Renal functionsRenal functions
Biochemistry II
Lecture 10 2008 (J.S.)
1
The main functions of the kidneysThe main functions of the kidneys
– Maintaining of the composition, osmolality, and volume of ECF– Maintaining of the composition, osmolality, and volume of ECF
– Excretion of nitrogenous catabolites (urea, uric acid, creatinine
and various hydrophilic drugs or toxins into the urine.
– Control of acid-base balance.
– An endocrine function (erythropoietin, renin, urodilatin, calcitriol).
The excretory function of the kidneys includes
filtration of the plasma in the glomeruli – glomerular filtration,filtration of the plasma in the glomeruli – glomerular filtration,
transport of water and solutes from the tubular lumen into the blood
– tubular resorption,– tubular resorption,
and transport of substances from tubular cells to the lumen
– tubular secretion,
The blood flow through the kidney is about 1.2 – 1.8 l / min.
2
The urine
Urinary excretion of selected compoundsUrinary excretion of selected compounds
depends on the dietary intake.
Approximate ranges of amounts excreted daily in adults:
Inorganic ions
Na+ 120 – 240 2.8 – 5.6
24 h-urine:mmol / d g / d
Na+ 120 – 240 2.8 – 5.6
K+ 45 – 90 1.8 – 3.6
Ca2+ 1.2 – 10 0.05 – 0.4
Mg2+ 2 – 6 0.05 – 0.14
Cl– 120 – 240 4.3 – 8.6
Phosphates 16 – 48 0.5 – 1.5 (P)Phosphates 16 – 48 0.5 – 1.5 (P)
SO4
2– 8 – 35 0.3 – 1.1 (S)
Nitrogenous compounds % of total nitrogen
NH4
+ 30 – 50 0.5 – 0.9 ~ 5
Urea 330 – 600 20 – 30 ~ 84
Creatinine 9 – 16 1.0 – 1.8 ~ 4Creatinine 9 – 16 1.0 – 1.8 ~ 4
Uric acid 1.5 – 6 0.25 – 1.0 ~ 4
Amino acids 3.5 – 14 0.4 – 1.7 ~ 1
3
Other – – < 1
The osmolality is mostly much higher than that of blood plasma, it varies
from about 80 to 1200 mmol / kgH2O. The osmolality of the glomerular
filtrate is about 300 mmol / kgH2O , therefore the maximal increase
in urine osmolality is approximately fourfold.in urine osmolality is approximately fourfold.
There are substantial differences in the increases
of particular solute concentrations.of particular solute concentrations.
Approximate values of urine / plasma concentration ratio
Na+ 1.0
K+ 10
Ca2+ 1.3
Cl– 1.2
Phosphate 15Phosphate 15
NH4
+ 700
Urea 100Urea 100
Creatinine 100
Uric acid 10
4
Amounts of solutes excreted into the urine
during a given period
The amount of a solute excreted into the urineThe amount of a solute excreted into the urine
depends on
– the amount that has been filtered in the glomeruli– the amount that has been filtered in the glomeruli
nfiltered / t = cplasma × VGF / t = cplasma × GFR
(GFR is glomerular filtration rate, l / d or ml / s)(GFR is glomerular filtration rate, l / d or ml / s)
– the amount reabsorbed in the tubules nabs / t, and
–– the amount secreted from the tubular cells nsecr / t.
The total amount excreted during a given period equalsThe total amount excreted during a given period equals
curine × Vurine / t = cplasma VGF / t + (nsecr – nabs) / t
From the equation can be calculated the fraction of the amount excreted
into the urine from the amount that has appeared in the glomerular filtrate
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into the urine from the amount that has appeared in the glomerular filtrate
within a given period – the fractional excretion E/F.
The clearance of substances from plasma
The quantity renal clearance is commonly used to express the efficiency of
the elimination of a particular solute from blood plasma into the urine,
Renal clearance, simply clearance of a solute X (Cx) is the ratio of the
amount of a solute X that is excreted in a unit of time into the urine
(c × V / t ) to its concentration in blood plasma c :(curine × Vurine / t ) to its concentration in blood plasma cplasma :
Cx = curine × Vurine t–1 / cplasma (in ml / s or l / d)
Thus the clearance of a solute X may be understood as the volume of
plasma that is completely cleared of that substance in a unit of time.
Cx = curine × Vurine t / cplasma
plasma that is completely cleared of that substance in a unit of time.
Clearance is a very informative quantity.
For example, the clearance of the compound that is
completely filtered and neither reabsorbed nor secreted
in the renal tubules (as inulin or, with certain limitations,in the renal tubules (as inulin or, with certain limitations,
endogenous creatinine) is equal to
the glomerular filtration rate GFR, the volume of
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the glomerular filtration rate GFR, the volume of
filtrate formed in a unit of time.
Another example:
p-Aminohippuric acid is an aromatic acid that is both filtered in the
glomeruli and secreted by the cells of proximal renal tubules, so that
Another example:
glomeruli and secreted by the cells of proximal renal tubules, so that
the blood plasma is completely cleared of it during the sole passage
through the renal vessels.
If p-aminohippurate (PAH) is applied intravenously tillIf p-aminohippurate (PAH) is applied intravenously till
the steady concentration is reached, concentrations of
the compound can be measured in plasma and urinethe compound can be measured in plasma and urine
and the clearance CPAH calculated. Its value corresponds
to the renal plasma flow in a time unit.
The renal plasma flow is 8 – 13 ml / sThe renal plasma flow is 8 – 13 ml / s
(500 – 800 ml / min).
NH–CH –COOH
–CONH2–
p-aminohippuric acid
(PAH, p-aminobenzoylglycine)
NH–CH2–COOH
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The nephron
FILTRATION
The nephron
FILTRATION
Controlled
REABSORPTION
Obligatory
isoosmotic
REABSORPTION
REABSORPTION
Isotonic
cortex
REABSORPTION
Tubular
SECRETION
Hyperosmolal
renal medulla
Countercurrent mechanism
of the loop of Henle and vasa recta
Mostly hypertonic
URINE
of the loop of Henle and vasa recta
forms a high osmolality environment
in the medulla
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Glomerular filtration
In renal glomeruli, the blood plasma is filtered.In renal glomeruli, the blood plasma is filtered.
The composition of ions and small molecules in glomerular
filtrate is quite similar to that of plasma.filtrate is quite similar to that of plasma.
A common statement that glomerular filtrate is a protein-free
fluid is not right. Low concentrations of proteins are present
(predominantly of those with M < 30 000), about 10 – 30 mg(predominantly of those with Mr < 30 000), about 10 – 30 mg
per litre of filtrate, but most of proteins are reabsorbed in the
tubules.
fenestrated endothelial layercapillary lumen (plasma)
The glomerular filtration barrier
fenestrated endothelial layer
(about 30 % of the basement membrane
not covered by the endothelial cells)
the thick basement membrane
capillary lumen (plasma)
the thick basement membrane
~ 300 nm
the slit membrane (pore size ~ 5 nm)
-
-
- -
-
--- - - - -- -
-
-
--
the processes of podocytes
(visceral epithelium) and
filtration slits
the slit membrane (pore size ~ 5 nm)
-
--
-
-
-
-
-
-
-
--
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filtration slits
Bowman´s space (tubular fluid)
The basement membrane consists of type IV collagen fibres and certain amount
of laminin and proteoglycans. Heparan sulfate in the membrane and sialic acidof laminin and proteoglycans. Heparan sulfate in the membrane and sialic acid
containing glycoproteins in the filtration slits have negative electrical charges.
Podocytes with their
interdigitating foot processesinterdigitating foot processes
separated by filtration slits
cover the basement membranes
of capillary wallsof capillary walls
(scanning electron micrograph).
Plasma proteins with a M above approx. 120 000 are excluded by filtration.Plasma proteins with a Mr above approx. 120 000 are excluded by filtration.
Proteins with a Mr above 65 000 and anionic character (albumin and
transferrin) are prevented from entering the urine by an electrostatic filter,transferrin) are prevented from entering the urine by an electrostatic filter,
concentration of albumin in the filtrate is about 4 mg/l (0.01 % plasma concn.).
Low-molecular plasma proteins (Mr 10 000 – 60 000) cross the filtration barrier, their
concentration in glomerular filtrate can reach 50 – 90 % concentration in plasma.
10
r
concentration in glomerular filtrate can reach 50 – 90 % concentration in plasma.
Healthy adults excrete less than 150 mg of total urinary protein per 24 h:
albumin 7 – 11 mg / d (less than 20 mg / d),
transferrin < 1 mg / d,
α1-acid glycoprotein < 10 mg / d,α1-acid glycoprotein < 10 mg / d,
α1-microglobulin 1 – 5 mg / d,
retinol-binding protein < 0.5 mg / d,
β -microglobulin < 0.3 mg / d, etc.
Proteinuria – more than 300 mg of total urinary protein per 24 h .
β2-microglobulin < 0.3 mg / d, etc.
Glomerular proteinuria – the normal glomerular barrier to plasma proteins
is disrupted, proteins with molecular mass higher than 65 000 are present
in the urine (albumin 67 000, transferrin 79 000, immunoglobulinsin the urine (albumin 67 000, transferrin 79 000, immunoglobulins
> 150 000). Low-molecular proteins are reabsorbed in the tubules.
Tubular proteinuria – the cause is in incomplete proximal tubularTubular proteinuria – the cause is in incomplete proximal tubular
reabsorption (in the presence of normal glomerular permeability),
normally filtered low-molecular-mass plasma proteins appear in the urinenormally filtered low-molecular-mass plasma proteins appear in the urine
in increased amounts.
Tubular proteinuria can occur alone or in association with glomerular
proteinuria.
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proteinuria.
Test for microalbuminuria (Micral-test®)
Microalbuminuria is excretion of albumin in the range from 30 mg / d toMicroalbuminuria is excretion of albumin in the range from 30 mg / d to
200 – 300 mg /d (to obvious proteinuria). It often predicts development of
nephropathy. It is important to detect microalbuminuria early, because kidneynephropathy. It is important to detect microalbuminuria early, because kidney
damages are minimal and are still reversible. Measurements of urinary
albumin is especially important for diabetic and hypertensive patients.
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Glomerular filtration rate (GFR)Glomerular filtration rate (GFR)
is the volume of glomerular filtrate formed in a unit of time.
Normal range 1.33 – 2.33 ml / s i.e. 80 – 140 ml / min
The ideal marker for GFR
Normal range 1.33 – 2.33 ml / s i.e. 80 – 140 ml / min
( 115 – 200 l / d )
– would appear endogenously in the plasma at a constant concentration,
– would be freely filtered at the glomerulus,
– would be neither reabsorbed nor secreted by the renal tubule, and– would be neither reabsorbed nor secreted by the renal tubule, and
– would undergo no extrarenal elimination from the body.
Clearance of inulin or with certain limitations alsoClearance of inulin or with certain limitations also
clearance of endogenous creatinine are equal to GFR.
Clearance of inulinClearance of inulin
is a very exact measure of GFR, suitable more for scientific research than for
routine use.routine use.
Inulin is a plant (or synthetic) polyfructosan. It must be infused intravenously,
about 50 mg/kg body weight. The samples of blood as well as urine cannot be taken
before a steady concentration of inulin in plasma is reached.
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before a steady concentration of inulin in plasma is reached.
Creatinine clearance (Ccreat)
Creatinine is excreted predominantly through glomerular filtration. There
serves as an routine estimate of GFR for more than 60 years, because
it is a very simple test..
Creatinine is excreted predominantly through glomerular filtration. There
is no tubular reabsorption, but (namely at higher plasma concentrations)
the amount of creatinine secreted in the tubules increases.the amount of creatinine secreted in the tubules increases.
Clearance of creatinine depends on age and gender, timed samples of urine
must be collected, and the analytical method is not quite specific.
Creatinine clearances have slightly higher values when compared withCreatinine clearances have slightly higher values when compared with
inulin clearances (about 2.33 and 2.00, resp.).
Calculation:Calculation:
Entries - cplasma(creatinine) in mmol/l (normal value about 115 µmol/l)
curine(creatinine) in mmol/l
V / t in ml / sVurine / t in ml / s
Ccreat = uncorrected GFR = curine × Vurine t–1 / cplasma (ml/s)
Glomerular filtration rate corrected to the standard body surface area 1.73 m2:
GFRcorr = GFR × A / 1.73 (ml/s)
14
Body surface A = 0.167 × (in m2)w×h
Estimate of GFR from cystatin C concentration in serum
Cystatin C is a low-molecular protein (Mr ≈ 13 400) that acts as an inhibitor of
cysteine proteinases and is released uniformly from all nuclear cells into the
circulating blood. Its concentration is stable (e.g., it doesn't depend oncirculating blood. Its concentration is stable (e.g., it doesn't depend on
inflammatory processes).
Like other low-molecular weight proteins, cystatin C is eliminated from theLike other low-molecular weight proteins, cystatin C is eliminated from the
plasma exclusively by glomerular filtration and decomposed in tubular cells.
Cystatin C concentration in serum is indirectly related to GFR.Cystatin C concentration in serum is indirectly related to GFR.
The interindividual variability in cystatin C concentration is lower than that of
creatinine, what enables the early detection of decrease in GFR.
Concentration of cystatin C in serum or plasma is determined by means of an
immunoturbidimetric method or ELISA. There is no need to collect urine.
The estimate of GRF corrected to the standard body surface area is calculated
in adults as
GFRcystatin (ml / s) = 1.41 × ρρρρ (cystatin C, mg/l) –1.68 ,
in adolescents under the age of 14 multiplied by the "praepubertal" factor 1.384 .
Estimates of GFRcorr from the clearance of creatinine are progressively substituted by
15
corr
GFRcystatin.
Glomerular filtration - laboratory investigationsGlomerular filtration - laboratory investigations
Serum creatinine concentration
~ 100 µmol/l ( 55 – 120 µmol/l)~ 100 µmol/l ( 55 – 120 µmol/l)
Rough estimates of GFR from the creatinine concentration were
derived in the past (e.g. the Cockcroft-Gault formula).derived in the past (e.g. the Cockcroft-Gault formula).
Glomerular filtration rate.
1.5 – 2.5 ml/s – estimated either from serum cystatin C concentration
or as creatinine clearance corrected to body surface area 1.73 m .or as creatinine clearance corrected to body surface area 1.73 m2.
Serum urea concentration
2.5 – 6.6 mmol/l2.5 – 6.6 mmol/l
High serum urea in any cause of impaired renal perfusion,
reduced GFR, or obstruction to urine outflow.
Detection of proteinuria / microalbuminuria
Quantification of urinary protein excretion
(albumin < 20 mg/d, total protein < 150 mg/d)(albumin < 20 mg/d, total protein < 150 mg/d)
Serum albumin concentration, determination of proteinuria type
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The functions of renal tubulesThe functions of renal tubules
The proximal tubuleThe proximal tubule
Efficient reabsorption of most amino acids,
nearly all glucose, unless its supply is greaternearly all glucose, unless its supply is greater
than the capacity of the transfer into the cells
- a threshold approximately at 10 mmol/l,- a threshold approximately at 10 mmol/l,
most Na+ (50 – 60 %), K+, Cl–, phosphates, HCO3
–, etc.,
driven by Na+,K+-ATPase located within the basolateral membranes.driven by Na ,K -ATPase located within the basolateral membranes.
Passive reabsorption of water (70 – 80 %, isotonic and "obligatory",
independent on ADH).
Tubular secretion of organic ions, basic drugs.
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Proximal tubule
K+
Basolateral membraneApical plasma membrane
Proximal tubule
Tubular lumen Blood plasma
GLUT2
tight junctions
K+
Na+
ATP
Na+
glucose
H2O
Na+, Cl–
solvent drag
Reabsorption of GLUT2Na+
Na+
Na+
phosphate
glucose
amino acids
Reabsorption of
70 – 80 % water
50 – 60 % Na+
aquaporin 3
phosphate
H2Oaquaporin 1
H2O
Reabsorption of
(not shown here)
> 90 % K+,
aquaporin 3
Na+/Ca2+
H+
aquaporin 1> 90 % K ,
85 % Cl–,
90 % HCO3
– ,
50 – 70 % phosphates,
Tubular secretion
– anions of weak acids
– cations of organic bases
– amphions (e.g. EDTA)
50 – 70 % phosphates,
65 % Ca2+,
urate,
small proteins, etc. – amphions (e.g. EDTA)small proteins, etc.
18
form the osmotic gradient between the renal cortex and medulla.
The loop of Henle and vasa recta
form the osmotic gradient between the renal cortex and medulla.
High osmolality of the medullary peritubular interstitial fluid is essential for
the efficient reabsorption of water in the collecting ducts, for concentrationthe efficient reabsorption of water in the collecting ducts, for concentration
of urine. The osmolality increases from the cortex to the medulla, and it is
maintained by the countercurrent mechanism that consists ofmaintained by the countercurrent mechanism that consists of
- countercurrent multiplication of the loop of Henle, and
- passive countercurrent exchange of water and urea between vasa
recta, the descending loop of Henle, and collecting ducts.
In the thick ascending limb, which is impermeable for water, Na+,K+-ATPase drives
the active ion transport out from tubules (increase in osmolality of interstitial fluid). .the active ion transport out from tubules (increase in osmolality of interstitial fluid). .
In the thin descending limb, water moves freely from the tubules into the
hyperosmolal interstitial fluid.
The medullary parts of collecting ducts are permeable for water (controlled by ADH)
and urea, so that water may be efficiently reabsorbed (similarly to the thin
descending limb of the loop) into the hyperosmolal interstitial fluid and drained todescending limb of the loop) into the hyperosmolal interstitial fluid and drained to
the cortex by vasa recta. There is also a high concentration of urea in the collecting
ducts, urea freely diffuses into the interstitial fluid, into the thick ascending parts of
the loop of Henle and vasa recta (urea recycling).
19
the loop of Henle and vasa recta (urea recycling).
The thin descending limb of the loop
There are numerous aquaporins in the plasma membrane (AQP 1 in the apicaI part)
that make the membranes freely permeable to water, which moves out of the
lumen into the hyperosmolal surrounding tissue; ion transporters are absent.
The thick ascending limb of the loop
lumen into the hyperosmolal surrounding tissue; ion transporters are absent.
Apical membrane of the thick
ascendent limb of the loop
The thick ascending limb of the loop
Na+
Na+
K+
ascendent limb of the loop
is impermeable for water.
Na
Na+-K+-2Cl–
efficient symport
Cl–
K+
ATP
recirculation of K+
Cl–
Cl– K+
Cl–Na+, K+, and Cl– are pumped out
against the concentration gradient
Cl–
against the concentration gradient
into the hyperosmolal interstitial fluid
(the process is driven by Na+,K+-ATPase.
20
Osmolality of the tubular and peritubular interstitial fluidOsmolality of the tubular and peritubular interstitial fluid
renal cortex
renal medullarenal medulla
urea
recirculation of
Na+, Cl–, and urea
21
Distal tubules and collecting ducts
– Passive reabsorption of water into the hyperosmolal interstitium
(controlled by antidiuretic hormone) – the final concentration of urine.
– Resorption of Na+ (driven by Na+,K+-ATPase) and
– tubular secretion of K+ (most of K+ excreted into the urine) –– tubular secretion of K+ (most of K+ excreted into the urine) –
both under the control of aldosterone or natriuretic peptides
– Excretion of Ca2+ and phosphates under the control of parathyrin– Excretion of Ca2+ and phosphates under the control of parathyrin
and calcitonin.
– A part of tubular secretion of H+ in the form of H2PO4
– and NH4
+ depends
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– A part of tubular secretion of H in the form of H2PO4 and NH4 depends
on the acid-base status.
Distal tubuleDistal tubule
reabsorption driven
by Na+,K+-ATPase
Na+
Symport Na+ Cl–
(no K+ transport)
K+
Na+
Cl–
recirculation of K+
leakage of K+leakage of K+
only at very high
intracellular [K+]
The cells of distal tubules represent the sites of Ca2+ reabsorption
(about 10 % of total reabsorbed) and phosphate leakage controlled(about 10 % of total reabsorbed) and phosphate leakage controlled
by parathyrin and to a less extent by calcitonin.
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Collecting ducts
3 Na+
Tubular lumen
Aldosterone
Blood plasma
The principal tubular cells
In spite of reabsorption of only about
3 % of total filtered Na+ ions Na+Na+
3 Na+
2 K+
3 % of total filtered Na+ ions
in the collecting ducts, changes in
that relatively small percentage are
decisive in natriuresis, elimination
K+K+
Na+Na+
ATP
decisive in natriuresis, elimination
of Na+ from the body.
Both Na+ and K+ channels are
inhibited by "potassium saving" H2O
aquaporin 3
H2O
0
receptorsinhibited by "potassium saving"
diuretics amilorid and spironolacton.
H2O 0
aquaporin 2 receptors
V2 for ADH
Aldosterone enlarges reabsorption of Na+ equally with losses of K+Aldosterone enlarges reabsorption of Na+ equally with losses of K+
by exposition of Na+ and K+ channels and also by partial stimulation of Na+,K+-ATPase.
Antidiuretic hormone (ADH, Arg-vasopressin) increases reabsorption of water.
It binds onto membrane V receptors and activation of proteinkinases A is a cause ofIt binds onto membrane V2 receptors and activation of proteinkinases A is a cause of
exposition of aquaporin AQP-2 in the apical membrane.
Natriuretic peptides inhibit Na+ and K+ channels (in addition to the vasodilating effect) so
that they support Na+ excretion and retention of K+.
The intercalated cells
have their major role in excretion of H+ and reabsorption of HCO3
–.
that they support Na+ excretion and retention of K+.
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have their major role in excretion of H+ and reabsorption of HCO3
–.
Natriuresis - the renal excretion of sodium ions
Diuretics are drugs that support elimination of water from the body
by stimulating natriuresis through different mechanisms. Most diureticsby stimulating natriuresis through different mechanisms. Most diuretics
influence the cells from the tubular fluid (the apical part of plasma
membranes).
distal tubules
5 – 8 % of total reabsorbed Na+
proximal tubules
50 - 60 % reabsorbed 5 – 8 % of total reabsorbed Na+
inhibition by thiazide diuretics
(partly by "loop" diuretics, too)
50 - 60 % reabsorbed
thick ascending limb
30 – 40 % of total reabsorbed Na+
inhibition by "loop" diuretics
collecting ducts
2 – 3 % of total reabsorbed Na+
inhibition by "loop" diuretics
(e.g. furosemide)
2 – 3 % of total reabsorbed Na+
(regulated by aldosterone)
inhibition by
potassium- saving diureticspotassium- saving diuretics
(e.g. amiloride, spironolactone)
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Tubular functions - laboratory investigation
Capacity of the kidneys top concentrate the urine
(formerly tested by thirsting – healthy subjects up to
osmolality 800 – 1100 mmol/kgH2O or density 1026 – 1032 g/l)
Osmolar clearance Cosm
should not exceed 0.05 ml/s to prevent solute lossesshould not exceed 0.05 ml/s to prevent solute losses
Fractional excretion of solutes E/Fosm normal values ≤ 0.035 (≤ 3.5 %)
Clearance of electrolyte-free water (EWC) CEWClearance of electrolyte-free water (EWC) CEW
negative values – amount of water which has to be added to the urine
to become isotonic with the plasma
positive values – amount of water which has to be relieved from thepositive values – amount of water which has to be relieved from the
urine to become isotonic with the plasma
the usual range – 0.002 ± 0.008 ml/s
(positive values only temporarily in healthy persons after high water intake)(positive values only temporarily in healthy persons after high water intake)
Urinary Na+ output
must be proportional to the intake, about 100 – 200 mmol/d.must be proportional to the intake, about 100 – 200 mmol/d.
Fractional excretion of Na+ E/FNa+ normal range 0.004 – 0.012 (0.4 – 1.2 %)
Fractional excretion of K+ E/F normal range 0.04 – 0.19 (4 – 19 %)
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Fractional excretion of K+ E/FK+ normal range 0.04 – 0.19 (4 – 19 %)
The endocrine function of the kidney
Erythropoietin (EPO) is the primary regulatory factor of erythropoiesis
(formation of red blood cells in the bone marrow). EPO is a glycoprotein
(165 AA, M ~ 34 000), released in the kidney (about 10 % also in the liver)(165 AA, Mr ~ 34 000), released in the kidney (about 10 % also in the liver)
by splitting of the precursor protein by the action of a specific proteinase.
Hypoxia and decrease in blood haemoglobin stimulate the release of EPOHypoxia and decrease in blood haemoglobin stimulate the release of EPO
from the kidneys.
Calcitriol (1α,25-dihydroxycalciol) originates from circulating calcidiolCalcitriol (1α,25-dihydroxycalciol) originates from circulating calcidiol
(25-hydroxycalciol) by hydroxylation in the renal tubular cells.
The specific hydroxylating system is stimulated by parathyrine.The specific hydroxylating system is stimulated by parathyrine.
Urodilatin is the natriuretic peptide synthesized in the kidney (4 amino
acid residues more than ANP, M ~ 3 500) being more paracrine, it isacid residues more than ANP, Mr ~ 3 500) being more paracrine, it is
secreted into the urine. Urodilatin regulates water and sodium reabsorption
in the collecting duct by inhibition of Na+ channels and vasodilation.
Renin is a proteinase secreted from the juxtaglomerular cells that starts
the renin-angiotensin system – RAS: ./.
27
the renin-angiotensin system – RAS: ./.
The juxtaglomerular apparatus and the renin-angiotensin system
afferent arteriole
and the juxtaglomerular cells
distal tubule
and cells of the macula densa
The juxtaglomerular apparatus responds to decreased renal perfusion pressure
by secreting a proteinase, renin, that uses angiotensinogen (one of the plasmaby secreting a proteinase, renin, that uses angiotensinogen (one of the plasma
glycoproteins in the α2-globulin fraction) as its substrate and liberates angiotensin I
(a decapeptide) from angiotensinogen. Angiotensin I is transformed into
a octapeptide angiotensin II (by angiotensin-converting enzyme, ACE) that stimulatesa octapeptide angiotensin II (by angiotensin-converting enzyme, ACE) that stimulates
the synthesis and release of a mineralocorticoid aldosterone.
The macula densa also senses the tubular chloride concentration.
28
The macula densa also senses the tubular chloride concentration.
Control of acid-base balance by the kidneysControl of acid-base balance by the kidneys
In healthy persons,
50 – 100 mmol H+ / d (from non-volatile acids) have to be excreted.50 – 100 mmol H+ / d (from non-volatile acids) have to be excreted.
Although the urine is more acidic than blood plasma, excretion of free
H+ ions in this way (actual acidity) may be neglected: Only 0.01 mmol H+H ions in this way (actual acidity) may be neglected: Only 0.01 mmol H
is excreted in one litre urine pH 5.0 .
– Tubular cells excrete H+ ions in the form of H2PO4
– ions (H+ bound onto– Tubular cells excrete H+ ions in the form of H2PO4
– ions (H+ bound onto
HPO4
2–), the urine so becomes slightly acidic - this titratable acidity
represents approximately 10 – 30 mmol H+ / d eliminated from the body.
– Tubular cells excrete NH4
+ ions formed from NH3 by binding H+ ; NH3
is released from glutamine (and glutamate). About 30 – 50 mmol H+ / d
are excreted in this way.are excreted in this way.
– Reabsorption of HCO3
– ions from tubular fluid saves the main plasma
buffer base.buffer base.
In alkalosis, HCO3
– ions are secreted into the urine.
29
Reabsorption of HCO3
–
90 % HCO3
– reabsorbed in the proximal tubule (pars recta),90 % HCO3
– reabsorbed in the proximal tubule (pars recta),
10 % in the collecting ducts (by intercalated cells)
Reabsorption is regulated by pCO2.
H+ ions transported into
the tubular fluid are
not excreted into the urine,
they give water.
HCO3
– ions are secretedHCO3
– ions are secreted
in alkalosis: When [HCO3
–] in blood exceeds 28 mmol/l, Na+/H+ antiport is diminished
and Cl–/HCO3
– antiporters are inserted into the apical membrane of separate base-secreting
tubular cells by a triggered exocytosis. A steady state with a maximal HCO – excretion is
30
tubular cells by a triggered exocytosis. A steady state with a maximal HCO3
– excretion is
reached in the course of several days.
Excretion of H+ in the form of H2PO4
–
Cells of straight part of proximal tubules and intercalating cells of collecting ductsCells of straight part of proximal tubules and intercalating cells of collecting ducts
H+ ions bound onto hydrogen phosphate changes the ratio [HPO4
2–] / [H2PO4
–], so that they
result in only a slight decrease in pH value. The amount of H+ excreted in this way can be
measured as "titratable" acidity of the urine.
Tubular lumen Na+
Na+
K+
ATP
HPO4
2–
H+
proton-producing reactions
K+
ATP
ATP
H+
Cl–
proton-producing reactions
and/or increased pCO2H2CO3
HCO3
–
H2PO4
–
exposition of the
vesicular H+-ATPase
Under physiological conditions, 10 – 30 mmol H+/d are excreted in this way. The increase
of that amount is limited by the accessibility of HPO4
2– in the tubular fluid to a maximum
of about 40 – 50 mmol/d, i.e. to the urinary pH 4.5).
31
of about 40 – 50 mmol/d, i.e. to the urinary pH 4.5).
The excretion of H+ in the form of NH4
+
Proximal tubules, distal tubules, and intercalated cells of collecting ductsProximal tubules, distal tubules, and intercalated cells of collecting ducts
– without any decrease in pH value of the urine.
Tubular lumenTubular lumen
K+
Na+
Na+
glutamine
ATP
production of glutamine
in the liver preferred
NH4
+
instead of H+
glutamate
oxoglutarate
in the liver preferred
in acidosis
transfer of NH + into the blood
NH4
+
NH4
+
Na+
instead of K+
in K+ channel
transfer of NH4
+ into the blood
in alkalosis
(NH4
+ is the substrate
for ureosynthesis thatfor ureosynthesis that
is a proton-producing process)
Under physiological conditions, 30 – 50 mmol H+/d are excreted in this way.
In an extreme acidosis, the excretion of NH4
+ may reach (stepwise during 5 days)
200 – 500 mmol/d; NH4
+ can accumulate in the renal medullary interstitium.
32
200 – 500 mmol/d; NH4 can accumulate in the renal medullary interstitium.