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 Premature infant Term infant First 3 days First 3 days2 weeks8 weeks1 year Daily excretion of urine ml/kg/24h15-7520-7525-12080-13040-100 % of fluid intake40-80 50-7045-6540-60 Maximal urine osmolality (mOsm/kg H 2 O) 400-500500-600700-8001000-12001200-1400 Glomerular filtration rate (ml/min/1.73m 2 ) 10-1515-2035-4575-8090-110

7. Feeding Mature breast milkCow’s milk Electropositive elements (mEq/l)41149 Na (mg/l)180768 Ca (mg/l)300530 Electronegative elements (mEq/l)28108 Phosphate (mg/l)150920

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 ECFICF 2 months30%43% 9 months27%35%

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 HCO 3 - and H +

13. Acid-base balance Renal threshold for bicarbonate – Term infant18-20 mmol/l – Adult24-26 mmol/l – Premature infantas 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 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.

17. 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.

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 ductus arteriosus, 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/1.73m 2 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/1.73m 2 ) 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% – Ca 2+ 60% – HCO 3 - 80% – Nutrients>99%(glucose, amino acids) – H 2 O65% – ProteinsVariable

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 V d )

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

38. Other factors when prescribing ?

39. Drug interactions Renal function Liver function

40. Drug interactions ?

41. Absorption Metabolism – Induction of enzymes – Inhibition of enzymes Protein binding Excretion Information in the BNF

42. Prescribing in renal failure ?

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

44. ANY QUESTIONS?