glomerular filtration

week 4 ctb

urine formation

• nephron= functional unit of kidney

• 3 main processes performed by nephron:

  1. filtration

  2. reabsorption

  3. secretion

• urinary excretion of any substance reflects sum of these processes

renal handling of substances

• different substances handled in different ways by the kidney

• processes can be altered according to needs of body to either lose or retain a substance

• filtration is first step in process of urine formation

• high rate of filtration needed to help clear substances from plasma efficiently

renal blood flow (RBF)

• filtration requires good blood flow to kidney

• kidneys receive 22% cardiac output (5l/min)

• renal blood flow= 1100ml/min (haematocrti ~0.4)

• renal plasma flow= 660ml/min

• 20% of renal plasma flow passes through filtration barrier to form filtrate

• filtration fraction= CFR/RBF= 132ml/min

• ~180l/day of filtrate formed

renal corpuscle

• renal corpuscle made up of glomerulus (glomerular capillaries) and Bowman’s capsule

• arteriole at either end of glomerular capillary bed: facilitates high pressure in glomerulus for filtration

• filters blood to form an initial ultrafiltrate

• ultrafiltrate in Bowman’s capsule identical to plasma except it lacks plasma proteins and cellular components of blood

filtration barrier

• glomerular filtration barrier formed from:

  1. glomerular capillary endothelium (fenestrated)

  2. basement membrane (-ve charge)

  3. epithelial cells (podocytes) (interdigitating foot processes and filtration slits)

fenestrated endothelium

• glomerular capillary endotheliu, is fenestrated

• pores 70-100nM in diameter

• water, solutes and plasma proteins can pass through pores

• too small to allow cells and platelets through

basement membrane

• similar but much thicker than other basement membranes (multi layered)

• negatively charged

  • type IV collagen, laminin, fibronectin, entactin, other negatively charged glycoproteins

• doesn’t permit filtration of plasma proteins

specialised epithelium

• specialised epithelial cells called podocytes

• primary processes wrap around the glomerular capillaries strengthen them against high pressures

• secondary foot processes interdigitate to form filtration slits

• foot processes are bound to basement membrane via nephrin to form a slit diaphragm

regulating filtration

• limits passage of substances based on their size, charge and shape

• blood cells and most plasma proteins (including substances bound to them) are excluded from filtrate

• filtrate has an almost identical composition to plasma

• disease processes may alter the properties of the barrier allowing protein to appear in the filtrate (proteinuria)

factors determining filtration

• GFR= volume of filtrate formed by all the nephrons in both kidneys per unit time

• determined by:

  1. glomerular capillary filtration coefficient (Kf)

  2. net filtration pressure (NFP)

GFR= Kf x NFP

filtration coefficient (Kf)

• glomerular capillaru filtration coefficient, Kf reflects the:

  1. surface area available for filtration

  2. hydraulic conductivity (permeability) of the filtration barrier per unit area

• changes in Kf aren’t the major part of the physiological regulation of GFR but may be affected in disease processes

• eg reduced number of nephrons or processes which damage the filtration barrier will decrease SA or permeability, therefore decreasing GFR

net filtration pressure (NFP)

• net filtration pressure is given by the sum of the pressures acting across the filtration barrier (Starling forces)

1. hydrostatic pressures (favours filtration: forces pushing water and other solutes out of the compartment they're in)

   • P_G: glomerular (pushing plasma out of capillaries and into Bowman’s capsule)

   • P_B: Bowman’s capsule (pushes filtrate 

2. colloid osmotic (oncotic) pressures (opposing filtration: forces holding water/solutes in the compartment they’re in)

   • π_G: glomerular

   • π_B:Bowman’s capsule

typical NFP

• oppose filtration:

  • Pb

  • Pig

• favour filtration:

  • Pg

  • Pib

• NFP= P_G - P_B - π_G + π_B

typical NFP diagram 

NFP= 45-10-19+0

regulation of GFR

• most physiological regulation of GFR occurs due to changes in glomerular hydrostatic pressure (P_G)

• P_G depends on:

  • systemic arterial pressure

  • afferent arteriole resistance

  • efferent arteriole resistance

• can vary P_G by varying resistance of afferent and efferent arterioles

leaky hose analogy

• can vary P_G by varying resistance of afferent and efferent arterioles

• balance of AA and EA resistances help determine GFR

increasing GFR via P_G

• EA constriction increases GFR

• AA dilation increases GFR

decreasing GFR via P_G

• AA constriction decreases GFR

• EA dilation decreases GFR

balancing GFR

• AA dilation and EA constriction increases GFR

• AA constriction and EA dilation decreases GFR

humoral modulators of GFR

• presenc/absence of vasoactive substances all have an effect on P_G and therefore GFR

• e.g:

  • angiotensin II preferentially constricts EA: therefore increasing P_G

  • prostaglandins and artial natriuretic peptide (ANP) vasodilate AA: therefore increasing P_G

  • noradrenaline, adrenosine and endothelin vasoconstrict AA: therefore reducing P_G

autoregulation of GFR

• renal blood flow and GFR stays relatively constant across a range of systemic blood pressures (80-180 mmHg)

• prevents large fluctuations in renal excretion of water and soluted

2 main mechanisms of autoregulation

1. myogenic response

2. tubuloglomerular feedback

myogenic autoregulation

inherent ability of smooth muscle in afferent arterioles to respond to changed in vessel diameter by contracting/relaxing

1. increase in arterial BP

2. increased RBF and GFR

3. increased stretch of AA SMCs

4. opens Ca2+ channels

5. reflex contraction of AA smooth muscle

6. vasoconstriction of AA

7. increased resistance to flow

8. decreased RBD and decreased GFR

9. restoration of RBF and GFR to normal levels

tubuloglomerular feedback (TGF)

• tubuloglomerular feedback mechanism links changes in NaCl in tubule lumen to constrol of own AA resistance in same nephron

• utilises juxtaglomerular apparatus 

juxtaglomerular apparatus

• macula densa cells in early part of distal tubule sense (NaCl)

• when arterial BP id increased, it causes increased GFR which increases flow and NaCl delivered to distal tubule

• when arterial BP is reduced, it causes decreased GFR which decreases flow and NaCl delivered to distal tubule

TGF mechanism increases BP

• Na+ and Cl- in filtered load sensed by NKCC2 transporter on macula densa cell membranes

• paracrine mediator (adenosine) released by macula densa cells

• AA vasoconstriction results in increased resistance and decreased P_G

• net result = decreased P_G and restoration of GFR

TGF mechanism decreases BP

• decreased release of paracrine factor from macula densa leads to AA dilation and decreased resistance

• angiotensin II preferentially constricts EE

• net result = increased P_G and GFR

indicators of renal decline

• urinanalyses and plasma analysis

  • indicated proteinuria/albuminuria

  • haematuria

• indicate function

  • calcium/phosphate homeostasis

  • electrolytes/pH

  • fluid balance/urine vol

  • haemoglobin

• indicates function

  • GFR/estimated GFR

  • serum creatinine/urea

measuring renal function (GFR)

• GFR= vol of filtrate formed by all the nephrons in both kidneys per unit time

• GFR is directly related to function of nephrons

• declines in all forms of progressive kidney diseases

• GFR= usually accepted as best overall index of kidney

• linked to SA of body: typical young male GFR= 120 ml/min

• GFR is linked to age, sex and body size: declines with increasing age

routine measures of GFR

• if something that is normally entirely filtered by the kidney builds up in the blood it indicates decreased GFR and therefore decreased renal function

• measurement using exogenous markers is more accurate but can be time-consuming and expensive (eg insulin infusion)

• measurement via endogenous markers more cost effective and used routinely in clinical practice

3 tests used routinely to assess renal function

1. serum urea

2. serum creatinine

3. estimated GFR (eGFR)

they all use a single serum (blood) measurement and are therefore more convenient for the routine assessment and monitoring of renal function

serum creatinine

• serum creatinine more accurately reflects GFR than urea

• creatinine is formed from breakdown of creatine (skeletal muscle component)

• usually produced at a steady rate for a given individual and is cleared from body fluid almost entirely by glomerular filtration

• eGFR is relatively inaccurate as a point measure of GFR though useful for monitoring trends

• inaccuracies result from way its production varies between individuals and relates to muscle mass

• remains a useful clinical tool for monitoring trends in kidney function

estimated GFR (eGFR)

• eGFR uses equations to calculate GFR based on a single serum measurement of a substance

• incorporates simple clinical information along with single serum measurement to generate an eGFR

• most use serum creatinine, age and sex to calculat

• normal eGFR= >90ml/min

• new tests use serum cystatin C (eGFR_cystatinC)

limitations of eGFR

• no part of CKD-EPI equation includes a measure of body size and is based on serum creatinine, age and sex

• eGFR results can be influenced by factors that alter muscle mass

• limitations on its use

  • children

  • AKI

  • drug dose calculations for highly toxic drugs

• eGFR more accurate than serum creatinine alone

• useful in monitoring renal function and in detecting early decline