GFR)

Osmotic Equilibrium

- Osmotic pressures in the ECF = ICF - If OP in ECF < ICF, H20 will move in (swelling) - If OP in ECF > ICF, H20 will move out

PAH Clearance as a Measurement of RPF

- Para amino Hippurate (PAH) is non endogenous but is filtered and secreted - Renal extraction of PAH is ~ 90% (good enough that we can use it to estimate if blood is adequately reaching the kidneys) - we can say Cpah (clearance) ~ RPF

Macula Densa

- Part of the juxtaglomerular apparatus, modified epithelium - Senses composition of tubular fluid, Na-K-Cl symporter in luminal membrane senses high NaCl triggering adenosine which contracts the afferent arteriole -When the system sense low NaCl the Juxtaglomerular cells trigger Renin which triggers RAAS which triggers a decrease in sodium excretion ***negative feedback control mechanism

Hydrostatic Pressure

- Pressure caused by a volume pushing on it's container - The pressure that forces fluid out of the capillary

Anti-Diuresis State

- Serves to conserve water - Urine will be highly concentrated

Peritubular capillaries

- Site of reabsorption -Reabsorption is a two step process 1. Filtrate is transported from the proximal tubule to the interstitial space 2. Filtrate is transported from the Interstitial space to the peritubular capillaries via Starling's forces

Oncotic Pressure

- The fraction of osmotic pressure resulting just from the plasma proteins - This pressure should be 0 in the interstitial space because proteins should not leave the plasma

Colloid Osmotic Pressure

- The pressure of proteins within the capillary which pulls fluid into the capillary

Sodium Balance in the Human Body

- To keep steady state, input must equal output - at all time there is non-exchangable sodium in the bone, exchangeable in the bone, connective tissue and cartiliage etc. - Main factors are sodium input and renal excretion of sodium

How is blood volume and ECF volume measured?

- body cannot directly measure, instead volumes are indirectly determined by responding to changes in blood pressure

Assessment of GFR by Inulin Clearance

-Mass balance of inulin is established by a single nephron because it is 100% excreted GFR = (Urine Flow * [x] in the urine)/ ([x] in the artery)

Tight Junctions

-Separate the apical (inner) and basal (outer) cell membranes -Mechanism for paracellular pathway transport - Not actually tight - very leaky in proximal tubal (which is where the paracellular pathway matters)

Systemic vs. Glomerular Capillaries

-Systemic capillaries have 1 site of variable resistance in the arterioles and an average pressure of 25 mmHg - Glomerular capillaries have two sites of variable resistance in the afferent and efferent arterioles (which allow the pressure gradient to form) and an average pressure of 50 mmHg

Osmoregulation

-The renal regulation of plasma osmotic pressure -VERY tightly regulated (probably more than anything in the body)

Osmoreceptors

-detectors in hypothalamus, respond to very small changes in blood osmolarity (<1%) - Trigger release of ADH, trigger increased reabsorption of H20 to prevent further OsM increase -Signal strength varies based on need - WAYYYYY more responsive than baroreceptors

Autoregulation: Tubuloglomerular Feedback Loop

1. BP rises 2. GFR inceases 3. Flow through tubule, nephron increases 4. Flow past macula densa increases 5. Paracrine signals (ATP, Adenosine) from macula densa to afferent arteriole are sent 6. Vasoconstriction of arterioles occurs 7. Hydrostatic pressure in glomerulus decreases 8. GFR decreases ****NO NEURAL SIGNALS INVOLVED

Reflex and Voluntary Control of Micturition

1. Bladder fills, triggering signal to stretch receptors From there -> reflex control: stretch receptors trigger the parasympathetic nervous system which signals to bladder to signal contraction which opens internal urethral sphincter voluntary control: stretch receptors send signal to motor neurons to release the external sphincter

2 Mechanisms to Alter Sodium Excretion

1. Changes in GFR (if it drops, we conserve sodium and volume) 2. Changes in Tubular Reabsorption Ultimately: If you retain Na, you retain volume and reverse Controlled by: sympathetic nerves, aldosterone (RAAS), natriuretic peptide

Dehydration Adjustment Mechanism

1. Dehydration occurs 2. Increased osmolality of plasma 3. Osmoreceptors in hypothalamus are triggered which a. release ADH to trigger the posterior gland to trigger increased ADH secretion b. trigger thirst 4. Increased ADH (vasopressin) secretion causes increased reabsorption of water *** negative feedback loop

Two Types (Location) of Nephrons

1. Mid corticular nephron - in cortex above the medulla 2. Juxtamedullary nephron - beings in cortex and dips deeps into medulla

Transcellular Pathway Mechanisms

1. Na + is transported across the cell using primary active transport 2. Cl - is transported using secondary active transport resulting from electrochemical gradient created by sodium 3. Water moves my osmosis and so is dragged by solute transport 4. Other solute concentration rises as volume in lumen decreases, thus permeable solutes are able to pass simply by diffusion (Ca, K, urea)

How is Na pumped from the tubule lumen to the interstitial fluid?

1. Na enters the epithelial cell membranes using membrane proteins to move down (high to low) the concentration gradient 2. Na is then pumped from low to high concentration from the epithelium to the interstitial fluid (across basolateral side of cell) via the Na-K-ATPase *** concentration of sodium in Bowman's capsule should be equal to that in the plasma

How is Glucose pumped from the tubule lumen to the interstitial fluid?

1. Na moving high to low creates favorable electrochemical gradient, so the same protein transport can pull glucose into the cell against its concentration gradient (2 active transport) 2. Glucose diffuses out of the basolateral side of the cell using the GLUT protein 3. Na+ is pumped out by Na-K-ATPase

7 Basic Functions of the Renal System

1. Regulation of Plasma Osmolality (via ADH) 2. Regulation of ECF volume and blood pressure (via RAAS and ANP) 3. Maintenance of electrolyte balance of sodium, potassium, calcium, magnesium, chloride, phosphate 4. Regulation of plasma pH by the conservation of and generation of new bicarbonate 5. Excretion of metabolic wastes, such as urea, uric acid and creatinine 6. Production of the hormone erythropoietin (which regulates the production of red blood cells) 7. Activation of Vitamin D (which regulates calcium balance)

What is GFR?

= Glomerular Filtration Rate = Kf * Pnet

Renal Portal Circulation Pathway

Afferent Arteriole -> Glomerular Capillaries -> Efferent Arteriole -> Peritubular Capillaries -> Renal Vein

Buffers in the body?

Bicarbonate in ECF, proteins/hemoglobin/phosphates in cells, phosphates/ammonia in urine

Nervous System Control of the Urinary System

Bladder/Sphincters: Controlled by sensory neurons (stretch receptors), sympathetic neurons (internal sphincters), parasympathetic neurons (bladder), Motor neurons (external sphincters) Kidney: Innervated only by the sympathetic nervous system

Renin Angiotensin Aldosterone System (RAAS) and Na Conservation

Blood Pressure Drops: GFR rises, NaCl transport decreases across Macula Densa which triggers granular cells of afferent arterioles (Which are also triggered by a drop in blood pressure (directly) and also an increase sympathetic activity Liver: Constantly produces Angiotensin which is converted to Ang I in plasma (slightly active), which is converted to Ang II in plasma which triggers to the hypothalamus oh ymg od its on slide 11 of lecture 306

Path of Filtrate Through the Nephron

Bowman's capsule -> Proximal Tubule -> Thick Descending Limp -> Thin Descending Limb -> Loop of Henle -> Thin Ascending Limb -> Thick Ascending Limb -> Distal Tubule -> Collecting Duct

General Clearance Equation

Clearance of x (Cx) = (Urine Flow * [x] in urine)/ [x] in the artery *** clearance is the volume of plasma cleared of x per unit time

Where are peritubular capillaries located?

Cortex

Urinanry Excretion of Acid Equation

Diet + Metabolism + Stool Loss (acid from stomach, bicarbonate from pancreas evens out)

Organization of Glomerular Filter + Glomerulus

Filter is composed of: 1. Capillary endothelium (Innermost) 2. Basal Lamina 3. Podocytes (Outermost) - Filtrate passes through pores in the endothelium, the collagen like basal lamina and then through the filtration slit (gap) in the podocytes *****FILTER MAINTAINS A FIXED NEGATIVE CHARGE Also Have Mesangial Cells which are the contractile cells of the glomerulus (can cause 1 kind of hypertension)

Filtrate is transferred from _______ to ______

Filtration occurs between the glomerular capillaries and bowmans capsule so that the filtrate may be passed through and processed by the nephron

Podocytes

Foot like projections - found on the glomerulus to provide structural support due to the increased pressures in these capillaries

Nephron

Functional unit of the kidney - primarily contained within the cortex of the kidney

Common Diuretics and Results

Furosemide - Works of the thick ascending loop of Henle, blocks Na-K-Cl pumps, collapses osmotic gradient, forces water to leave (25% reabsorption occurs here so very strong to block it) Chlorothiazide - Works on distal convoluted tubule (Na/Cl blocked), treats high blood pressure, more gently only blocks 3-5% of reabsorption because of where it is Amiloride - Works on collecting duct, blocks sodium channel, only changes reabsorption by ~3%

Fenestrated Capillaries

In glomerulus - have large pores that permit high volumes of fluid to pass between the plasma and the interstitial fluid

Van Hoff's Law

Osmotic Pressure = RT * summation of the number of things in solute - low osmotic pressure indicates high concentration of water -Typically want osmotic pressure to be applied such that water doesn't move - kidneys purposefully disrupt balance to move water - as solute concentration increases, the number of water molecules in volume goes down (see further 305, slide 5)

How do we replace bicarbonate breathed out?

Kidneys!!!! - exchanged in proximal tubule by proton transfer (secondary active transport) - catalyzed by carbonic anhydrous -Bicarbonate leaves via facilitated diffusion (to recover and conserve bicarbonate - we need to not discrete it)

Where are pressures sensors and baroreceptors found?

Low Pressure sensors are found in 1. cardiac atria, 2. Pulmonary vasculature High Pressure sensors are found in 1. carotid sinus 2. aortic arch 3. juxtaglomerular apparatus of the kidney and also in the central nervous system, hepatic system

Secretion (Process)

Movement of filtrate from blood to the lumen

Segmental Sodium Reabsorption Distrubution in Nephron and Collecting Duct

Proximal Tubal - about 67% of filtrate (water and sodium, 100% other nutrients absorbed) is reabsorbed in the proximal tubule Thick Ascending Limb - 25% of sodium (NO WATER) reabsorbed here (Diluting limb) Distal Tubule - 5% filtrate reabsorbed Collecting Duct - 3% filtrate reabsorbed (These decide both water and Na excretion)

Osmolality of Tubular Fluid through the Nephron

Proximal Tubule: Osm is about 300, osmotic pressure is constant but there is a 2/3 reduction of volume, the end Osm is at about 600 Descending Loop: Only water is reabsorbed here so solute gradient rises rapidly to about 900 Loop of Henle: At curve of loop, volume has dropped to a minimum and Osm has reached max at about 1200 Thick Ascending Loop (Dilute Segment): Impermeable to water, 25% of solute is reabsorbed and so gradient quickly drops backs to dilution Distal Tubule/ Collecting Duct: Variable sites for reabsorption of water and solutes based on regulation by ADH (ADH makes it permeable to water, if it is no there water cannot be reabsorbed)

Mass Balance in the Kidneys

Px,a * RPFa = (Px,v * RPFv) + (Ux *Vu) ([x] in the artery * plasma flow rate in the renal artery) = ([x] in the renal vein * plasma flow rate in renal vein) + ([x] in the urine + urine flow rt) or Arterial Input = Venous Output + Urine Output

Renal Plasma Flow Equation

RPF = ([x] in the urine * Urine flow rate)/ [x] in the artery (assumes every molecule of x that enters the kidney is excreted in the urine) RPF = (1-hematocrit) * RBF Can tell us whether blood is adequately reaching the kidneys

How does acid leave the body?

Renal and Ventilation

Organic Anion Secretion by the Proximal Tubule

Selection for Secretion is very simplistic simply must: 1. Have Charge (there are separate transporters for anions/cations) 2. Be Organic - Tertiary active transport occurs via Alpha-KG transport for PAH (which is not endogenous)

Selectivity of the Glomerular Filter

Selectivity is determined by: 1. Size 2. Electrical Charge - Ultimately exclude blood, plasma proteins (because size/charge) - if there is protein in the urine then there's an issue with the filter

Action of Aldosterone on the Principal Cell and Sodium Reabsorption

Slide 11, Lecture 306

Sodium Balance vs. Water Balance

Sodium balance takes a significantly longer to obtain than water balance

Juxtaglomerular Apparatus

Space in individual nephron composed of Bowman's capsules, glomerulus start of proximal tubule arterioles and overlap of arteries and the ascending loop of henle

Total Body Water (TBW)

TBW = ICF (about ~2/3 vol) + ECF (about ~1/3 vol)

How is acid added to the body?

Through the diet or through metabolism (Lactic acid, carbonic acid, ketoacids)

How are Volatile and Non Volatile Acids excreted?

Volatile -> respiratory (CO2, H2O Non-Volatile -> renal (Amino acid breakdown can make acids or bases)

Maintenance of steady state requires...

an equal level of input and output

How does vasopressin increase water retention?

by causing the insertion of aquaporins into the apical membrane

Increase arteriole resistance in the efferent arteriole...

decreases renal blood flow to increase Hydrostatic Pressure and thus GFR to compensate for a drop in renal pressure upstream

Constriction of the afferent arteriole...

increases resistance and decreases renal blood floow, capillary blood pressure and GFR

Water moves from regions of _____ osmotic pressure to a region of _____ osmotic pressure

low, high

Filtration (Process)

movement of fluid from blood to the lumen (but this only occurs in glomerular capillaries)

Reabsorption (Process)

movement of fluid from lumen to the blood

Alkalemia

pH above 7.45 ([H] less than 35 NM) and below 7.8 - result from metabolic or respiratory

Acidemia

pH below 7.35 and above 6.8 - results from metabolic or respiratory

Kidney control of water loss regulates ______

reabsorption (NOT SECRETION)

Osmolality

the concentration of a solution expressed as the total number of solute particles per kilogram (Osm)

Osmolarity

the number of osmoles/ liter of solution (OsM)