1. GLOMERULAR FILTERATION Dr.Mohammed Sharique Ahmed Quadri Assistant prof. Physiology Al Maarefa College

2. OBJECTIVES Identify three basic processes involved in urine formation; glomerular filtration, tubular reabsorption and tubular secretion Define GFR and quote normal value in men and women Describe the composition of the glomerular filtrate Detect the structural & functional peculiarities of the glomerular filtration membrane Outline the factors controlling GFR Given capillary and Bowman’s capsule hydrostatic and oncotic pressures calculate the net filtration pressure. Correlate between net filtration pressure along glomerulus and plasma flow List the characteristics that a compound must have before it can be used for measuring GFR e.g. Inulin, creatinine etc. Given the data, calculate GFR.

3. Basic Renal Processes Glomerular filtration Tubular reabsorption Tubular secretion Urine results from these three processes.

4. Glomerular filtration Is the first step in urine formation. Definition: Glomerular filtration is the transfer of fluid and solutes from the glomerular capillaries along a pressure gradient into Bowman's capsule.

5. Composition of the Glomerular Filtrate It is the fluid within the Bowman’s capsule that is essentially cell-free and protein-free and contains crystalloids in virtually the same concentrations as in the plasma. It is free from: – Blood cells – Protein – Protein-bound molecules (calcium, fatty aids, amino acids)

6. Glomerular Filtration Fluid filtered pass through three layers of the glomerular membrane – Glomerular capillary wall Single layer of endothelial cells More permeable to water and solutes than capillaries elsewhere in the body – Basement membrane Acellular gelatinous layer Composed of collagen and glycoproteins – Inner layer of Bowman’s capsule Consists of podocytes that encircle the glomerulus tuft

7. Glomerular Capillary Filtration Barrier  Endothelium (fenestrated)  Basement Membrane negatively charged, restriction site for proteins  Epithelial Cells, restriction site for proteins. Characterized by foot-like processes (podocytes).

8. Filtration Despite the three layers of the barrier, the glomerulus filters several hundred times as much water and solutes as the usual capillary membrane. Even with this high rate of filtration, the glomerular capillary membrane normally prevents filtration of plasma proteins.

9. Glomerular Capillary Membrane Filterability depends on:  Size of the molecule – the pores of the glomerular membrane are about 8 nanometers (80 angstroms)  Electrical Charge of the molecule – positively charged molecules are filtered much more easily than negatively charged molecules of equal molecular size. – the negative charges of the basement membrane and the podocytes provide an important means for restricting negatively charged molecules, including the plasma proteins. – Diameter of albumin is only about 6 nanometers, but negatively charged.

10. Clinical Significance of Proteinuria Early detection of renal disease in at-risk patients - Hypertension: Hypertensive renal disease - Diabetes: Diabetic nephropathy - Pregnancy: gestational proteinuric hypertension (pre-eclampsia) - annual “check-up”: renal disease can be silent Assessment and monitoring of known renal disease

11. Microalbuminuria Definition: urine excretion of > 25-30 but < 150mg albumin per day Causes: early diabetes, hypertension Prognostic Value: diabetic patients with microalbuminuria are 10-20 fold more likely to develop persistent proteinuria

12. Glomerular Filtration Rate (GFR) GFR: The volume of plasma filtered from both kidneys per minute. GFR = 125 ml/min = 180 liters/day Plasma volume is filtered 60 times per day GFR = Filtration Coefficient (K f ) x Net Filtration Pressure(NFP)

13. Factors Affecting GFR Filtration Coefficient (K f ) Net Filtration Pressure(NFP)

14. Filtration coefficient Filtration coefficient (K f ): A measure of the product of the hydraulic conductivity (water permeability) and filtering surface area of the capillaries. glomerular capillary filtration coefficient = 12.5 ml/min per mmHg, or 4.2 ml/min per mmHg/ 100gm (400 x greater than in tissues such a muscle)

15. Increased Glomerular Capillary Filtration Coefficient (Kf) Increases GFR Normally not highly variable K f reduces by reducing the number of functional glomerulus (decrease surface area) or by increasing the thickness BM (reducing its hydraulic conductivity). Diseases that can reduce K f and eventually GFR - Chronic hypertension - Diabetes mellitus - Glomerulonephritis

16. Forces determining Net Filtration Pressure (NFP) Three physical forces involved – Glomerular capillary blood hydrostatic pressure – Plasma-colloid osmotic osmotic pressure – Bowman’s capsule hydrostatic hydrostatic pressure

17. NET FILTRATION PRESSURE (NFP) =GBHP – CHP – BCOP = 55 mmHg 15 mmHg 30 mmHg = 10 mmHg GLOMERULAR BLOOD HYDROSTATIC PRESSURE (GBHP) = 55 mmHg Capsular space Glomerular (Bowman's) capsule Efferent arteriole Afferent arteriole 1 Proximal convoluted tubule NET FILTRATION PRESSURE (NFP) =GBHP – CHP – BCOP = 55 mmHg 15 mmHg 30 mmHg = 10 mmHg CAPSULAR HYDROSTATIC PRESSURE (CHP) = 15 mmHg GLOMERULAR BLOOD HYDROSTATIC PRESSURE (GBHP) = 55 mmHg Capsular space Glomerular (Bowman's) capsule Efferent arteriole Afferent arteriole 1 2 Proximal convoluted tubule NET FILTRATION PRESSURE (NFP) =GBHP – CHP – BCOP = 55 mmHg 15 mmHg 30 mmHg = 10 mmHg BLOOD COLLOID OSMOTIC PRESSURE (BCOP) = 30 mmHg CAPSULAR HYDROSTATIC PRESSURE (CHP) = 15 mmHg GLOMERULAR BLOOD HYDROSTATIC PRESSURE (GBHP) = 55 mmHg Capsular space Glomerular (Bowman's) capsule Efferent arteriole Afferent arteriole 1 2 3 Proximal convoluted tubule

18. Net (effective) Filtration Pressure (NFP) Definition: = NFP is an algebraic sum of opposing hydrostatic and osmotic forces acting across the capillary NFP = forces inducing filtration - forces opposing filtration NFP = ( P GC +  BC ) - ( P BC +  GC ) – P GC Glomerular hydrostatic pressure –  GC Glomerular oncotic pressure – P BC Bowman’s capsule hydrostatic pressure –  BC Bowman’s capsule oncotic pressure NB: as there is virtually no protein,  BC ~ 0, therefore NFP = P GC - (P BC +  GC ) P GC P BC  BC  GC

19. Glomerular Filtration Rate Net filtration pressure = glomerular capillary blood pressure – (plasma-colloid osmotic pressure + Bowman’s capsule hydrostatic pressure) For example: 55 mm Hg – (30 mm Hg + 15 mm Hg) = 10 mm Hg Glomerular filtration rate (GFR) – Depends on Net filtration pressure How much glomerular surface area is available for penetration How permeable the glomerular membrane is

20. Unregulated influences on the GFR Increased Bowman’s Capsule Hydrostatic Pressure (P Bc ) Decreases GFR Do not serve as physiological regulator of GFR Increase of P Bc can be caused by Tubular Obstruction kidney stones tubular necrosis Urinary tract obstruction Prostatic enlargement

21. Unregulated influences on the GFR plasma colloid osmotic pressure Do not serve as physiological regulator of GFR Plasma-colloid osmotic pressure Severely burned patient ↑ GFR Dehydrating diarrhea ↓ GFR

22. Glomerular Filtration Rate Controlled adjustments in GFR – Glomerular capillary hdrostatic pressure can be controlled to adjust GFR to suit the body’s needs – Two major control mechanisms Extrinsic sympathetic control -by adjusting the constriction of afferent/efferent arterioles – Mediated by sympathetic nervous system input to afferent arterioles – Baroreceptor reflex Autoregulation (aimed at preventing spontaneous changes in GFR) – Myogenic mechanism – Tubuloglomerular feedback (TGF)

23. Adjustments of Afferent Arteriole Caliber to Alter The GFR

25. Baroreceptor Reflex Influence on the GFR

26. GFR = Filtration Coefficient (Kf ) x Net Filtration Pressure (NFP) GFR = 12.5 x 10 = 125 ml/min = 180 liters/day GFR in females is less (110 ml/min) Plasma volume is filtered 60 times per day Calculation of Glomerular Filtration Rate (GFR)

27. Autoregulation Myogenic autoregulation Tubuloglomerular feedback The major function of autoregulation in the kidneys is to maintain a relatively constant GFR and renal blood flow despite considerable arterial pressure fluctuations that can occur. Autoregulation:

28. Myogenic Mechanism Stretch of Blood Vessel Cell Ca ++ Permeability Arterial Pressure Intracell. Ca ++ Blood Flow Vascular Resistance Vascular smooth muscle contraction in response to increased stretch

29. Macula Densa Feedback ( Tubuloglomerular feedback) GFR Distal NaCl Delivery Macula Densa NaCl Reabsorption Afferent Arteriolar Resistance GFR (return toward normal) (macula densa feedback)

30. Macula Densa feedback mechanism for GFR autoregulation

31. What is a Glomerular Filtration Fraction? The Filtration Fraction (FF) is the ratio of the GFR to the renal plasma flow (GFR/TRPF). Renal blood flow = 1.1 L/min 20-25% of total cardiac output (5 L/min). Of the 625 ml of plasma enters the glomeruli via the afferent, 125 (the GFR) filters in the Bowman’s capsule, the remaining passing via efferent arterioles into the peritubular capillaries Filtration fraction = (GFR/TRPF) = 0.2 So, GFR is About 20% of the Renal Plasma Flow

32. The filtration fraction The Filtration Fraction (FF) is the ratio of the GFR to the renal plasma flow = (GFR/TRPF).

33. References Human physiology by Lauralee Sherwood, seventh edition Text book physiology by Guyton &Hall,11 th edition Text book of physiology by Linda.s contanzo,third edition