Glomerular Filtration: Hemodynamics

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Glomerular Filtration Hemodynamics

• Frederick Kaskel, MD, PhD
• Professor Vice Chairman of Pediatrics
• Director, Division of Pediatric Nephrology
• Childrens Hospital at Montefiore
• Albert Einstein College of Medicine

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Kidneys They Make Urine, Dont They?

• How much urine per day? How much filtrate per
  day?

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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

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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.
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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.

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Nephron Structure
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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)

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Arteriogram of a Postmortem Human Kidney
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Renal Cortical Circulation
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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.

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Glomerular Capillaries are located between two
Arterioles
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• Hydrostatic (hydraulic) pressure gradient

• Structure of the capillary wall itself
  (permeability)
• Plasma Protein Concentration (Oncotic Pressure)

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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

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Determinants of Glomerular Filtration
Jv k S (?P - ?p) k S (PGc - Pt)-(?Gc
- ?t)
Jv Flux k Hydraulic conductivity P
Hydraulic Pressure S Surface Area p
Oncotic Pressure
t Tubule Gc Glomerular
Capillary ? Gradient
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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.

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High Hydraulic Conductivity of the Glomerular
Capillary Wall
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Glomerular Structure
AA Afferent Arteriole GC Juxtaglomerular
cells M Mesangial Cells PO Podocytes E
Endothelial Cells GBM Glomerular Basement
Membrane US Urinary Space PE Parietal
Epithelial Cells EGM Extraglomerular
Mesangium EA Efferent Arteriole MD Macula
Densa P Proximal Tubule Cell
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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.

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Angiotensin II Effect Reduced Filtration
Surface Area
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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.

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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.

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Glomerular Micropuncture
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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)

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Direct Measurement of Glomerular Capillary
Pressure
From Brenner et al. J. Clin. Invest. 50 1776,
1971
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Hydraulic Pressure Profile in the Renal
Vasculature
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Relationship between plasma protein concentration
and oncotic pressure
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The effective ultrafiltration pressure (PUF)
changes along the length of the glomerular
capillary
Filtration Pressure Equilibrium
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Influence of Glomerular Hemodynamics on
Peritubular Starling Forces
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Profile of Dp with low (A) and high (B) plasma
flow rate
Filtration Pressure Equilibrium
Filtration Pressure Disequilibrium
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Impact of changes in the determinants of GFR
Solid Hydropenia, Dashed Euvolemia
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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

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Nephron Structure
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Angiotensin II Infusion Effect on Glomerular
Hemodynamics
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Angiotensin II differentially constricts pre-
and post-glomerular arterioles
From Edwards Am. J. Physiol. 244 F526, 1983.
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Autoregulation of GFR is dependent on
Angiotensin II
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Carotid Sinus Pressure (CSP) Regulates Renal
Nerve Activity (RSNA)
From Kawada et al Am. J. Physiol. H1581,
2001.
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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
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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.

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Macula Densa
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Tubuloglomerular Feedback Micropuncture Technique
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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).
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Tubuloglomerular Feedback (TGF)Regulates GFR
Through Afferent Arteriolar Vasoconstriction
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Adenosine As the Mediator of Tubuloglomerular
Feedback
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Macula Densa nNOS
From Wilcox et al PNAS 89 11993, 1992
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Macula Densa NO modulates afferent arteriolar
tone
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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.

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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

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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