Renal Clearance and its Physiological Mechanisms
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August 2021, Padova, Italy
Introduction
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Note : relation between lipophilicity and renal clearance
Introduction
Smith, 1996, Med. Res. Rev.
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Introduction
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Smith, 1996, Med. Res. Rev.
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Note : relation between lipophilicity and renal clearance
Renal clearance
Introduction
Physiological mechanisms and clearance
Glomerular filtration
Tubular secretion
Reabsorption
Methods to measure renal clearance
5
Processes of elimination, secretion and reabsorption
occur at the nephron’s level
6
Introduction
Scheme of a nephron
and its vascularisation
F
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Loop of Henle
Glomerulus
Proximal tubule
Distal tubule
Collecting tube
Physiological mechanisms
7
Scheme of a nephron
Rate
renal elimination
= Rate
filtration
+ Rate
secretion
- Rate
reabsorption
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Physiological mechanisms
8
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Rate
renal elimiationn
Rate
filtration
Rate
secretion
- Rate
reabsorption
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Physiological mechanisms
9
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Physiological mechanisms
Glomerular filtration
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Physiological mechanisms
Glomerular filtration
Passive mechanism
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Haraldsson et al, Physiol Rev 88: 451-487, 2008
Albumin = 40g/L
Albumin = 0.004 g/L
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PM(da)
Ultrafiltration/plasma
(%)
0
100
50
20000
69000
Albumin
Myoglobin
Inulin
Physiological mechanisms
Glomerular filtration
12
13
Physiological mechanisms
Glomerular filtration
Rate
filtration
= GFR x C
free
C
free
= f
u
x C
tot
Rate
filtration
= GFR x f
u
x C
tot
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Physiological mechanisms
Glomerular filtration
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There is only filtration in kidney
Application
Measurement of GFR
Assessment of renal function
Conditions
Molecule with only renal elimination
Molecule filtered, not secreted, not reabsorbed
No binding to plasma proteins
15
Physiological mechanisms
Glomerular filtration
I
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Completely filtered (no binding to plasma proteins)
Not reabsorbed
Not secreted
16
Physiological mechanisms
Glomerular filtration
Conditions
Molecule with only renal elimination
Molecule filtered, not secreted or reabsorbed
No binding to plasma proteins
Cl
total_inu or creat
= GFR
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Physiological mechanisms
17
Physiological mechanisms
Tubular secretion
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Proximal Convoluted Tubule (PCT)
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Note : secretion of penicillin can be limited by concomitant administration of probenecid
PAH
Penicillins
Salicylate
Sulfonamides
Furosemide
Thiazides
Cephalosporins
Fluoroquinolones
19
Physiological mechanisms
Tubular secretion
E
x
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Note: examples of molecules with different renal extraction coefficient
20
Physiological mechanisms
Tubular secretion
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Physiological mechanisms
Tubular secretion
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Physiological mechanisms
22
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Transporters / endogenous compounds
Organic molecules: glucose, amino acids, vitamins
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+
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, HCO
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23
Physiological mechanisms
Reabsorption
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•
lipophilicity
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ionization
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molecular weight
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•
urine output
•
urine pH
24
Physiological mechanisms
Reabsorption
urine pH
5 6
6.5
8 8.5
Influence of the urinary pH
Weak acids
Weak Bases
Rate of elimination
-
(AH =reabs)
+
(BH
+
= no reabs)
+
(A
-
= no reabs)
-
(B= reabs)
25
Physiological mechanisms
Reabsorption
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H
Kamiya et al. J Pharm Sci, 1983, 72:440
Inulin
100
Sulfanilamide
95
Ampicillin
90
Sulfamethizole
20
Cephalexin
80
55
40
134
224
123
21
122
444
246
278
100
27
Physiological mechanisms
Summary: different combinations
Provided values are normalized
for inulin glomerular filtration
C
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Methods of measurement
28
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C
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Methods of measurement
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X
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P
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29
A
p
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G
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Methods of measurement
30
C
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a
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=
C
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f
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+
C
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-
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Summary
31
GFR
f
u
Active
transports
Passive
(ionization)
This content delves into the concept of renal clearance, exploring its relation to lipophilicity and mechanisms such as glomerular filtration, tubular secretion, and reabsorption. The processes occurring at the nephron level and the vascularization scheme are detailed, along with a breakdown of physiological mechanisms like filtration, reabsorption, and secretion. Key points include the rates of renal elimination, filtration, secretion, and reabsorption, as well as factors influencing glomerular filtration rates and renal blood flow.
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Presentation Transcript
Renal clearance Aude Ferran August 2021, Padova, Italy 1
Introduction Hydrophobic molecule Hydrophilic molecule Liver Kidneys More hydrophilic metabolite Urine 2
Introduction Note : relation between lipophilicity and renal clearance 10 Renal clearance (mL/min/kg) Beta-blockers NSAIDs 1 0.1 0.01 0.001 -3 -2 -1 0 1 2 Log D pH= 7.4 3 Smith, 1996, Med. Res. Rev.
Introduction Note : relation between lipophilicity and renal clearance Carboxylic acids 15 Renal clearance (mL/min/kg) Renal clearance Hepatic clearance 10 5 0 -1 0 1 2 Log D Smith, 1996, Med. Res. Rev.
Renal clearance Introduction Physiological mechanisms and clearance Glomerular filtration Tubular secretion Reabsorption Methods to measure renal clearance 5
Introduction Processes of elimination, secretion and reabsorption occur at the nephron s level Scheme of a nephron and its vascularisation 6
Physiological mechanisms Filtration Reabsorption (passive) Collecting tube Proximal tubule Distal tubule Glomerulus Secretion (active) Loop of Henle Scheme of a nephron 7
Physiological mechanisms To urine To plasma Raterenal elimination= Ratefiltration + Ratesecretion - Ratereabsorption Raterenal elimiationn Ratefiltration Ratesecretion - Ratereabsorption = + C C C ClRenal = Clfiltration + Clsecretion - Clreabsorption 8
Physiological mechanisms ClRenal = Clfiltration + Clsecretion - Clreabsorption 9
Physiological mechanisms Glomerular filtration FLOW RATES Renal blood flow: 20-25% of cardiac output Glomerular Filtration Rate (GFR): 10% of renal blood flow GFR 10
Physiological mechanisms Glomerular filtration Albumin = 0.004 g/L = ULTRAFILTRATION Passive mechanism Molecules of MW < 68 kDa Only the free fraction is filtered Albumin = 40g/L Haraldsson et al, Physiol Rev 88: 451-487, 2008 11
Physiological mechanisms Glomerular filtration The main factor that determines filtration is the molecular weight of the substance Inulin 100 Ultrafiltration/plasma Myoglobin Albumin (%) 50 0 20000 69000 PM(da) 12
Physiological mechanisms Glomerular filtration Ratefiltration = GFR x Cfree Cfree = fu x Ctot Ratefiltration = GFR x fu x Ctot ?????????????? ???? =?? ???? ??? ???? ????????????= = ?? ??? ????????????= ?? ??? 13
Physiological mechanisms Glomerular filtration Estimated filtration capacity If ClRenal = Clfiltration There is only filtration in kidney QRenal x ERenal = fu x GFR ??? ?????? ERENAL= 1 . 0 ??????= And if fu = 1 Filtration alone can purify at maximum 10% of renal blood flow 14
Physiological mechanisms Glomerular filtration Application Measurement of GFR Assessment of renal function Conditions Molecule with only renal elimination Molecule filtered, not secreted, not reabsorbed No binding to plasma proteins ???????= ???????= ??? 15
Physiological mechanisms Glomerular filtration Conditions Molecule with only renal elimination Molecule filtered, not secreted or reabsorbed No binding to plasma proteins INULINE or creatinine Completely filtered (no binding to plasma proteins) Not reabsorbed Not secreted Cltotal_inu or creat = GFR in humans 16
Physiological mechanisms ClRenal = Clfiltration + Clsecretion - Clreabsorption 17
Physiological mechanisms Tubular secretion Secretion (active) FEATURES Proximal Convoluted Tubule (PCT) Active Transport Saturable process = possible competition 18
Physiological mechanisms Tubular secretion Examples PAH Penicillins Salicylate Sulfonamides Furosemide Thiazides Cephalosporins Fluoroquinolones Note : secretion of penicillin can be limited by concomitant administration of probenecid 19
Physiological mechanisms Tubular secretion If Erenal higher than 0.1 => there is a secretion Note: examples of molecules with different renal extraction coefficient Low (<0.3) Medium (0.3-0.7) High (>0.7) Amoxicillin Cimetidin Glucuronides Digoxin Sulfates Gentamicin Tetracycline 20
Physiological mechanisms Tubular secretion PAH ParaAminoHippuric acid Filtered And completely secreted by the TCP =>Erenal=1 =>PAH clearance is equal to renal plasma flow = Method to estimate the renal plasma flow in humans 21
Physiological mechanisms ClRenal = Clfiltration + Clsecretion - Clreabsorption 22
Physiological mechanisms Reabsorption ACTIVE (proximal convoluted tubules) Transporters / endogenous compounds Organic molecules: glucose, amino acids, vitamins Electrolytes : Na+,Cl -, Ca++, K+, HCO3- PASSIVE Water follows Na+(concentration of primary urine in final urine) Xenobiotics 23
Physiological mechanisms Reabsorption Individual factors urine output urine pH Xenobiotic Factors influencing reabsorption Physico-chemical properties of the drug lipophilicity ionization molecular weight 24
Physiological mechanisms Reabsorption Influence of the urinary pH Rate of elimination 5 6 6.5 8 8.5 urine pH - + Weak acids (AH =reabs) (A- = no reabs) - (B= reabs) + Weak Bases (BH+= no reabs) 25
Phenylbutazone Phenylbutazone urine concentrations of urine concentrations of horses horses at different pH
Physiological mechanisms Summary: different combinations Inulin 100 Sulfanilamide 95 Ampicillin 90 Sulfamethizole 20 Cephalexin 80 444 123 134 40 246 21 100 55 224 122 278 Kamiya et al. J Pharm Sci, 1983, 72:440 Provided values are normalized for inulin glomerular filtration 27
Methods of measurement dX dt RENALE= u CL ( ) t C Collection of urine ??/ ? ????????, ? ???????= Plasma collection 28
Methods of measurement Application to GFR measurement by creatinine Conc Plasma collection Cmean, T XU / T Collection of urine time 29
Methods of measurement Plasma collection Collection of urine dX dt RENALE= u CL ( ) t C Conc ??/ ? ????????, ? ???????= X TOTALE u, AUC = CL AUC RENALE TOTALE time Collection of urine XU 30
Summary GFR fu Passive (ionization) Active transports ClRenal = Clfiltration + Clsecretion - Clreabsorption 31
