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 infancyPremature infant

Term infant

First 3 days

First 3 days 2 weeks 8 weeks 1 year

Daily excretion of urine

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

FeedingMature breast milk Cow’s milk

Electropositive elements (mEq/l) 41 149

Na (mg/l) 180 768

Ca (mg/l) 300 530

Electronegative elements (mEq/l) 28 108

Phosphate (mg/l) 150 920

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

• 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 18-20 mmol/l– Adult 24-26 mmol/l– Premature infant 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/lRate of creatinine excretion =

GFR contd.

• If Creatinine clearance (CrCl) = 100 mls/min and serum creatinine = 100 µmol/lRate of creatinine excretion = 10 µmol/min

GFR contd.

• If Creatinine clearance (CrCl) = 100 mls/min and serum creatinine = 100 µmol/lRate 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/lRate 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/lVolume = 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+ 65%– Cl- 50%– K+ 70%– Ca2+ 60%– HCO3

- 80%– Nutrients >99% (glucose, amino acids)– H2O 65%– Proteins 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.• 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

• Increase dose interval• Decrease dose• Problems exacerbated if drug is nephrotoxic• Therapeutic drug monitoring

ANY QUESTIONS?