Transcript What*s different about children*s kidneys

What’s different about children?
For more about paediatric nephrology
go to:
http://paedstudent.cf.ac.uk
Aims of talk
• Reminder about normal renal embryogenesis
and neonatal development
• Paediatric renal physiology
• Impact on management of children
Embryology
• Nephrogenesis starts at 5 weeks gestation
• During fetal life, body fluid homeostasis
carried out by the placenta
• Fetal urine produced from 10 weeks
• By 22 weeks urine production is 2-5 ml/h
• By term this is 25-40 ml/h
• At birth, 60% of amniotic fluid is urine
Newborn
• Urine output falls to 1-3 ml/h
• Blood biochemistry = Maternal biochemistry
• Glomerular and tubular function is very
immature
• As a result the kidneys are ill-equipped to deal
with physiological stress
Renal function during infancy
Premature Term infant
infant
First
3 days
First
3 days
2 weeks
8 weeks
1 year
ml/kg/24h
15-75
20-75
25-120
80-130
40-100
% of fluid intake
40-80
40-80
50-70
45-65
40-60
Maximal urine osmolality
(mOsm/kg H2O)
400-500
500-600
700-800
1000-1200
1200-1400
Glomerular filtration rate
(ml/min/1.73m2)
10-15
15-20
35-45
75-80
90-110
Daily excretion of urine
Feeding
Mature breast milk
Electropositive elements (mEq/l)
Cow’s milk
41
149
Na (mg/l)
180
768
Ca (mg/l)
300
530
28
108
150
920
Electronegative elements (mEq/l)
Phosphate (mg/l)
Glomerular filtration rate
• At birth, systemic bp is low and vascular
resistance extremely high → low driving force
for filtration.
• Filtration surface severely limited.
• Therefore GFR very low.
• This limits all renal functions, particularly with
regard to water and electrolyte homeostasis
and the excretion of waste products.
Glomerular filtration rate
• During the first month of life GFR increases
rapidly due to ↑ systemic bp, ↓ renal
vascular resistance and enlargement of the
filtration surface.
• GFR reaches adult levels by 1 year.
Neonatal fluid homeostasis
• At birth TBW is high (75% body mass)
• 40% of total body mass is ECF
• After birth – amount of body water decreases
and it redistributes with ↓ECF and ↑ICF
• Subsequently:
% of body weight
ECF
ICF
2 months
30%
43%
9 months
27%
35%
Neonatal fluid homeostasis
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Lose 5-10% birth weight in first few days
Mainly from ECF space
Neonatal membranes are leaky
Neonatal kidneys have low urinary
concentrating ability
• Therefore easily become dehydrated
• Matures rapidly in first few months
Acid-base balance
• Tight regulation of [H+] achieved through
intra- and extracellular buffers and the lungs
and kidneys
• At birth, buffers well developed and
respiratory responses good
• Renal compensatory mechanisms are slow
and limited because of low GFR and
suboptimal tubular transport of HCO3- and H+
Acid-base balance
• Renal threshold for bicarbonate
– Term infant
– Adult
– Premature infant
18-20 mmol/l
24-26 mmol/l
as low as 14 mmol/l
• Leads to a physiological metabolic acidosis in
the newborn
Renal effects of angiotensin II
• Constricts glomerular arterioles; greater effect
on efferent arterioles than afferent.
• Constriction of afferent arterioles increases
the arteriolar resistance, raising systemic
arterial blood pressure and decreasing the
blood flow.
• To maintain glomerular blood pressure
angiotensin II constricts efferent arterioles
• GFR thus maintained despite lowered overall
kidney blood flow
Renal effects of angiotensin II
• Filtration fraction ↑ → ↓ plasma fluid in the
downstream peritubular capillaries →
↓ hydrostatic pressure + ↑ osmotic pressure
(due to unfiltered plasma proteins) in the
peritubular capillaies → ↑ reabsorption of
tubular fluid.
• ↓ medullary blood flow through the vasa
recta → ↓ washout of NaCl and urea in the
kidney medullary space → ↑ [NaCl] + [urea]
in the medulla → ↑ absorption of tubular
fluid.
Fetal renin-angiotensin system
• In the fetus, the renin-angiotensin system is
predominantly a sodium-losing system, as
angiotensin II has little or no effect on
aldosterone levels.
• Renin levels are high in the fetus, while
angiotensin II levels are significantly lower.
• This is due to the limited pulmonary blood
flow, preventing ACE (found predominantly in
the pulmonary circulation) from having its
maximum effect.
ACEi in pregnancy
• ACE inhibitors taken during the first trimester
have been reported to cause major congenital
malformations, stillbirths, and neonatal
deaths.
• Commonly reported fetal abnormalities
include hypotension, renal dysplasia,
anuria/oliguria, oligohydramnios, intrauterine
growth retardation, pulmonary hypoplasia,
patent ductus arteriosus, and incomplete
ossification of the skull.
Biochemical tests of renal function
• How do we assess kidney function?
– Glomerular function
– Tubular function
Glomerular function
• Serum creatinine
– break-down product of creatine phosphate in
muscle
– produced at a fairly constant rate by the body
(depending on muscle mass)
– Freely filtered by glomerulus
– Also some tubular secretion
Glomerular filtration rate (GFR)
• Equivalent to the clearance of a freely filtered
solute e.g. Creatinine
• Units – mls/min/1.73m2
• If creatinine clearance = 100 mls/min
– 100 mls of blood CLEARED of creatinine
each minute
GFR contd.
• If Creatinine clearance (CrCl) = 100 mls/min
and serum creatinine = 100 µmol/l
Rate of creatinine excretion =
GFR contd.
• If Creatinine clearance (CrCl) = 100 mls/min
and serum creatinine = 100 µmol/l
Rate of creatinine excretion = 10 µmol/min
GFR contd.
• If Creatinine clearance (CrCl) = 100 mls/min
and serum creatinine = 100 µmol/l
Rate of creatinine excretion = 10 µmol/min
• If serum creatinine then rises to a steady level
of 200 µmol/l, what is the CrCl now?
GFR contd.
• If Creatinine clearance (CrCl) = 100 mls/min
and serum creatinine = 100 µmol/l
Rate of creatinine excretion = 10 µmol/min
• If serum creatinine then rises to a steady level
of 200 µmol/l, what is the CrCl now?
Still producing 10 µmol of creatinine/min
 still excreting 10 µmol of creatinine/min
GFR contd.
• What volume of blood now contains 10 µmol
of creatinine?
GFR contd.
• What volume of blood now contains 10 µmol
of creatinine?
[Creatinine] = 200 µmol/l
Volume = 10/200 = 0.05 litres = 50 mls
 CrCl = 50 mls/min
• GFR  1 / [Creatinine]
eGFR (mls/min/1.73m2)
MDRD equation :
186 x (Creat / 88.4)-1.154 x (Age)-0.203 x
(0.742 if female) x (1.210 if black)
Schwartz equation:
eGFR = k x (Ht(cm) / Serum [creatinine])
Tubular function
• Primarily proximal tubular reabsorption
– Na+
– Cl– K+
– Ca2+
– HCO3– Nutrients
– H2O
– Proteins
65%
50%
70%
60%
80%
>99% (glucose, amino acids)
65%
Variable
Fractional excretion
FEx = (Ux / Px) x (Pcr / Ucr) x 100
• FEx = fractional excretion of solute x
(expressed as %)
• Ux = urine concentration of solute
• Px = plasma concentration of solute
• Pcr = plasma concentration of creatinine
• Ucr = urine concentration of creatinine
(Check units)
Tubular reabsorption
TRx = 100 - FEx
Practical implications
• Fluid prescribing
• Drug prescribing
• Interpretation of blood results
Prescribing
• Children will need less than adults but how
much less?
• Metabolism  Body surface area (BSA)
• Children’s BSA / kg >> Adult’s
if basing prescription on weight, dose/kg is
greater in children than adults
Fluids
• 100 mls/kg for first 10 kg
• 50 mls/kg for second 10 kg
• 20 mls/kg for each kg above 20 kg
Drug prescribing
• Clinical Pharmacokinetics
– Quantitative study of the relationship between a
drug dosage regimen and the concentration
profile over time.
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Bioavailability
Volume of distribution
Clearance
Elimination half-life (dependent on clearance and Vd)
Drug prescribing contd.
• Consult the Children’s BNF!
Other factors when prescribing
• ?
Other factors when prescribing
• Drug interactions
• Renal function
• Liver function
Drug interactions
• ?
Drug interactions
• Absorption
• Metabolism
– Induction of enzymes
– Inhibition of enzymes
• Protein binding
• Excretion
• Information in the BNF
Prescribing in renal failure
• ?
Prescribing in renal failure
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Increase dose interval
Decrease dose
Problems exacerbated if drug is nephrotoxic
Therapeutic drug monitoring
ANY QUESTIONS?