Glomerular Filtration: Hemodynamics
Frederick Kaskel, MD, PhDProfessor & Vice Chairman of PediatricsDirector, Division of Pediatric Nephrology
Children’s Hospital at MontefioreAlbert Einstein College of Medicine
Kidneys: They Make Urine, Don’t They?
How much urine per day? How much filtrate per day?
Normal Parameters in Adult Humans
• Cardiac Output: 4,500 - 6,000 ml/min
• Renal Blood Flow: 900 - 1,500 ml/min• Renal Plasma Flow : 540 - 900 ml/min• GFR: 100 - 125 ml/min• Urine Flow Rate: 1 - 2 ml/min Urine flow rate is determined largely by the rate of
reabsorption of the filtered load, GFR is autoregulated and remains constant, even with variations in renal plasma flow rate and/or cardiac output
If 98-99% of filtrate is reabsorbed anyway, why filter so much? Considering the amount of energy (ATP) expended to reabsorb the filtered sodium etc., this seems to be a hugely inefficient system.
Major Functions of the Kidney• Glomerular ultrafiltrate consists of water and small solutes;
normally, it is essentially protein-free.
• 98-99% of filtered water, sodium chloride and sodium bicarbonate are reabsorbed by the tubules
• Regulated reabsorption of water and solutes allows for regulation of extracelluar fluid volume, osmolality, acid-base balance, and homeostasis of whole body phosphate, calcium and potassium balance.
• Other solutes, for example urea, creatinine, are freely filtered but not reabsorbed. Filtration of solutes that are not reabsorbed serves as an effective mechanism for their excretion.
Nephron Structure
Glomerular Function
Formation of a cell- and protein-free plasma filtrate (ultrafiltrate) at a rapid and near-constant rate of 100-125 ml/min. (150-180 L/day)
Arteriogram of a Postmortem Human Kidney
Renal Cortical Circulation
Renal Blood and Plasma Flow Rates
• Renal blood flow represents approximately 20 % of total cardiac output (0.8 - 1 L/min).
• Given a red cell mass of about 40% in blood, renal plasma flow rate = 0.5 - 0.6 L/min.
• The filtration fraction generally measures 20-25 %, hence the normal glomerular filtration rate (GFR) = 125 - 150 ml/min.
Glomerular Capillaries are located between two Arterioles
• Hydrostatic (hydraulic) pressure gradient
B. What Opposes Movement of Water and Solutes Across the Capillary Wall?
• Structure of the capillary wall itself (permeability)• Plasma Protein Concentration (Oncotic Pressure)
A. What Forces Cause Movement of Water and Solutes Across the Capillary Wall?
Key Parameters Governing Glomerular Filtration
• Physical Parameters of the Capillary Wall (Kf)– Hydraulic Conductivity– Surface Area
• Filtration Governed by Starling Forces– Hydraulic Pressure Gradients– Oncotic Pressure Gradients– Filtration Pressure Equilibrium
• Filtration is Dependent on Plasma Flow Rate• Filtration is Dynamically Regulated
– Glomerular Capillaries lie between Resistance Vessels– Neural and Hormonal Control over Afferent and Efferent
Resistances– Tubuloglomerular Feedback
• Permselectivity
Determinants of Glomerular Filtration
Jv = k • S ( P - r a )= k • S [(PGc - Pt)-(PGc - P t)]
Jv = Flux
k = Hydraulic conductivity P = Hydraulic PressureS = Surface Area = Oncotic Pressure
Gc = Glomerular Capillary t = Tubule = Gradient
Hydraulic Conductivity
• Hydraulic conductivity is defined as the flux of water (and small solutes) per unit time for a defined pressure gradient and surface area
• The hydraulic conductivity of the glomerular capillary wall is 40 - 50 fold higher than other capillaries.
High Hydraulic Conductivity of the Glomerular Capillary Wall
Glomerular Structure:
AA: Afferent ArterioleGC: Juxtaglomerular cellsM: Mesangial CellsPO: PodocytesE: Endothelial CellsGBM: Glomerular Basement MembraneUS: Urinary SpacePE: Parietal Epithelial
CellsEGM: Extraglomerular MesangiumEA: Efferent ArterioleMD: Macula DensaP: Proximal Tubule Cell
Copyright ©2008 American Physiological Society
Haraldsson, B. et al. Physiol. Rev. 88: 451-487 2008;doi:10.1152/physrev.00055.2006
FIG. 1. Schematic drawing of the glomerular barrier
Copyright ©2008 American Physiological Society
Haraldsson, B. et al. Physiol. Rev. 88: 451-487 2008;doi:10.1152/physrev.00055.2006
FIG. 2. Scanning electron micrograph showing a mouse glomerulus (A) with several capillary loops, capillary lumen, and podocytes with their foot processes
Surface Area
• Human glomeruli measure, on average, 200 µm in diameter.
• The surface area of single glomeruli has been estimated at 0.15 mm2
• Estimated glomerular number: ~ 2 X 106 • Total glomerular capillary surface area in
humans: ~ 0.3 m2.
Angiotensin II Effect: Reduced Filtration Surface Area
Ultrafiltration Coefficient
• The glomerular ultrafiltration coefficient (Kf) is the product of the hydraulic conductivity and the glomerular capillary surface area.
• Micropuncture techniques allow measurement of glomerular capillary pressure, glomerular capillary plasma flow rate and oncotic pressure. Kf is calculated.
Key Parameters Governing Glomerular Filtration
• Physical Parameters of the Capillary Wall (Kf)– Hydraulic Conductivity– Surface Area
• Filtration Governed by Starling Forces– Hydraulic Pressure Gradients– Oncotic Pressure Gradients– Filtration Pressure Equilibrium
• Filtration is Dependent on Plasma Flow Rate• Filtration is Dynamically Regulated
– Glomerular Capillaries lie between Resistance Vessels– Myogenic, Neural and Hormonal regulation of Afferent
and Efferent Resistances– Tubuloglomerular Feedback regulates Afferent
Arteriolar Diameter and Resistance.
Glomerular Micropuncture
Glomerular Micropuncture: Measured and Calculated Parameters
• Measured:– Renal Perfusion Pressure– Efferent Arteriolar Hydraulic Pressure– Inulin Clearance (SNGFR)– Glomerular Capillary Pressure (PGC)– Proximal Tubule Hydraulic Pressure (PT)– Afferent Total Protein Concentration– Efferent Total Protein Concentration
• Calculated Parameter:– Glomerular Capillary Ultrafiltration Coefficient (Kf)
Direct Measurement of Glomerular Capillary Pressure
From: Brenner et al. J. Clin. Invest. 50: 1776, 1971
Hydraulic Pressure Profile in the Renal Vasculature
Relationship between plasma protein concentration and oncotic pressure
The effective ultrafiltration pressure (PUF) changes along the length
of the glomerular capillary
Filtration Pressure Equilibrium
Influence of Glomerular Hemodynamics on Peritubular Starling Forces
Profile of ∆π with low (A) and high (B) plasma flow rate
Filtration Pressure Equilibrium
Filtration Pressure Disequilibrium
Impact of changes in the determinants of GFR
Solid: “Hydropenia”, Dashed: “Euvolemia”
GFR is Regulated Moment-to-Moment
• Where would you put sensor(s) – Hydraulic Pressure – GFR
• Where would you put control elements– To regulate intracapillary hydraulic pressure plasma
flow rate, and hence GFR– To regulate filtration surface area– To regulate permeability
Nephron Structure
Key Parameters Governing Glomerular Filtration
• Physical Parameters of the Capillary Wall (Kf)– Hydraulic Conductivity– Surface Area
• Filtration Governed by Starling Forces– Hydraulic Pressure Gradients– Oncotic Pressure Gradients– Filtration Pressure Equilibrium
• Filtration is Dependent on Plasma Flow Rate• Filtration is Dynamically Regulated
– Glomerular Capillaries lie between Resistance Vessels– Myogenic, Neural and Hormonal regulation of Afferent
and Efferent Resistances– Tubuloglomerular Feedback regulates Afferent Arteriolar
Diameter and Resistance.
Angiotensin II Infusion: Effect on Glomerular
Hemodynamics
From: Edwards Am. J. Physiol. 244: F526, 1983.
Angiotensin II differentially constricts pre- and post-glomerular arterioles
Autoregulation of GFR is dependent on Angiotensin II
Carotid Sinus Pressure (CSP) Regulates
Renal Nerve Activity (RSNA)
From: Kawada et al: Am. J. Physiol. H1581, 2001.
Dynamic Regulation of Glomerular Hemodynamics
• Differential regulation of efferent and afferent glomerular arteriolar resistances is required for maintaining stability of GFR.
Vasoconstrictors: Angiotensin II Endothelin I Sympathetic Nerve Activity Thromboxane A2 Adenosine
Vasodilators: Nitric Oxide Prostaglandin E2 Prostacylin Atrial Natriuretic Peptide
Key Parameters Governing Glomerular Filtration
• Physical Parameters of the Capillary Wall (Kf)– Hydraulic Conductivity– Surface Area
• Filtration Governed by Starling Forces– Hydraulic Pressure Gradients– Oncotic Pressure Gradients– Filtration Pressure Equilibrium
• Filtration is Dependent on Plasma Flow Rate• Filtration is Dynamically Regulated
– Glomerular Capillaries lie between Resistance Vessels– Myogenic, Neural and Hormonal regulation of Afferent
and Efferent Resistances– Tubuloglomerular Feedback regulates Afferent Arteriolar
Diameter and Resistance.
TGF: The Concept of Tubuloglomerular Feedback
• Changes in tubule fluid flow rate, and NaCl delivery to the ascending limb of Henle regulate SNGFR
• This phenomenon is termed “Tubuloglomerular Feedback” • TG feedback depends on Macula Densa salt transport; it is
inhibited by furosemide and other inhibitors of the NaK2Cl transporter (This is the sensor of GFR)
• The TG feedback response is mediated by variations in afferent arteriolar resistance
• The nature of the TG feedback signal was not clear until recently.
Macula Densa
Tubuloglomerular Feedback Micropuncture Technique
The Tubuloglomerular Feedback Response (Stop-flow Pressure)
Perfusion of the macula densa at 10 vs 35 nl/min produces an abrupt decline in glomerular capillary pressure (stop-flow pressure).
Tubuloglomerular Feedback (TGF)Regulates GFR Through Afferent Arteriolar Vasoconstriction
Adenosine As the Mediator of Tubuloglomerular Feedback
Macula Densa nNOS
From Wilcox et al PNAS 89: 11993, 1992
Macula Densa NO modulates afferent arteriolar tone
Regulation of GFR by Tubuloglomerular Feedback
• TG-Feedback reduces the filtered load when macula densa NaCl delivery is excessive (sudden increase in perfusion pressure)
• Adenosine, produced from ATP by NaK ATPase, is the principal mediator of TG-feedback
• Adenosine selectively constricts afferent glomerular arterioles, resulting in a reduction of PGC, QA and SNGFR.
• Macula densa cells produce NO (from nNOS) and prostaglandin E2 (from COX 2), both vasodilators that offset the vasoconstrictor effect of adenosine.
• Inhibitors of the COX 2 or nNOS enzymes produce exaggerated TG-feedback responses.
Hydrostatic mechanisms
Treating systemic hypertension
- all agents
Reducing efferent arteriolar tone
- ACEI, ARB
Summary - part 1
• The nephron is the functional unit of the kidney• Excretion of substances is achieved by formation of a
large volume of ultrafiltrate, followed by selective reabsorption in the tubule
• Hydraulic pressure gradient and Renal Plasma Flow are major determinants of GFR
• Autoregulation of GFR protects against excessive loss of fluid and solutes
• Differential regulation of afferent and efferent arterioles is required to auto-regulate GFR
Summary- part 2
• Blood supply to the glomerulus is in series with peritubular capillaries. Tubulo-glomerular balance links proximal tubular reabsorption to GFR
• Tubulo-glomerular feedback (TGF) links tubular flow and NaCl delivery to PFR and glomerular hydraulic pressure
• TGF is dependent on NaCl uptake in macula densa cells, and adenosine acting on the afferent arteriole
• TGF is modulated by NO and prostaglandins
