1. Lecture 2 RENAL BLOOD FLOW, FILTRATION AND CLEARANCE Macrophage white blood cell and red blood cells

2. Basic Renal Processes 1.Filtration (F) 2.Reabsorption (R) 3.Secretion (S) Excretion = F + S - R Urine Formation Afferent Arteriole Efferent Arteriole Glomerulus Bowman’s Capsule Renal Tubule Peritubular Capillary Conceptual Point : Filtration is the most basic “mode” of renal substance handling. - solutes need pass the filter barrier - no specific transport processes - if there is no reabsorption or secretion, then the substance will be excreted. There are very few “filtered-only” solutes. Most are also reabsorbed and/or secreted. Some Examples: Substances that are Filtered then Reabsorbed >99.9%799.5 ∼ 0.5 800Glucose mM/day >99.9%4,498 ∼2∼2 4,500HCO 3 mM/day 99.3%19,85015020,000Cl mM/day 99.4%24,85015025,000Na mM/day 99.2%178.5 ∼ 1.5 180H 2 O L/day % of filtered load reabsorbed Amount Reabsorbed Amount Excreted Amount Filtered Substance, units ► This “filtered then almost completely reabsorbed” scenario is certainly not the case for all solutes.

3. Some Important Renal Physiology Numbers ► Renal Blood FlowRBF1.1 L/min ► Renal Plasma FlowRPF625 ml/min RPF = RBF x (1 – hematocrit) typical hematocrit is ~0.43, so RPF is 1.1x0.57. ► Glomerular Filtration RateGFR125 ml/min ► Urine Flow Rate 1 ml/min ► Filtration FractionGFR/RPF 20% 20% of plasma entering a glomerulus is filtered. Thus, 20% of any freely-filtered solute present enters Bowman’s space. Note that values given above can vary in different circumstances. Also remember that RBF far exceeds what kidney cells need to stay alive so RBF can vary dramatically without affecting kidney cell vitality.

4. Glomerular Filtration The renal circulation traverses 2 capillary beds: glomerular & peritubular Most Capillaries in Body Fluid Filtration  Reabsorption

5. Glomerular Filtration The renal circulation traverses 2 capillary beds: glomerular & peritubular Glomerular Capillaries There is net filtration along entire length of the glomerular capillaries Most Capillaries in Body Fluid Filtration  Reabsorption

6. Glomerular Filtration The renal circulation traverses 2 capillary beds: glomerular & peritubular Most Capillaries in Body Glomerular Capillaries Point #2: Glomerular Capillaries work at higher pressure. (This is because efferent arteriole is usually smaller diameter than the afferent arteriole) Fluid Filtration  Reabsorption

7. Glomerular Filtration The renal circulation traverses 2 capillary beds: glomerular & peritubular Most Capillaries in Body Glomerular Capillaries Point #3: Hydrostatic pressure is constant in glomerular capillaries. (Most capillaries have high resistance so pressure drops. The multiple parallel loops provide very low resistance.) Fluid Filtration  Reabsorption

8. Glomerular Filtration The renal circulation traverses 2 capillary beds: glomerular & peritubular Most Capillaries in Body Glomerular Capillaries Point #4: COP (colloid oncotic pressure) increases in glomerular capillaries. (This is because a huge amount of fluid exits the blood leaving plasma proteins behind.) Hydrostatic pressure inside Bowman’s Capsule is low & constant. Fluid Filtration  Reabsorption

9. Net Filtration Pressure Summary of forces driving glomerular filtration Net Filtration Pressure (NFP) NFP = P GC – ( π GC + P BS ) where, P GC is average glomerular capillary hydrostatic pressure. π GC is average plasma oncotic pressure P BS is average hydrostatic pressure inside Bowman’s capsule Thus, NFP = 55 – (30 + 15) or 10 mm Hg GFR of course depends on this value but not just this value  GFR = Kf x NFP Filtration Coefficient: - Fluid permeability of Glom.Caps. (i.e. the size of holes in filter) - Surface area of Glom.Caps. (i.e. the numerous parallel loops in glomerulus) Main Point : Glomerular capillaries are specialized for filtration. No reabsorption of fluid occurs in the glomerular capillaries.

10. Factors that Influence GFR GFR = Kf x NFP Glomerular permeability & surface area Hydrostatic & oncotic pressures Renal Artery Stenosis Renal Artery Stenosisreduced hydrostatic pressure in glomerular capillaries (P GC ) will reduced GFR Nephritic Disease Nephritic Diseasereduced number of working nephrons, less surface area for filtration (Kf) and reduced GFR Sympathetic Stimulation Sympathetic Stimulationdecreased afferent arteriole diameter will decrease hydrostatic pressure in glomerulus (P GC ), reducing GFR. Mesangial cell contraction will decrease the available surface area for filtration and decrease GFR Starvation Starvation (or renal disease) decreased plasma protein content lowers plasma oncotic pressure ( π GC ) and this will increase GFR. Blood Pressure Blood Pressure (MAP) increased/decrease hydrostatic pressure in glomerular capillaries (P GC ) will increase/decrease GFR. Kidney Stone Kidney Stonecould increase hydrostatic pressure in Bowman’s capsule (P BS ) reducing GFR 2001 NFP = P GC – ( π GC + P BS )

11. Kidney’s Resist Changes in GFR (and RBF) Autoregulation : intrinsic property of the kidney (no nerves/hormones needed) can be over-ridden by extrinsic factors (nerves/hormones) 1.1 L/min 125 ml/min Mechanisms: 1) myogenic (relatively minor in kidneys) 2) tubuloglomerular feedback

12. Tubuloglomerular Feedback Juxtaglomerular Apparatus (JGA)

13. Macula Densa ► Macula Densa: Cells sense fluid flow in distal tubule (involving NaCl & swelling) & secrete vasoconstriction agent (probably ATP). This agent diffuses to nearby afferent arteriole influencing GFR. Note: Granular cells secrete renin which is involved in generating extra-renal angiotensin II. (renin does not contribute to renal autoregulation) Tubuloglomerular Feedback

14. Concept of Clearance (traditionally difficult to understand)  Clearance is just a way to quantify renal handling of a substance. Clearance is defined as the volume of plasma “cleared” of a substance by the kidneys per minute. ( ml/min )  Clearance of a substance is often used to evaluate renal function. First…. we will define clearance in words. Volume of Plasma Cleared Now….Let’s see how we can calculate clearance. Note: Clearance units are volume per time. Clearance is not the amount of the substance removed but instead the volume of plasma from which it was removed. ▼ Every minute- 625 ml plasma goes to the kidney (RPF) 125ml/min are filtered forming filtrate (GFR) Remaining 500ml/min remain in the blood and enter into PC

15. Concept of Clearance To calculate clearance of substance X- (C X ), first need to calculate amount of X excreted in urine per unit time. Urine volume per min (ml/min) Urine X concentration Another hand the amount of substance X in “cleared plasma” can be expressed This formula is convenient because U X, P X and V are easily measured. you will need to remember this formula Product of plasma volume per unit time Plasma X concentration amount of X excreted in urine = U X · V amount of X in cleared plasma = P X · C X (amount X in cleared plasma) P X · C X = U X · V (amount X excreted in urine) PXPX C X = U X · V

16. Now….Let’s apply this to the renal world.

17. Inulin Clearance Inulin:polysaccharide, not a naturally occurring substance in body freely filtered but not reabsorbed or secreted….so all inulin that is filtered will end up in the urine C INULIN is the “gold standard” for measuring GFR Volume filtered is volume cleared. GFR = C INULIN = U INULIN · V P INULIN V = urine produced in ml/min U INULIN = urine inulin concentration P INULIN = plasma inulin concentration The main clinical drawback here is that inulin must be continuously infused while urine is collected (this is usually a day or so).

18. PAH Clearance PAH:para-aminohippurate is also not naturally in the body robustly secreted it is freely filtered and robustly secreted….so both filtered and secreted PAH will end up in the urine C PAH is clinically used to estimate RPF RPF = C PAH = U PAH · V P PAH V = urine produced in ml/min U PAH = urine PAH concentration P PAH = plasma PAH concentration Cleared volume much larger than filtered volume. So large in fact that it “effectively” approaches RPF Recall that…. RPF = RBF x (1- 0.43) so…. RBF = C PAH 0.57 hematocrit Nearly all (90%) of the PAH in the plasma entering the kidney being excreted in the urine

19. Glucose Clearance Glucose: is freely filtered like inulin. However that no glucose appears in the urine because glucose is completely reabsorbed as it passes through tubules This means all of the glucose that comes to the kidney is saved and leaves the kidney in the plasma membrane Glucose 0 Completely reabsorbed Inulin 125 Not reabsorbed and not secreted PAH 625 Completely secreted Normal Clearance Value (ml/min)

20. Creatinine Clearance Creatinine:produced from creatine metabolism in muscle production rate usually very constant (if muscle mass constant) freely filtered and not reabsorbed …little bit is secreted (this makes it a good but imperfect substitute for inulin) C CR is clinically used to routinely access GFR “GFR” = C CR = U CR · V P CR V = urine produced in ml/min U CR = urine CR concentration P CR = plasma CR concentration There is a nice inverse relationship between P CR and “GFR” Normal P CR = 1 mg/dl P CR

21. If GFR drops by 50%, then P CR doubles ( 2 mg/dl ). Creatinine Clearance Creatinine:produced from creatine metabolism in muscle production rate usually very constant (if muscle mass constant) freely filtered and not reabsorbed …little bit is secreted (this makes it a good but imperfect substitute for inulin) C CR is clinically used to routinely access GFR “GFR” = C CR = U CR · V P CR V = urine produced in ml/min U CR = urine CR concentration P CR = plasma CR concentration There is a nice inverse relationship between P CR and “GFR” Normal P CR = 1 mg/dl 50% GFR ●Thus, a single P CR value can be used to roughly estimate GFR. (level of creatinine excreation = level creatinine balance concept production in the body - balance concept)