Chronic Renal Failure in Children and Adolescents

1. Chronic Renal Failure in Children and Adolescents Dr Ian Ramage Consultant Paediatric Nephrologist Glasgow

2. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

3. Definition - Adults

4. Definition - Adults

5. Definition - Children • (a) Kidney damage for > 3 months, as defined by structural or functional abnormalities determined by kidney biopsy, imaging tests or composition of the blood or urine, with or without decreased GFR; AND • (b) GFR < 60ml/min/1.73m2 for ≥ 3 months, with or without the signs of kidney damage listed above

6. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

7. Increases with age 9 (MARP) 0-4 years 14 (MARP) 10-14 years 28 (MARP) 15-19 years ESRF 9.9 (MARP) Prevalence increased 22.9 in 1980 62.1 in 2000 Higher in males Higher in Blacks/Indigenous Epidemiology

8. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

9. Aetiology

10. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

11. Nutrition • Dietician • Protein • Calcium and Phosphate • Calories • Lipids • Fluids • Vitamins & Minerals • Iron, Copper, Zinc • Feeding Disorders

12. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

13. Growth • Prenatal • Infantile • Nutrition > GH • Max growth from >25cm/yr at birth • 18cm/yr age 1yr • 10cm/yr age 2 yr • Childhood • GH and Thyroid hormone dependent • Children grow along percentile achieved at the end of 2 years of life (Van Dyck M Pediatr Nephrol 1999) • Pubertal • Delayed peak height velocity of ~ 2.5 years • Growth spurt delayed & shortened with reduced growth velocity • Only 65% of healthy children • Loss of pulsatile hypothalamic release ofGnRH

14. Growth • Children with CKD fail to reach adult height potential (Haffner D N Eng J Med 2000) • 36% of CKD patients have growth impairment • Average Ht SDS at transplantation – 1.85 • Greatest in Males • Greatest in Younger Patients • Increased morbidity and mortality (Furth NL Pediatr Nephrol 2002) • Each SDS decrease associated with a 14% increase in death (Wong CS A J Kid Dis 2000)

15. Growth • Dietician • Nutrition • Supplemental Feeding • Gastro-oesophageal reflux • NG/Gastrostomy • Fundoplication • Growth Hormone (Haffner D N Eng J Med 2000) • Everything Else

16. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

17. Renal Osteodystrophy • Nutrition • Dietician • Pharmacist • Psychologist • Nurse Specialist • Doctor

18. Renal Osteodystrophy CKD – Mineral and Bone Disorder (Moe S Kidney Int 2006) • Abnormalities of calcium, phosphorous, PTH and vitamin D metabolism • Abnormalities in bone turnover, mineralisation, volume, linear growth or strength • Vascular and other soft tissue calcification

19. Renal Osteodystrophy Abnormalities of calcium, phosphorous, PTH and vitamin D metabolism (Wesseling K Pediatr Nephrol 2008) • Kidneys hydroxylate vitamin D to calcitriol • Reduction in calcitriol early in CKD • Decreased intestinal Calcium absorption • Increased PTH release • Initially N or low PO4 • Later ↓ GFR ↓ PO4 excretion with ↓ hydroxylation and ↑ PTH • Renal and skeletal PTH resistance • Increased PTH • Antagonised by Vitamin D • If unchecked • Parathyroid hyperplasia • Autonomous unregulated Parathyroid growth and hormone release

20. Renal OsteodystrophyAbnormalities in bone turnover, mineralisation, volume, linear growth or strength (Wesseling K Pediatr Nephrol 2008) • Bone Turnover • Characteristically “High Turnover” • Increased Osteoclastic and Osteoblastic Activity • Can occur early in CKD • “Low Turnover” – Adynamic bone disease • Only reported in dialysis patients • Excess of Vitamin D and Calcium with PTH suppression • Increased fractures and growth retardation

21. Renal OsteodystrophyAbnormalities in bone turnover, mineralisation, volume, linear growth or strength (Wesseling K Pediatr Nephrol 2008) • Bone Mineralisation • Increased Osteoid (unmineralised bone) • Defective mineralisation • Increased Fractures • Growth retardation • Bone Abnormalities • Bone Volume • PTH is anabolic to trabecular bone • Increased bone volume • Steroid therapy

22. Renal OsteodystrophyAbnormalities in bone turnover, mineralisation, volume, linear growth or strength (Wesseling K Pediatr Nephrol 2008) • Linear Growth • Target PTH level unclear • GH Resistance • ↓ IGF1 Bioactivity • Strength • Epiphyseal widening • Slipped Epiphysis • Genu Valgum • Femoral and wrist abnormalities • Avascular necrosis • Pathological fractures • - NKF K/DOQI 2005 Am J Kid Dis • 41 – Klaus G EWPDG 2006 Pediatr Nephrol

23. Renal Osteodystrophy Vascular and other soft tissue calcification (Wesseling K Pediatr Nephrol 2008) • Vascular calcification is present in children (Milliner DS 1990 Kidney Int, Goodman WG N Eng J Med 2000) • Risk factors* (Russo D Am J Kid Dis 2004, Mitsnefes MM JASN 2005) • Hypercalcaemia • Hyperphosphataemia • Increased Ca x Po4 product • High dose vitamin D • Pathophysiology • Menchymal to osteoblast conversion • Upregulation of Na dependent PO4 transporter • Upregulation of pro mineralisation factors • Calcium based PO4 binders – PREVENTABLE (Chertow GM Kidney Int 2002, Block GA Kidney Int 2005)

24. Renal Osteodystrophy - Treatment • Dietician • Phosphate Binders • Calcium based binders used most commonly • Aim to keep Ca intake < double DRI • If ↑ Ca stop binder ± Vitamin D • Sevelamer • Non calcium based • Halts progression of vascular calcification (Block GA Kidney Int 2005) • Lower mortality rates (Block GA Kidney Int 2007) • Lanthanum • Accumulation in liver, bone and growth plate (Spasovski GB Nephrol Dial Transpl 2006, Slatopolsky E Kidney Int 2005) • Intensive Dialysis

25. Renal Osteodystrophy - Treatment • Secondary Hyperparathyroidism • Vitamin D • Ergocalciferol/Cholecalciferol • Calcitriol • Paracalcitriol* • Calcimimetics • Cinacalcet

26. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

27. CKD - Anaemia • Adequately treated anaemia (Morris KP Arch Dis Child 1994, Morris KP Arch Dis Child 1993, Jabs K Pediatr Nephrol 1996, Warady BA Pediatr Nephrol 2003) • Mortality • Quality of life • Exercise tolerance • Growth • Cardiovascular Function

28. CKD - Anaemia • Published success (Children v Adults) (Chavers BM Kidney Int 2004) • Haemodialysis - 54% v 40% • Peritoneal Dialysis 69% v 55% • CKD – 36.6% (Wong H Kidney Int 2006) • CKD 1 – 31% • CKD 4/5 – 93%

29. CKD – Anaemia (Hollowell JG 2005) Initiate anaemia work-up when Hb < 5th percentile(NKF – K/DOQI 2006 AM J Kid Dis)

30. CKD – Anaemia • Erythropoeitin Deficiency • Iron Deficiency • Blood Loss • Phlebotomy • Haemodoalysis • Menses • GI • Dietary insufficiency or poor absorption • Depletion during EPO therapy • Decreased RBC survival • Bone Marrow suppression • Inadequate dialysis • Malnutrition • Infection and Inflammation • Hyperparathyroidism • B12 or Folate Deficiency • Carnitine Deficiency • Medications

31. CKD – Anaemia Koshy SM & Geary DF Pediatr Nephrol 2008

32. CKD – Anaemia Treatment • Measure pre-dialysis ? • Measurement • Monthly if stable • 1-2 weeks if changes made ? (Greenbaum LA, Comprehensive Pediatric Nephrology, Elsvier 2008) • Iron • Erythropoeitin • Darbopoeitin • Mircera

33. CKD – Anaemia Treatment • Iron • Monitoring Iron stores • Ferritin • Acute phase protein • ESA’s cause functional iron deficiency • Normal or elevated level doesn’t exclude deficiency • TSAT – Serum Iron/TIBC - <20% • Iron therapy • Oral • IV • Age specific

34. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

35. CKD - Hypertension • Very common (Wong H Kidney In 2006) • CKD I – 63% • CKD 4/5 – 80% • ESDR 50% uncontrolled (Tcakzyk K 2006 Nephrol Dial Transplant, Mitsnefes MM J Am Soc Nephol 2005) • Progression of CKD (Wingen AM Lancet 1997, Mitsnefes MM J Am Soc Nephol 2003) • Cardiovascular mortality (Kroothoff JW Kidney Int 2002) • Aetiology ↑BP = ↑ CO X ↑ TPR Hadstein C & Schaefer F Ped Nephrol 2008

36. CKD – Hypertension Aetiology ↑BP = ↑ CO X ↑ TPR • RAS • Fluid Overload • Sympathetic system • Catecholamines & Renalase • Nitrous Oxide • NO synthetase • ADMA (Zocalli C Lancet 2001, Fliser D 2002 J Am Soc Nephrol) • Drugs Hadstein C & Schaefer F Ped Nephrol 2008

37. CKD Hypertension Surveillance

38. CKD Hypertension Treatment • Fluid management • Dialysis prescription • Lifestyle changes • Salt • Calories • Exercise

39. CKD Hypertension Treatment • ACE • ARB • ACE/ARB • Calcium Channel Blockers • β – blockers • Diuretics • Others • Escape Trial Group N Eng J Med 2009 • CONCLUSIONS: Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition.

40. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

41. CKD – Cardiovascular Disease • CKD Patient Survival • 40-60 yrs less for dialysis • 20-25 yrs less for transplants • CV Disease 40-50% (Oh J Circulation 2002, Groothoff JW Kidney Int 2002, McDonald SP 2004 N Eng J Med) • Sudden Cardiac Death • Arrythmias • Dilated Hypertrophic Cardiomyopathies • LVH • Ischaemic Heart Disease ? Mitsnefes MM 2008 Ped Nephrol

42. CKD – Cardiovascular Disease • Treatment - Minimise Risk Factors • Transplantation • ↓ Cardiac Death by 80% • ↑ Life expectancy by 20-25 years • Hypertension, Hyperlipidaemia, CAN • Hypertension • Proteinuria • Anaemia • Dyslipidaemia • Renal Osteodystrophy • Therapeutic Lifestyle Changes (TLC) • No evidence for hyperhomocysteinaemia or chronic inflammmation

43. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

44. CKD Neurodevelopment • Neuroimaging • 12-23% Cerebral atrophy • Chronic Infarct lesions • Electrophysiology • EEG abnormalities 30-40% • Predominantly slow wave increase • Cognitive Function • Variable Results • Largest deficit in infants* • Lower IQ particularly non-verbal • Variable Improvement post transplantation

45. CKD Neurodevelopment • Specific Neurocognitive Functions (Hulstijn-Dirkmaat GM 1995 Ped Nephrol, Ledermann 2000 J Pediatr, Warady BA 1999 Ped Nephrol) • Attention and executive functions • Language • Visual-spatial • Memory • Academic Achievement and School Performance • Poorer Performance than peers (Brouhard PH 2000 Ped Transplant) • Transplanted patients perform better (Gipson DS 2006 Child Neuropsychol) • 15% Special Educational Needs • 77% had CNS Infarcts (Qvist E 2002Ped Tansplant) • Assessment and early intervention key

46. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

47. Chronic Renal Failure in Children and Adolescents • Definition • Epidemiology • Aetiology • Clinical • Nutrition • Growth • Bones • Anaemia • Blood Pressure • Cardiovascular Disease • Neurodevelopment • Psychosocial • Pharmacy • Treatment • Outcome

48. CKD - Progression • Age of attainment of renal mass deficit • Gender • Underlying Disease & Genetic Pathology • Polymorphic Genetic Variation • Dyslipidaemia and Insulin Resistance • Nutrition • Anaemia • Disorders of Calcium & Phosphate • Proteinuria • Hypertension Gonzalez Celedon C 2007 Pediatr Nephrol

49. CKD Progression - Proteinuria • REIN Study (Kramer BK 1997 Lancet) • ItalKid Study (Ardissino G 2004 Ped Nephrol) • Escape Study (2009 N Eng J Med) • Summary • 1G/day reduction in proteinuria reduces GFR decline by 2ml/min/year • Target < 300mg/m2/day • Associated benefit of treating BP Wingen AM Lancet 1997

50. CKD Progression - Blood Pressure • ACE Inhibition • 30-40% reduction in doubling creatinine or ESRD in those with proteinuria (Jaffar TH 2001 Ann Intern Med, Remuzzi G 2001 Lancet) • “Aldosterone Escape” • Gradual introduction • Initial response predictive of long term benefit • May see 10-15% drop in GFR • Positive predictor of renoprotection • May not persist in children (Wuhl E 2006 Pediatr Nephrol) Wingen AM Lancet 1997