OS 206 Renal Physiology

Dr. Elizabeth S. Montemayor

OS206

3

Abdomen and Pelvis

Lec 2: Overview of Renal Physiology Lecture Outline:   

I.   Functional Renal Anatomy 

A. Major Functions of the Kidney  B. The Nephron  C. Renal Vasculature  D. Basic Renal Processes  II.   Renal Blood Flow  III.  Glomerular Filtration  A. Filtration Membrane  B. Glomerular Filtration Rate  C. Autoregulation  V.   Clearance Principle  VI.  Appendix 

FUNCTIONAL RENAL ANATOMY

A. MAJOR FUNCTIONS OF THE KIDNEYS Regulation of body fluid osmolality and volumes Regulation of electrolyte balance Regulation of acid-base balance Excretion of metabolic end-products (urea, uric acid & creatinine) & foreign substances (drugs, xenobiotics, etc.) Production and secretion of hormones. The kidneys function as endocrine glands that produce and secrete renin, calcitriol and erythropoietin. 1. Renin o manufactured, produced and secreted by granular cells in juxtaglomerular apparatus. o activates the Renin-angiotensinaldosterone system i. The kidney produces renin, w/c converts angiotensinogen (from liver) into angiotensin I. This is the first step and the rate-limiting step of the reninangiotensin-aldosterone system ii. Angiotensin I is converted into angiotensin II by ACE (angiotensin converting enzyme) iii. Angiotensin II produces the following effects: formation of aldosterone (important in Na and fluid retention, more importantly enhances Na retention, w/c leads to an increase in blood volume and pressure) Direct systemic vasoconstriction w/c can lead to hypertension Cardiac and vascular hypertrophy Indirect increase of blood volume through stimulation of the thirst mechanism. Stimulation of ADH (antiduiretic hormone) secretion by the posterior lobe of the pituitary gland w/c also leads water conservation

o Generally, it affects the adrenal cortex, kidney, intestine, CNS, PNS, vascular smooth muscle and the heart to maintain or increase extracellular volume (ECV), total peripheral resistance and cardiac output. Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

2. Calcitriol (an active metabolite of vitamin D) o Recall: Previtamin D in skin (through sun exposure), also from diet (milk), deep sea fish (salmon) is converted to: 25(OH)D (calcidiol) in the liver and processed by the prostate gland, breast, colon, lungs, immune cells to 1,25(OH)2D used for regulation of cell growth or immune function. 1,25(OH)2D (calcitriol) in the mitochondria of the convoluted & straight proximal tubules of the kidney. It increases GI Ca absorption, stimulates osteoclastic Ca resorption from bone, facilitates the effect parathyroid hormone (PTH) has on bone resorption, & increases renal tubular absorption of Ca. It is essential for muscle and bone health and aids in the regulation of blood pressure. 3. Erythropoietin o Produced by the by the peritubular capillary endothelial cells in the kidney to stimulate RBC production in the erythroid marrow o As the pluripotential stem cell differentiates, it begins to produce receptors for erythropoietin. o In the presence of erythropoietin, the differentiated/dedicated stem cells become progenitor cells. o In the absence of erythropoietin, a dedicated stem cell will undergo apoptosis. o As they differentiate into precursor cells, erythropoietin receptors are lost & depend on other substrates for further differentiation. o Feedback mechanism: Hypoxia is the most potent stimulator of erythropoietin. In hypoxic conditions, erythropoietin is secreted stimulating the marrow to produce RBCs. Increase in RBC production leads to increase in O2 circulation and removal of hypoxic stimulus. o Decreased RBC production is a cause of anemia seen in chronic renal failure.

B. THE NEPHRON basic structural and functional unit of the kidney Each human kidney contains approx. 1 Million nephrons, w/c consists of specialized tubular structure & closely associated blood vessels. Number of nephrons at birth remains constant through adulthood. Implication: premature babies who are born with less nephrons are at greater risk for end-stage renal disease The nephron consists of: a. Renal corpuscle: a. Glomerulus a tuft of capillaries supplied by the afferent arteriole and drained by the efferent arteriole covered by epithelial cells - podocytes

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Dr. Elizabeth S. Montemayor

OS206

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Lec 2: Overview of Renal Physiology b. Bowman’s capsule visceral layer – formed by podocytes parietal layer Bowman’s space – capsular space bet. the visceral and parietal layer; lumen of the proximal tubule (at the urinary pole)

Figure 2. Tubular Segments of a [Juxtaglomerular] Nephron

Figure 1. Cellular Features of Renal Corpuscle

b. Renal tubule a. Proximal convoluted tubule (PCT) several coils that descends toward the medulla PCT cells extensively amplified apical membrane (urine side) – brush border highly invaginated basolateral membrane (blood side) – many mitochondria b. Loop of Henle Straight part of the proximal tubule Descending thin limb, DTL (ending in hairpin turn) Ascending thin limb, ATL (in nephrons w/ long loops of Henle) DTL and ATL – poorly developed apical and basolateral membrane; few mitochondria Thick ascending limb abundant mitochondria; extensive infoldings of the basolateral membrane Macula densa (portion of the thick ascending limb passing between afferent and efferent arterioles) c. Distal Convoluted Tubule d. Collecting Duct (cortical CD J outer medullary CD J inner medullary CD); 2 types of cells i. Principal cells – moderately invaginated basolateral membrane; few mitochondria ii. Intercalated cells – high density of mitochondria inner medullary CD – poorly developed apical and basolateral surfaces; few mitochondria Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

There are two types of nephrons: 1. Cortical or superficial (~85%) – glomeruli are near the periphery of cortex and nephron loops in the outer medulla; characterized by a short loop of Henle and an almost absent thin ascending limb 2. Juxtamedullary – glomeruli are near the corticomedullary junction and have relatively long nephron loops that extend deep into the medulla. The efferent arteriole of juxamedullary nephron forms not only a network of peritubular capillaries, but also a series of vascular loops called the vasa recta. *** Vasa recta series of vascular loops that descends into medulla, form capillary networks surrounding collecting ducts and ascending limbs of Henle’s loop blood returns to the cortex in the ascending vasa recta receives < 0.7% of renal blood flow Functions: 1) conveys oxygen and important nutrients to nephron segments; 2) delivers substances to the nephron for secretion; 3) serves as a pathway for the return of reabsorbed water and solutes to the circulatory system, & 4) concentrates and dilutes urine ***The renal medulla (pyramid) consists of two zones: Outer zone a. Outer stripe b. Inner stripe Inner zone All segments of Henle’s Loop end at the same area of the medulla, i.e. for a juxtamedullary nephron, the straight part of the proximal tubule nephron will always end at the junction between the inner and outer medullary stripe.

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Dr. Elizabeth S. Montemayor

OS206

3

Abdomen and Pelvis

Lec 2: Overview of Renal Physiology C. BASIC RENAL PROCESSES

Figure 3. Two Types of Nephrons. Schematic of relations between blood vessels and tubular structures and differences between cortical and juxtamedullary nephrons. See Netter (4e), plate 336 for another depiction.

C. VASCULAR SUPPLY Extrarenal vasculature: arteriole JcapillaryJvenule Renal vasculature: arteriole J capillary J arteriole J capillary Main renal artery (from abdominal aorta) J segmental arteries (3-5;in the renal sinus ) J interlobar arteries (pass through the renal columns) J arcuate artery (traverses the base of the medullary pyramids) J interlobular arteries (important because this is where the arterioles come from) J afferent arterioles J glomerular capillary J efferent arterioles J o In cortical nephrons, these send branches to peritubular capillaries (formed within the cortical area, forming a complex system in the tubules) J interlobular vein J arcuate vein J interlobar vein J renal vein J IVC o In juxtamedullary nephrons, peritubular capillaries J vasa recta J interlobular vein J …. J IVC ***the vessels of the venous system, run parallel to the arterial vessels.

The coordinated actions of the nephron’s various segments determine the amount of substance that appears in the urine. This represents 3 general processes: 1. Glomerular Filtration - Filtration of plasma in the glomerulus, ultrafiltrate then collects in the urinary space of Bowman's capsule and flows downstream to the tubular lumen 2. Tubular Reabsorption - Transport of substances out of tubular lumen which are returned to the systemic circulation via the peritubular capillaries 3. Tubular Secretion - Transport of substances from the peritubular capillaries into the tubular lumen. ***In Focus: Glomerular filtration RENAL BLOOD FLOW Average renal blood flow of 1800 L/day urine flow of 2L/day In resting subjects, the blood flow to the kidneys ≈ 1.25 L/min ≈ 25% of cardiac output received by an organ less than 0.5% of total body weight. Cortex receives bulk of the blood flow (82%) while the rest goes to the medulla and the papilla. The papilla is the most hypoperfused part of kidney, making it more prone to necrosis; however, it still gets more perfusion than the heart, brain and lungs. Table 1. Comparison of the distribution of blood flow to the different organs Organs Blood Flow, mL/(g*min) Kidney 4.0 Heart 0.9 Brain 0.6 Liver 0.2 Resting muscle 0.1

Roles served by renal blood flow (from the lecture) Sustains filtration and excretion of end-products such as urea and creatinine Achieves rapid changes in body fluid volumes and composition through changes in renal excretion of water and solutes Serves a hemodynamic reserve function in case if extreme emergency (shock) by redistributing blood to other organs. That is, RBF can be reduced to very low levels to help sustain the blood flow in other organs (brain, heart, etc) Delivers sufficient oxygen and nutrients to the kidneys. Roles served by renal blood flow (more from Berne)

Figure 4. Vascular Supply of the Kidney. Please take note that the renal artery normally lies posterior to the renal vein. This is not shown in the figure above. The figure highlights the course of blood as it is supplied to and drained from the kidney.

Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

Deliver sufficient oxygen, nutrients and hormones to the cells of the nephron and returning carbon dioxide and reabsorbed fluid and solutes to the general circulation Indirectly determines the GFR Modifies the rate of solute and water reabsorption by the proximal tubule. Participates in the concentration and dilution of urine Delivers substrates for excretion in the urine

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Dr. Elizabeth S. Montemayor

OS206

3

Abdomen and Pelvis

Lec 2: Overview of Renal Physiology The blood flow through any organ may be represented by

GLOMERULAR FILTRATION

Q = ∆P / R where:

Q = blood flow ≈ RBF ∆P = mean arterial pressure – mean venous pressure R = total renal vascular resistance

Accordingly, renal blood flow, RBF is equal to the pressure difference between the renal artery and the renal vein (VP) divided by the total renal vascular resistance KVenous Pressure LRBF and KR L RBF Consider the forces that determine overall renal blood flow. The basic equation demonstrates that virtually all factors that influence total renal blood flow must do so by altering either the arterial blood pressure or the renal vascular resistance.

A. FILTRATION MEMBRANE “making urine is just like making coffee” essentials: filtration membrane solid parts and large molecules suspended in plasma or blood ultrafiltrate ||> GLOMERULAR FILTRATION Ultrafiltration of plasma performed because the Glomerular Filtration Membrane is an extremely fine molecular sieve ||> GLOMERULUS Pathway of fluid: ECL → BM → SM Glomerular Filtration Membrane has three layers for filtration: 1.) Endothelial Cell Layer (ECL) contains blood vessels and capillaries has sieve-like fenestrations (500-1000 Å) that allow the passage of small molecules whilst restraining the passage of large molecules most permeable 2.) Basement Membrane (BM) least permeable two layers: a. Lamina Densa - central dense layer b. Lamina Rara Interna & Externa thinner and more electrolucent outermost and innermost layers

Figure 5. Pressure changes across renal vasculature. The generally accepted pressure gradient through the renal vascular system. Areas of large pressure drops are main points of autoregulation.

The following notes come from 2013 trans. Those that were mentioned/emphasized in the lecture are in bold. There is a wide range of pressure in the kidneys because it reflects systemic pressure. Main point of resistance: afferent arteriole provides dissipation of pressure very high venous resistance to blood flow Hydrostatic pressure drops dramatically between the beginning of the afferent arteriole & glomerular capillary. Afferent arteriole has great influence on glomerular capillary by increasing or reducing resistance Second drop at the efferent arteriole; 2nd point of resistance. Most active segments are the afferent and efferent arterioles: segments that regulate blood flow Pressure at the glomerular and peritubular capillaries are constant. Initial pressure of efferent arteriole is the same as final pressure of afferent arteriole. Each of the capillary networks is exquisitely designed to serve the functional needs of the kidney. Every day 180 liters of fluid pass through the glomerular capillaries as filtrate. About 99% is recovered from the tubules and carried back into the general circulation via the peritubular capillaries. Remaining 1% continues on to its final presentation as urine. Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

3.) Slit Membrane (SM) the “diaphragm” of the glomerulus lies in between the podocytes of endothelial cells (“interdigitations”) moderately permeable because of the presence of slit pores (250 Å) Table 2. Filterability of some substances Substance MW Molecular radius (Å) Water (H2O) 18 0.1 Glucose 180 0.36 Inulin 5000 1.4 Hemoglobin 17000 2.0 Serum Albumin 69000 3.6 Cationic Dextran (+) 3.6 Neutral Dextran 3.6 Anionic Dextran (-) 3.6

[ Filtrate/ Plasma ] 1.0 1.0 1.0 0.03 0.001 0.42 0.15 0.01

↑ molecular size, the harder it is for the molecule to pass thru the filtration membrane ↑ filtrate to plasma ratio of a substance, the better it is filtered ||> FACTORS

AFFECTING FILTERABILITY

1.) Size (most important factor) substances of MW up to 5000 and radius less than 15 Å are freely filtered ↑ size, ↓ filterability 2.) Shape slender and flexible = ↑ filterability spherical and non-deformable = ↓ filterability

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Dr. Elizabeth S. Montemayor

OS206

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Abdomen and Pelvis

Lec 2: Overview of Renal Physiology 3.) Electrical Charge (+) charge = ↑ filterability (-) charge = ↓ filterability ***the glomerular filtration membrane bears negative charges due tah glycosaminoglycans, e.g. heparan sulfate [recall: like charges repel]

B. GLOMERULAR FILTRATION RATE total amount of filtrate formed by the Kidneys per unit time (normally in minutes). This is not how much blood passes through the glomerulus each minute, but instead; it is how much filtrate is removed from the blood each minute. unit = mL/min. mL normal value = 125 /min. a test for Kidney Function ||> STARLING

HYPOTHESIS the net movement of fluid out of a capillary is given by (equation from Berne):

Jv = Kf [(Pcap – Pif) – σ(πcap – πif)] where 1.) Jv = Net fluid movement between compartments ≈ GFR 2.) Kf = Coefficient of [Ultra]Filtration = a constant of proportionality = two components: a.) capillary surface area b.) capillary hydraulic conductance = area x hydraulic conductance = ↑Kf, more water-permeable capillary = ↓Kf, less water-permeable capillary 3.) σ = Reflection Coefficient = a correction factor = can have a value from 0 to 1 ***Dr. Montemayor didn’t really expound nor gave much attention to this. Anyway, glomerular capillaries have a σ value very close to 1

4.) Pcap = Capillary Hydrostatic Pressure = pressure brought about by water within capillaries directing water OUT of the capillary 5.) Pif

= Interstitial Hydrostatic Pressure = pressure brought about by water within the interstitium directing water INTO the capillary

6.) πcap = Capillary Oncotic (or Osmotic) Pressure = pressure brought about by the presence of proteins within the capillaries directing water INTO the capillary (recall the concept of gradients…water flows from higher concentration to lower concentration)

7.) πif

= Interstitial Oncotic (or Osmotic) Pressure = pressure brought about by the presence of proteins within the interstitium directing water OUT of the capillary (again…recall thuh concept of gradients…water flows from higher concentration to lower concentration)

Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

Figure 6. Glomerular Filtration is promoted by Capillary hydrostatic pressure and opposed by capsular hydrostatic pressure and blood colloid osmotic pressure.

Key: PH

π Pfluid

= Pcap = Capillary hydrostatic pressure = πcap = Capillary [colloid] oncotic (or osmotic) pressure gradient due to proteins in plasma but not in Bowman’s capsule = Pif = Fluid pressure created by fluid in Bowman’s capsule πif = Interstitial [colloid] oncotic pressure gradient due to proteins in in Bowman’s capsule. w/c promotes filtration. Under normal conditions, the concentration of protein in the glomerular filtrate is so low that the πif ~ zero. = Net Filtration Rate: Effective driving force for filtration. = (Pcap – Pif) – σ(πcap – πif) = Normally, 10 mm Hg (assuming σ ≈ 1)

NFR

GFR = Kf × net filtration pressure mL

Since normal value of GFR is 125 /min, the normal Kf is ml calculated to be about 12.5 /min·mmHg of filtration pressure Nice to know: when Kf is expressed per 100 g of kidney wt., it’s about 4.2 ml/min/mm Hg, a value about 400 times as high as the Kf of most other capillary systems of the body; the average Kf of many other tissues in the body is only about 0.01 ml/min/mm Hg per 100 grams. This high Kf for the glomerular capillaries contributes tremendously to their rapid rate of fluid filtration. However, changes in Kf probably do not provide a primary mechanism for the normal day-to-day regulation of GFR. (Guyton&Hall, 11e) ||> PRESSURE

PROFILE

in a SKELETAL MUSCLE capillary: hydrostatic pressure is high at the arterial end and low at the venous end; oncotic pressure is constant. filtration occurs at arterial end; absorption occurs at venous end initial hydrostatic pressure is 35 mmHg in a GLOMERULAR capillary: hydrostatic pressure profile is higher (> 55 mm Hg, initially) and declines only very little with distance, Hydrostatic pressure remains essentially constant from afferent arteriole to efferent arteriole (see Fig 5) oncotic pressure increases due to filtration of protein-free fluid (↑ protein content inside capillary)

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Dr. Elizabeth S. Montemayor

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Lec 2: Overview of Renal Physiology ||> DETERMINANTS

OF GLOMERULAR FILTRATION RATE

1.) Kf or permeability characteristic of glomerulus depends on: a. Surface area available for filtration – ↑ surface area, ↑ Kf, ↑GFR b. Mesangial cell activity* c. change in porosity of filtration membrane – ↑ holes or pores, ↑ fluid mov’t, ↑GFR – inflammation (e.g. insect bites) increases porosity *MESANGIAL CELLS o another type of cell in the glomerulus but not located within the capillaries o provide support for the glomerular capsule o secrete extracellular matrix o regulate blood flow o alter capillary surface area (w/c affects Kf & GFR) o secrete prostaglandins and cytokines; o with phagocytic activity 2.) (Pcap – Pif) or the hydrostatic pressure difference two kinds: a. Capillary Hydrostatic Pressure determined by aortic pressure or changes in the resistance at the afferent and/or efferent arteriole b. Hydrostatic Pressure at the Bowman’s Capsule [space] a.k.a. Interstitial Hydrostatic Pressure (Pif). ↑ Pif. ↓ GFR ↑ Pif is observed in patients w/ kidney stones (nephrolithiasis). Changes in tubular hydrostatic pressure: obstruction will increase tubular pressure to as high as capillary pressure and therefore no filtration can occur (GFR is zero). ♣ EFFECTS OF AFFERENT/EFFERENT DILATION/CONSTRICTION ON DIFFERENT VARIABLES – This is the subject of the take-home simulated laboratory experiment. Table 3. Effects of afferent and efferent dilation on RBF, HP, GFR, and FF Afferent Dilation Efferent Dilation

RBF

∆HP

GFR

FF

↑ ↑ ↓

↑ ↓ ↓

↑ ↓ ↓

↔ ↓ ↔

Afferent Constriction Efferent ↓ ↑ ↑ ↑ Constriction* * to compensate for the loss of nephrons, efferent arterioles constrict.

Variables: RBF = Renal Blood Flow ∆HP = Difference in Hydrostatic Pressure GFR = Glomerular Filtration Rate FF = Filtration Fraction Legend: ↑= increase, ↓ decrease, ↔ = same

Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

3.) (πcap – πif) as determined primarily by plasma oncotic pressure. Low plasma oncotic pressure increases the amount of filtrate. ↑ πcap ↓GFR. ↑ πcap is brought about by dehydration (↑ osmolarity), multiple myeloma and hyperviscosity syndrome. ||> SUBSTANCES

WHICH AFFECT GLOMERULAR FILTRATION RATE

1.) Angiotensin vasoconstrictor preferentially constricts the efferent arteriole; making it the preferred inhibitor for renal disease at higher plasma levels: contracts all mesangial cells generalized vasoconstriction (afferent and efferent) maintains central arterial pressure in expense of RBF and filtration 2.) Endothelin – vasoconstrictor 3.) Arginine Vasopressin (AVP) – vasoconstrictor 4.) Prostaglandins – vasodilator* 5.) Nitric Oxide (NO) – vasodilator 6.) Natriuretic Peptides – vasodilator *2 & 3 lower RBF while 4, 5, 6 counteract the effects of vasoconstrictors ||> FILTRATION

FRACTION and RENAL PLASMA FLOW

♣  FILTRATION FRACTION (FF) ratio of Glomerular Filtration Rate (GFR) to Renal Plasma Flow (RPF)* portion of the Renal Plasma Flow filtered in the kidneys represents the portion of the fluid reaching the kidneys which passes into the renal tubules normal value: 0.15 to 0.20 (e.g. only ~20% of the plasma that enters the glomerulus is actually filtered.

FF = GFR / RPF ♣  RENAL PLASMA FLOW (RPF) volume of blood plasma delivered to the kidneys per unit time the kidneys are hyperfiltrating units RPF = RBF x (1 – Hct); Blood consists of about 55% plasma and about 45% cellular components (mostly RBCs ≈ hematocrit, Hct) mL normal value: 650 /min For “higher learning” : The following outlines the computation of FF from the following “normal” values… Note the relationship of the different variables. a. Cardiac output (CO) = 6 L/min L b. Renal blood flow (RBF) 20-25% of CO = 1.25 /min

c. Renal plasma flow (RPF) =RBF x (1 – Hct); If the Hct level of the person is 45%. RPF = (1250 mL/min)(1 – 0.45) = 687.5 mL/min d. Glomerular filtration rate (GFR) = 125 mL/min e. FF = GFR / RPF = 125/687.5 = 0.182

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Dr. Elizabeth S. Montemayor

OS206

3

Abdomen and Pelvis

Lec 2: Overview of Renal Physiology Effector Mechanism: Adenosine + + with increased uptake of Na , K , Cl a.) increased generation of Adenosine b.) Adenosine activates Adenosine1 receptors triggering an increase in cytosolic Ca2+ in the extraglomerular mesangial cells c.) intensive coupling between juxtaglomerular granular cells containing renin and extraglomerular mesangial cells occurs, resulting in afferent arteriole constriction and renin inhibition

C. AUTOREGULATION ability of the kidneys to maintain constancy of Renal Blood Flow (RBF) and Glomerular Filtration Rate (GFR) over a wide range of Renal Perfusion Pressure or Blood Pressure Mechanisms: 1.) Myogenic Reflex (universal, i.e. peripheral and renal)

T=PxR where, T = vascular wall tension P = transmural pressure gradient R = inner radius of vessel In order for T to remain constant: R is forced to increase when P decreases and vice versa. Mechanism: – vascular smooth muscles reflexively contract (decreasing afferent arteriole diameter) when stretched, reducing blood flow. – vascular smooth muscles reflexively relax and dilate when not stretched, thereby increasing blood flow.

**the reverse occurs w/ decreased uptake of Na+, K+, Cl♣ JUXTAGLOMERULAR APPARATUS – layers: a.) Juxtaglomerular Granular Cells • located at the walls of afferent arterioles • contains specific granules which produce renin b.) Extraglomerular Mesangium • functional link between Macula Densa and Glomerular Arterioles • contains the Extraglomerular Mesangial Cells c.) Macula Densa • specific region of the thick ascending limb which acts as a sensor arm • where the cuboidal cells of the thick ascending limb become columnar

2.) Tubuloglomerular Feedback Mechanism due to the sensitivity of the macula densa cells of the juxtaglomerular apparatus to the filtrate osmolarity and/or rate of filtrate flow in the terminal portion of the ascending loop of Henle increase in GFR = increase in filtration = increase in delivery of solutes to the tubules to the macula densa

Figure 7. Tubulo-glomerular feedback mechanism. 1)GFR ↑ 2) Flow through tubule ↑ 3) Flow past macula densa ↑ 4) Paracrine from macula densa to afferent arteriole 5) Afferent arteriole constricts; Resistance in afferent arteriole ↑; Hydrostatic pressure in glomerulus ↓; GFR ↓

Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

3.) Sympathetic Control Sympathetic nerve fibers innervate all blood vessels of the kidney as an intrinsic regulation activity. Minimal influence during normal daily activity In extreme stress or blood loss, sympathetic stimulation overrides the autoregulatory mechanisms of the kidney. Increased sympathetic discharge causes intense constriction of all renal blood vessels w/c has the following results: The activity of the kidney is temporarily lessened or suspended as blood is shunted to other vital organs. GFR reduction causes minimal fluid loss from the blood maintaining higher blood volume and blood pressure for other vital functions. Reduction in filtration cannot go indefinitely, as waste products build up and metabolic imbalances increase in the blood. IV fluid must soon be administered to increase blood volume and pressure and to decrease sympathetic discharge and restore normal arteriole diameters and normalize GFR and filtrate flow.

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Lec 2: Overview of Renal Physiology Substituting equations (2) and (3) on equation (1) and rearranging for Cw

CLEARANCE PRINCIPLE Clearance is a term used to describe the rate of removal or clearing of a substance from the blood; The principle of renal clearance emphasizes the excretory function of the kidney. Thus, it is used to evaluate renal function. The clearance principle is based on the Fick principle (mass balance or conservation of mass).

•

•

Cw × Pw = U w × V

⇒

U ×V Cw = w Pw

The definition of clearance as a volume of plasma from which all the substance has been removed and excreted into the urine per unit time is somewhat misleading since for most substances cleared by the kidneys, only a portion is actually removed and excreted in a single pass through the kidneys. The volume of plasma in the above equation is an idealized volume. Nevertheless, the concept of clearance is important because it can be used to measure the GFR and renal plasma flow and to determine whether a substance is reabsorbed or secreted along the nephron. Exercise: Compute for the subject's GFR using inulin* clearance in mL/min

Figure 8. The Principle of Renal Clearnace. The renal artery is the single input source to the kidney, whereas the renal vein and ureter constitute the two output routes.

The following equation define the mass-balance relationship (input = output):

*inulin (from 2013 trans) o Prototype drug (Considered to be the first pure compound to have been discovered in any series of chemically or developmentally related therapeutic agents.)

o o o o o o

•

Pxa × RPF a = ( Pxv × RPF v ) + (U x × V )

Polymer of fructose (MW=5000) non-toxic to humans Administered intravenously, not produced by the body used to help measure kidney function by determining the GFR Freely filtered across the glomerulus into Bowman’s space Neither reabsorbed, secreted, nor metabolized by nephrons Amount of inulin excreted in the urine per minute equals the amount of inulin filtered at the glomerulus each minute

Given:

where

Plasma inulin conc = 4 mg/L Urine collected in 10 hrs = 1 L mg Urine inulin concentration = 300 /L mass of inulin filtered mass of inulin excreted = time time •

GFR = =

The equation above is valid for any substance that is 1. freely filterable at the renal corpuscle (small and not bound to a protein), across the glomerulus into the Bowman’s space 2. Neither secreted nor reabsorbed by the tubule 3. Not synthesized nor broken down by the tubules Useful derivations: Assume there is a susbtance (W) that meets the above criteria.

mass of W filtered mass of W excreted = time time mass of W filtered = Pw × Cw time • mass of W excreted =U w ×V time

eqn (1) eqn (2) eqn (3)

Note:

=

Thurs., Dec. 10, 2009

300 mg L × 1 L

10 h 4 mg L 300 mg L × 1000 mL

600 min

4 mg L

= 125 mL min Comparing the clearances of other substances For a certain substance, like inulin filtered through glomeruli and not reabsorbed or secreted by tubules, Clearance of inulin equals Glomerular Filtration Rate: Cx = Ci = GFR For a certain substance, x, that is filtered through glomeruli and reabsorbed by tubules, Clearance of x equals GFR minus Tubular Reabosorption Rate Cx = GFR – Tax Cx < Ci For a certain substance, x, that is filtered through glomeruli and secreted by tubules, Clearance of x equals GFR plus Tubular Reabosorption Rate Cx = GFR + TSx Cx > Ci

Pw = concentration of substance w in plasma Cw = “removal rate” or “clearance”; volume of plasma cleared of substance w per unit time (usually in mL/min) ≈ GFR (for substances that meet the above criteria) Uw = concentration of substance w in the urine . V = volume of urine per unit time (urine flow rate)

Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

U inulin × V Pinulin ×

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Lec 2: Overview of Renal Physiology For a certain substance, x, that is filtered through glomeruli and reaborbed and secreted along the tubules, Clearance of x equals GFR minus net reabsorption plus secretion rate Cx = GFR – Tax + TSx Cx > Ci  

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐End ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐  REFERENCES:  1.   2.  3.   3.    

Dra. Montemayor’s lecture notes transcribed by Marivic and Bryan  Physiology 5e by Berne, et al    2013 Transcription  Textbook of Medical Physiology 5e by Guyton and Hall  

APPENDIX Table 4.

ZÜxxà|Çzá Bry‐o‐chem: Woohoo! tis time fo greetin' 'gain!! this'd be a long one since  thuh last one i did wuz real short..well..here it goes! Hello tah thuh whole  of 2014! our effin openin' number wuz amazin! go europe! special thanks  tah  nico  'course..galing!  tah  those  who  helped  me  wit'  thuh  voiceovers,  thanks  a  bunch!  still  owe  ye  guys  a  lil  sumthin  sumthin..:P  congrats  din  sa'tin  fo  doin'  a  good  job  sa  chorale  competition!  anne,  dane,  ate  jana,  without  y'all..wala..haha!  go  tenor  2's!  A  hello  tah  mah  feedin'  program  din..na on‐hiatus sa ngayon (parang glee na sa april pa ang balik..)..haha!  we  should  have  sumthin'  befo'  thuh  break  guys,  yea?  hello  'course  tah  MPS: k‐ab, k‐flo, jb, tin, sam, alex, roland, therese, jason, marcus, karla! go  easy on me sa summer initiations! haha! hello tah mah fellow mss apps!  'course,  would  i  forget  tah  say  hi  tah  iMed!!  ano,  kelan  party?  nga  pala,  hello  tah  mah  roommates:  poch,  kuya  renzo  and  phantom!  now  fo  thuh  single greetings: Hello tah: patrick ang sumasayaw na conductor at LO na  nanonoxic, aa, christelle and mairre (di makasayaw si christelle nung mss  victory  party..wala  daw  kasi  si  mairre..haha!),  ma‐e..spleen!,  nic!,  jonas  and his sausage marvyn!, mommy carla that i always greet :D, fellow mpl  baby ko na si bossing!, sa bon‐casti duo,  coy‐tincee‐ricky‐leeann quartet,  dalvie!, franco and camille, migz and ate abby (ate abby..'yung tanong ko,  di mo pa sinasagot..:P), lance G!, ching‐lennie couple (wahaha!), southbro  carlos!, carlo‐glaiza pair, dana na kaya nang mag‐stay awake sa class fo' up  tah 20 minutes!!, david!, lolo aidz!, robert!, hun shayne!, chesca na nililink  ko  kay  cons..haha!,  faye!,  rr‐joreb‐luigi  wutta  great  drinkin'  night  we  had..til next time!, anna clau, april, mervyn na nagpapabati..may bonding  pa  tayo  bago  mag‐break!,  lau,  jesha..sisiw!,  yhan  na  namimiss  ko  na..awww,  marivic,  alphius,  dragons  and  virgins,  zane,  jam!,  janna,  kimongkimongki! peace!, scott!, roni‐jaypang dance pair!, tonch a.k.a. sid  ng  ice  age/donatello  ng  tmnt,  romeo  and  julieeeeee!,  edge!,  ado!,  kay!,  karl babe na mahilig kumain sa class, godfrey & bea na magkamukha, jere  & roger na miss na ang isa't isa, zie!, grace v.!, marvie na miss na miss ko  na  at  sure  na  miss  na  rin  niya'ko..2  months‐advanced  happy  birthday!  haha!  overnight  ulit  tayo!  :P,  pito..still  owe  ye  sumthin'  effin  long  overdue..lol..oyea, belated hb! chill sometime, yea?, peace&bounce! and  lastly hi tah jhing..thanx a lot! ;)   

Woah! Haba pala nun! :| ohwell..haha! Merry Christmas and Happy New  Year 2014!! Enjoy thuh break!! Chillax lang..sa January na mag‐aral! haha  b.i.!    

o  eto..game:  sa  trans  na  'to  (not  includin'  thuh  greetin'  part)..there're  two  words (only two!) that are part of mah text/e‐mail/ym language..find 'em and  show 'em tah me..may libreng dilly bar fro' dq ang pinakaunang makakahanap!  (trans  group  ko..di  kayo  kasama..haha!)  guess  that's  it!  Happy  Holidays  y'all!  Out!! Marivic: Happy Holidays! ☺☺☺    Waaahh  may  space  pa  kaya  naman    babatiin  ko  ang  Class  2014  para  sa  matagumpay  na  TRP  opening number, stage design at chorale number  ngayong  taon.  Syempre  special  greetings  sa  mga  kapwa ko aprikano, na binigay ang lahat sa maiksi  ngunit di‐malilimutang  parte sa opening number!  Inaantok  na  ako  para  isa‐isahing  batiin  ang  mga  tao na patuloy na nagbibigay ng kakaibang saya at  inspirasyon  sa  akin.  Mahaba  pa  ang  ating  pagsasamahan  at  sana  sa  mga  darating  pang  panahon ay mas makilala natin ang isa’t isa. Ayun!  Sa mga nakakasama, nakakausap, nakakatrabaho,  nakaka‐chat  at  nakakabiruan  ko  sa  araw‐araw  (kilala nyo na kung sino kayo) inaalay ko ang trans  na ito sa inyo… At sa iyo ____ hangad namin* ang  iyong kasiyahan at kapayapaan ng loob.   

Ayun.  Sa  mga  naki‐kidney  o  nababato  ngayong  bakasyon,  sana  ay  matuwa  kayo  sa  trans  namin.  Sana  palampasin  na  ang  mga  pagkukulang  tutal  maayos  naman  naming  nagawa  ito.  Sana  ay   makatulong nang lubos sa inyong pag‐aaral.   

Maraming  salamat  kay  Bryan  at  Marivic  na  gaya  ko ay binuno ang trans na ito.     Maligayang Pasko at Masaganang Bagong Taon sa  inyong lahat =) Labing‐apat! Walang katapat!    Nagpapasalamat para sa makabuluhang taon,  Alphius

Figure 9. Renal blood flow and GFR

Alphius | Bryan| Jean | Marivic Mark | Marvin | Mau |Schubert

Thurs., Dec. 10, 2009

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