Understanding Urine Formation by the Kidneys - Dr. Yanal A. Shafagoj

1. Urine Formation by the Kidneys: I. Glomerular Filtration, Renal Blood Flow and Their Control Yanal A Shafagoj. MD, PhD

2. Body fluid regulation.

3. Summary of Kidney Functions • Excretion of metabolic waste products • urea,creatinine, bilirubin, hydrogen • Excretion of foreign chemicals:drugs, toxins, • pesticides, food additives • Secretion, metabolism, and excretion of hormones • - renal erythropoetic factor (erythropoietin) • - 1,25 dihydroxycholecalciferol (Vitamin D) • - renin • Hormones metabolized and excreted by the kidney • - Most peptide hormones (e.g. insulin, angiotensin II, etc • Regulation of acid-base balance • Gluconeogenesis: glucose synthesis from amino acids • Control of arterial pressure • Regulation of water & electrolyte excretion

4. Excretion of Metabolic Waste Products • Urea (from protein metabolism) • Uric acid (from nucleic acid metabolism) • Creatinine (from muscle metabolism) • Bilirubin (from hemoglobin metabolism)

5. Excretion of Foreign Chemicals • Pesticides • Food additives • Toxins • Drugs

6. Regulation of Erythrocyte Production Erythropoetin O2 Delivery Kidney Erythrocyte Production in Bone Marrow

7. Regulation of Vitamin D Activity • Kidney produces active form of vitamin D (1,25 dihydroxy vitamin D3 ) • Vitamin D3 is important in calcium and phosphate metabolism

8. Regulation of Acid-Base Balance • Excrete acids (kidneys are the only means of excreting non-volatile acids) • Regulate body fluid buffers (e.g. Bicarbonate)

9. Glucose Synthesis Gluconeogenesis: kidneys synthesize glucose from precursors (e.g., amino acids) during prolonged fasting

10. Regulation of Arterial Pressure Endocrine Organ • renin-angiotensin system • prostaglandins • kallikrein-kinin system Control of Extracellular Fluid Volume

11. Regulation of Water and Electrolyte Balances • Sodium and Water • Potassium • Hydrogen Ions • Calcium, Phosphate, Magnesium

12. Effect of increasing sodium intake 10-fold on urinary sodium excretion and extracellular fluid volume

13. Organs of the urinary system University of Jordan University of Jordan 13

14. Internal anatomy of the kidneys 14 University of Jordan University of Jordan

15. Blood supply of the kidneys 15 University of Jordan University of Jordan

16. The kidney weighs 113-170 gm. • Renal artery arises as the fifth branch of the abdominal aorta. The renal artery arises from the aorta at the level of the second lumber vertebra. Because the aorta is to the left of the midline, the right renal artery is longer. The inferior vena cava lies to the right midline making the left renal vein two times longer than the right renal vein. For this reason it is better to take the donor left kidney (short artery, long vein) & place it in the right pelvis of the recipient. Multiple arteries & veins can supply the kidney.

17. Nephron Tubular Segments

18. Cortical and juxtamedullary nephrons

19. Basic Mechanisms of Urine Formation

20. Renal tubule and collecting duct Renal tubule and collecting duct. Epithelium to modify the ultrafiltrate Renal tubule and collecting duct Renal corpuscle Renal corpuscle Renal corpuscle Ultrafiltration \device Afferent arteriole Afferent arteriole Afferent arteriole Glomerular capsule Glomerular capsule Glomerular capsule Urine (contains excreted substances) Urine (contains excreted substances) Urine (contains excreted substances) Fluid in renal tubule Fluid in renal tubule Fluid in renal tubule 1 1 1 Filtration from blood plasma into nephron Filtration from blood plasma into nephron Filtration from blood plasma into nephron 2 2 3 Tubular reabsorption from fluid into blood Tubular reabsorption from fluid into blood Tubular secretion from blood into fluid Efferent arteriole Efferent arteriole Efferent arteriole Blood (contains reabsorbed substances) Blood (contains reabsorbed substances) Blood (contains reabsorbed substances) Peritubular capillaries Peritubular capillaries Peritubular capillaries Structures and functions of a nephron 20 20 University of Jordan University of Jordan

21. Excretion = Filtration - Reabsorption + Secretion Filtration : somewhat variable, not selective (except for proteins), averages 20% of renal plasma flow Reabsorption : highly variable and selective most electrolytes (e.g. Na+, K+, Cl-) and nutritional substances (e.g. glucose) are almost completely reabsorbed; most waste products (e.g. urea) poorly reabsorbed Secretion : highlyvariable; important for rapidly excreting some waste products (e.g. H+and K+), foreign substances (including drugs), and toxins

22. Renal Handling of Different Substances

23. Renal Handling of Water and Solutes Filtration Reabsorption Excretion Water 180 178.5 (liters/day) 1.5 Sodium 25,560 25,410 (mmol/day) 150 0 Glucose180 180 (gm/day) 0 Creatinine 1.8 1.8 (gm/day)

24. Glomerular Filtration GFR = 125 ml/min = 180 liters/day • Plasma volume is filtered 60 times per day • Glomerular filtrate composition is about the same as plasma, except for large proteins • Filtration fraction (GFR / Renal Plasma Flow) = 0.2 (i.e. 20% of plasma is filtered)

25. Glomerular capillary filtration barrier

26. Effects of size and electrical charge of dextran on filterability by glomerular capillaries.

27. Determinants of GlomerularFiltration Rate

28. Determinants of Glomerular Filtration Rate Normal Values: GFR = 125 ml/min Net Filt. Press = 10 mmHg Kf = 12.5 ml/min per mmHg, or 4.2 ml/min per mmHg/ 100gm (400 x greater than in many tissues)

29. Glomerular Capillary Filtration Coefficient (Kf) • Kf = hydraulic conductivity x surface area. Cannot b measured directly • Normally is not highly variable. 400 times as high as Kf of other tissues • Disease that can reduce Kf and GFR - chronic hypertension - obesity / diabetes mellitus increases the thickness of the basement membrane - glomerulonephritis

30. Bowman’s Capsule hydrostatic Pressure (PB) • Normally changes as a function of GFR, not a physiological regulator of GFR • Tubular Obstruction kidney stones tubular necrosis • Urinary tract obstruction Prostate hypertrophy/cancer

31. Factors Influencing Glomerular Capillary Oncotic Pressure ( G) • Filtration Fraction (FF) FF G • Arterial Plasma Oncotic Pressure (A) A G FF = GFR / Renal plasma flow = 125 / 650 ~ 0.2 (or 20%)

32. Increase in colloid osmotic pressure in plasma flowing through glomerular capillary

33. Net Filtration Pressure Decreases Along the Glomerulus Because of Increasing Glomerular Colloid Osmotic Pressure Net Filtration Pressure 14 PG = 60 G = 36 PG = 60 G = 28 G =32 6 PB = 18

34. Factors Influencing Glomerular Capillary Oncotic Pressure ( G) • Plasma Protein Concentration Arterial Plasma Oncotic Pressure (A) A G • Filtration Fraction (FF) FF G FF= GFR / Renal plasma flow

35. Measuring GFR • Clearance Measurement of GFR = Cinulin Inulin is a starch-like polymer of fructose (MW 5000).

37. Measuring GFR • Ccreatinine Cockcroftand Gault formula: eCcr Estimated creatinine clearance = (140–agein yr) x weight (kg) x 0.85 (if female)] divided by serum creatinineconcentration (mg/dl)X 72. In my case (140-54=86) X 82/(72) = 97 ml/min/1.73 mm2 According to Schwartz Formula in Children GFR (mL/min/1.73 m2) = k * Height (cm) / Serum Creatinine (mg/dl) k = 0.33 in premature Infants k = 0.45 in Term infants to 1 year old k = 0.55 in Children to 13 years k = 0.65 in Adolescent male

38. Glomerular Hydrostatic Pressure (PG) • Is the determinant of GFR snd is subject to physiological control • Factors that influence PG - arterial pressure (effect is buffered by autoregulation) - afferent arteriolar resistance - efferent arteriolar resistance

39. Kidney disease 150 200 50 100 Autoregulation of Glomerular Hydrostatic Pressure 80 Normal kidney Glomerular Hydrostatic Pressure (mmHg) 60 40 20 0 Arterial Pressure (mmHg)

40. Autoregulation of renal blood flow and GFR but not urine flow

41. Effect of afferent and efferent arteriolar constriction on glomerular pressure Ra Re PG PG Blood Flow Blood Flow GFR GFR Ra GFR + Renal Blood Flow Re GFR + Renal Blood Flow

42. Effect of changes in afferent arteriolaror efferent arteriolar resistance. Biphasic Effect

43. + PG G determined by : FF = GFR / RPF RBF G _ GFR RE

44. Summary of Determinants of GFR Kf GFR Renal Disease, DM,HP PB GFR Renal stones G GFR Decrease RBF A G FF G PG GFR RA PG RE PG GFR GFR GFR (as long as RE < 3-4 x normal)

45. Determinants of Renal Blood Flow (RBF) RBF = P / R P = difference between renal artery pressure and renal vein pressure = 100-4 mmHg R = total renal vascular resistance = Ra + Re + Rv = sum of all resistances in kidney vasculature

46. Table 26-3. Approximate Pressure and Vascular Resistances in the Circulation of Normal Kidney Afferent + efferent contribute to about 70% of the intrarenal vascular resistance (mainly efferent).

47. Renal blood flow • High blood flow 1100 ml/min (~22 % of cardiac output) • High blood flow needed for high GFR • Oxygen and nutrients delivered to kidneys normally greatly exceeds their metabolic needs • A large fraction of renal oxygen consumption is related to renal tubular sodium reabsorption

48. Blood flow in kidneys and other organs

49. Measurement of RPF: CPAH underestimate the RPF. The CPAH is the effective RPF. The true RPF is 10% higher. 10% of RBF goes to the medulla, hilum, pelvis etc. p-aminohippuric acid PAH is an exogenous organic anion and not produced in our body. Freely filtered, not reabsorbed, completely secreted. In the kidney it is not metabolized, accumulated, or produced. Tm = 80 mg/min Extraction ratio of PAH