THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Introduction to Kidney Function in Context of Body Fluid RegulationChristian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/Fluidreg.pptx

3. Aims The students should • appreciate kidney’s role in fluid homeostasis; • understand principles and concepts behind urine production (ultrafiltration, resorption, secretion, blood flow, plasma flow, clearance); • know variables that influence urine production / fluid homeostasis; • understand principles that determine ionic concentrations in urine (filtration, resorptionand secretion); and • be able to estimate renal creatinine clearance.

4. Contents • Overall role of the kidneys • Principles of fluid homeostasis • Facts about kidneys • Ultrafiltration • Measuring renal • (glomerular) filtration rate, • plasma flow and • blood flow.

5. Concepts Covered • Water homeostasis (drinking and excretion) • Ultrafiltrate • Filtration (Starling’s law of capillary) • Clearance • Glomerular filtration rate • Renal plasma flow • Renal blood flow

6. Physiological Roles of Kidney • Excretory role: Urine production (metabolites and drugs) • Fluid homeostasis (Block 2) • Volume control (ECF): via Na+ control • Osmo-control: via water volume control • Regulation of electrolyte balance • Regulation of acid-base balance • Blood pressure control • Endocrine organ (from different cells) • Renin (see Block 2) • Calcitriol (provitaminD; Block 6) • Erythropoietin (Block 5) • Arachidonic acid (locally; tissue hormone)

7. Water Balance Sheet: In- & Output Despopoulos & Silbernagl 2003 • Daily volume turnover: about 2.5 L/d (intake and excretion). • Drinking volume: ~ 1.3 L/d; thirst to compensate H2O deficits. • In-/decreased urine output to control H2O & solute volume.

8. Facts about the Kidneys • Weight: about 150 g each; i.e. 0.2% body weight. • Blood flow rate: 1.2 L/min; i.e. ~ 20 - 25% of CO. • Best perfused organ (by a factor of ~ 4). • O2 extraction: 18 mL/min; i.e. 8% of total. • Arterio-venous O2-difference: 1.5 - 2.0 vol.-% • One of lowest in body. • High energetic/metabolic “cost” sourced from • glucose (no net usage), • fatty acids, • ketone bodies, and • other metabolites. Usage cell-type specific.

9. Ultrafiltration • Urine results from ultrafiltration. • What is “ultrafiltrated”? Plasma. • What generates filter pressure? BP, ultimately heart. • What is the nature of the filter? Subendothelialbasal membrane. • What are filter properties? • Pore radius: 29 ± 10 Å; limiting MW 69’000. • Filterable: ions, sugars, metabolites, free drugs,.... • Non-filterable: most proteins (albumin 37 Å), globulins, AND what is bound to protein (drugs).

10. Determinants of Filtration Pressure Boron & Boulpaep, 2003 • Starling’s law of the capillary. • PUFat beginning of capillary: ~20 torr. • Filtration is also dependent on renal plasma flow (RPF, which Starling’s law does not encompass…). E.H. Starling, 1866 -1927

11. Result ofUltrafiltration • Ultrafiltrate (does not contain protein) – primary urine. • Prediction of filtration only: isotonic solute (to plasma), corrected for Gibbs-Donnan equilibrium (more Cl-, less Na+, etc. - because of lack of protein). • ~20% of PLV is filtered; i.e. 80% remain in vessel. • Predicted volume per day (other estimation of these numbers towards end): • CO = 5 L/min; 25% to kidney ≈ 1.2 L/min = 1’800 L/d (blood volume). • Hkt = 0.46; ≈ 900 L/d plasma volume (PLV). • With 20% of PLV filtered = 180 L/dultrafiltrate. • ~15 xfECF / d (~12 L in 70 kg male). • Given PLV = 3 L, 60 x filtered per day ≈ once every 24’.

12. Urine • Daily amount: 0.5 - 2.0 L/d depending on food intake/perspiration/respiration/faeces. • Volume excretion classification: • Polyuria: > 2.5 L/d • Eu-uria: 0.5 - 2.0 L/d • Oliguria: < 0.4 L/d • Anuria: < 0.1 L/d • Specific density: normal 1015 - 1022 g/L reference range (RR) 1001 - 1040 g/L • Osmolality: 50 - 1300 mOsm (plasma ~285) • pH value: normal ~ 6.0 (RR 5.6 - 7.0)

13. Kidney’s Task • Requirement to resorb >99% water & salt (solute); i.e. ≤ 1% (precision!). • Filtered NaCl: 25.2 mol/d ≈ 1.5 kg/d. • Excreted via urine: 0.3 mol/d ≈ 0.016 kg/d. • How to reabsorb so much ECF? via osmosis. • Na+ MUST be transported actively. • Large energy requirement for Na+ transport. • H2O follows passively (osmosis). • Several regulatory mechanisms for fine-tuning (hormonal, neural, etc.; see Block 2). • A substance in the kidney can be • filtered: “passive” process due to filtration pressure; • secreted: cells can actively secrete substances (organic acids…); and • resorbed: re-uptake of water & solute (tubuli).

14. Concept of Clearance Quantification of Excretion “Clearance” is virtual volume of blood that would be totally cleared of substance in a given time [mL/min]. Each molecule in blood has it’s own clearance value; can be defined for Na+, K+, Cl-, Ca2+, albumin, etc.

15. Renal Clearance Boron & Boulpaep, 2003 “Clearance” (CX) is virtual volume of blood that would be totally cleared of substance in a given time.

16. Example of Creatinine Clearance • Male patient; weight: 80 kg; height: 180 cm • [Creatinine]plasma = 207 µM (62 - 132 µM) • [Creatinine]Urine = 7680 µM • Urine volume (24 h) = 1.7 L

17. Properties of Clearance Indicators • Properties of an indicator of renal clearance: • Freely filterable. • Must not be metabolised (in kidney/urinary tract). • Must not alter renal function. • In regard to GFR: Filtered amount must not change due to resorption and/or secretion. • Precision: depends on substance’s ability to remain within filtrate without resorption, etc.

18. Indicators of GFR • If a substance is filteredonly (i.e. neither resorbed, nor secreted), it indicates total renal filtration rate: glomerular filtration rate (GFR). • Such substances are: inulin, polyfructosan S, endogenous creatinine, mannitol, etc. • Clinically used every day to monitor GFR (gold standard).

19. Indicators for Renal Plasma Flow • If a substance is filtered AND secreted such that it is totally cleared from plasma (in single passage), it indicates total renal plasma flow (RPF). • Such substances are: p-aminohippuric acid (PAH), some penicillins, iodide containing x-ray contrast agents (perabrodil, diodrast). • Clinically used every day to monitor renal perfusion (RPF).

20. Renal Blood Flow • If plasma flow is known, renal blood flow (RBF) scales with haematocrit (0.46). • Special considerations: • * might not be filtrated at all (protein bound, etc.).

21. Take-Home Messages • Body water (volume and osmolarity) is controlled via drinking and water excretion (urine, sweat, faeces, breathing). • Ultrafiltration is driven by pressure differences (hydrostatic and colloid-osmotic). • Large ultrafiltrate (180 L/d) requires efficient Na+and H2O resorption via osmosis. • Clearance corresponds to virtual blood volume that is totally cleared upon kidney passage. • Substances can be filtered, resorbed or secreted resulting in differential excretion.

22. MCQ Abdullah Zak, 54 year old male, had routine assessment of kidney function and gave blood and urine for chemical analysis, which were: Plasma creatinine 710 µM; urine creatinine 4320 µM and 24 h volume 142 mL. Which of the following values best estimates his creatinine clearance? • 0.06 mL/min • 0.60 mL/min • 6.00 mL/min • 60.0 mL/min • 600 mL/min

23. That’s it folks…

24. MCQ Abdullah Zak, 54 year old male, had routine assess-mentof kidney function and gave blood and urine for chemical analysis, which were: Plasma creatinine 710 µM; urine creatinine 4320 µM and 24 h volume 142 mL. Which of the following values best estimates his creatinine clearance? • 0.06 mL/min • 0.60 mL/min • 6.00 mL/min • 60.0 mL/min • 600 mL/min