What’s different about children?

1. What’s different about children?

2. For more about paediatric nephrology go to: http://paedstudent.cf.ac.uk

3. Aims of talk • Reminder about normal renal embryogenesis and neonatal development • Paediatric renal physiology • Impact on management of children

4. 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

5. 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

6. Renal function during infancy

7. Feeding

8. 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.

9. 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.

10. 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

11. 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

12. 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+

13. 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

15. 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

16. 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 peritubularcapillaies → ↑ 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.

17. Fetalrenin-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.

18. 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 ductusarteriosus, and incomplete ossification of the skull.

20. Biochemical tests of renal function • How do we assess kidney function? • Glomerular function • Tubular function

21. 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

22. 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

23. GFR contd. • If Creatinine clearance (CrCl) = 100 mls/min and serum creatinine = 100 µmol/l Rate of creatinine excretion =

24. GFR contd. • If Creatinine clearance (CrCl) = 100 mls/min and serum creatinine = 100 µmol/l Rate of creatinine excretion = 10 µmol/min

25. 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?

26. 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

27. GFR contd. • What volume of blood now contains 10 µmol of creatinine?

28. 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]

29. 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])

30. 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

31. 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)

32. Tubular reabsorption TRx = 100 - FEx

33. Practical implications • Fluid prescribing • Drug prescribing • Interpretation of blood results

34. 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

35. Fluids • 100 mls/kg for first 10 kg • 50 mls/kg for second 10 kg • 20 mls/kg for each kg above 20 kg

36. 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)

37. Drug prescribing contd. • Consult the Children’s BNF!

38. Other factors when prescribing • ?

39. Other factors when prescribing • Drug interactions • Renal function • Liver function

40. Drug interactions • ?

41. Drug interactions • Absorption • Metabolism • Induction of enzymes • Inhibition of enzymes • Protein binding • Excretion • Information in the BNF

42. Prescribing in renal failure • ?

43. Prescribing in renal failure • Increase dose interval • Decrease dose • Problems exacerbated if drug is nephrotoxic • Therapeutic drug monitoring

44. Any questions?