1. CHILDHOOD CKD PREVENTION PROGRAM IN TAIWAN:WHAT ARE WE GOING TO DO? You-Lin Tain MD, PhD, Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung, Taiwan

2. Purposes • (1)Intervention：which, when, and why？ • (2)CV measurement • (3)Efficiency of ACEI/ARB in CKD progression • (4)Cerebral accident in ESRD children: marker • (5) Primary prevention: • 1. Identify high risk group • 2. how to maintain GFR • (6) Early detection: how and why? • (7) Steering committee?

3. CKD prevention program is intended to raise awareness and increase detection of CKD, but most emphasis is placed on adults rather than children.

4. Prevalence of complications in children with CKD Wang et al., KI, 2006 • CKD Stage • I 57% • II 29% • III 10.4% • IV+V 4.1%

5. Screening for kidney disease in children on World Kidney Day in Jalisco, Mexico Koshy et al., PN, 2009 • 240 children: 8.9 ± 4.1 years; 44.2% male • Proteinuria: 16.1% • Hematuria:17.5% • BMI > 95th percentile for age: 15% • Systolic hypertension: ~7% • Reduced GFR (<60ml/min; CKD stage 3): 1.7% • CKD1-3 • ~15-20%

6. Criteria How to screen? What kinds of screen? Which population? Intervention OR prevention Subcommittee Iseki K, Int Med, 2008

7. Outlines • Cr-based eGFR • Questionnaire design • Which phenotype: High risk group • CKD screen: which parameter(s) • Global status of CKD prevention programs in children • Intervention: ACEi, ARB, OR? • CVD in CKD • Sub-committee OR interesting topic • 林: FGF-23, Ghrelin • 邱: Solitary kidney outcome/LN/Cystic kidney • 田: ADMA and SDMA

8. Outlines • Cr-based eGFR • Questionnaire design • Which phenotype: High risk group • CKD screen: which parameter(s) • Global status of CKD prevention programs in children • Intervention: ACEi, ARB, OR? • CVD in CKD • Sub-committee OR interesting topic • 林: FGF-23, Ghrelin • 邱: Solitary kidney outcome/LN/Cystic kidney • 田: ADMA and SDMA

9. CKD Staging • Stage 1：腎功能正常但有①病理學檢查異常; ②腎損傷的指標：包括血、尿成分異常或影像學檢查異常。eGFR：≧90 ml/min/1.73 m2。 • Stage 2：輕度慢性腎衰竭eGFR：60~89 ml/min/1.73 m2。 • Stage 3：中度慢性腎衰竭eGFR：30~59 ml/min/1.73 m2。 • Stage 4：重度慢性腎衰竭eGFR：15~29 ml/min/1.73 m2。 • Stage 5：末期腎臟病變eGFR：＜15 ml/min/1.73 m2。

11. Estimated GFR in children (NKF K/DOQI )

12. Schwartz Formula Schwartz et al, Pediatrics 58:259,1976 • GFR (mL/min/1.73 m2) = k (Height) / Serum Creatinine • k = Constant • k = 0.33 in premature infants • k = 0.45 for infant • k = 0.70 for pubertal males • k = 0.55 for all other children • Height in cm • Serum Creatinine in mg/dL

14. Creatinine Standardization Recommendations by NKDEP Clinical Chemistry 2006;52(1):5-18. • Jaffe Cr assay • Enzymatic Cr assay • HPLC • IDMS: Cr assays that are traceable to an isotope dilution mass spectroscopy (IDMS) reference measurement procedure. • IDMS-traceable Cr << Jaffe Cr •  overestimate GFR by 20% to 40%

16. K=0.41

17. Calculating eGFR for children http://www.nkdep.nih.gov/labprofessionals/labgfr_children.htm • The older equations for eGFR in children and infants will no longer be valid. • Blood creatinine values will generally be lower for methods that have been calibrated to be traceable to an IDMS reference-measurement procedure. • Not to estimate GFR for children when using an alkaline picrate (“Jaffe”) method with calibration traceable to IDMS. • The interim Schwartz equation (k=0.41) is intended only for enzymatic creatinine methods with calibration traceable to IDMS.

18. K=0.435

19. Not Cinulin?

20. Outlines • Cr-based eGFR • Questionnaire design • Which phenotype: High risk group • CKD screen: which parameter(s) • Global status of CKD prevention programs in children • Intervention: ACEi, ARB, OR? • CVD in CKD • Sub-committee OR interesting topic • 林: FGF-23, Ghrelin • 邱: Solitary kidney outcome/LN/Cystic kidney • 田: ADMA and SDMA

22. High Risk Group • 遺傳性腎臟病家族史(例如多囊腎) • 單一腎臟(任何原因) • 雙側腎發育異常(hypoplasia/dysplasia) • 低出生體重兒於6個月大以上超音波腎/肝強度超過1 • 嚴重腎水腫或阻塞性水腎 • 雙側重度膀胱輸尿管逆流(grade IV-V) • 尿道及膀胱頸之閉鎖及狹窄 • 神經性膀胱 • 除steroid-sensitive nephrotic syndrome外之中重度蛋白尿(≧1公克/天) • 紅班性狼瘡 • 溶血性尿毒症候群 • 高血壓(≧同年齡95%之血壓)

23. High Risk Groups (1) Hogg et al., Pediatrics, 2003

24. High Risk Groups • Hypodysplastic renal disease, VUR • ItalKid • Hematuria, albuminuria, obesity, hypertension • Haysom et al., AJKD, 2009 (Australia) • Low birth weight, nephron number, and kidney disease. • Brenner et al., AJKD, 1994 • ~7% LBW per year in Taiwan • DM type 1 &2 • ~10/100,000 children in Taiwan

25. SCreening for Occult REnal Disease (SCORED) Arch Intern Med. 2007;167(4):374-381

26. Ca, P?

27. Status of CKD Prevention Programs Smith et al., KI, 2008 • International Federation of Kidney Foundations (IFKF) survey: 28 countries response (56%) • Most countries are not focused on children • KEEP - Kidney Early Evaluation Program - USA • KEY - Kidney Evaluation for You - Australia • IKEAJ - International Kdiney Early Evaluation Program – Japan • NICE guideline – UK • …….. • Mass Urinary Screening: Taiwan, Japan, Korea…. • Chronic Kidney Disease in Children (CKiD) study- USA • Italkid Project- Italy

29. Chronic Kidney Disease in Children (CKiD) study • Glomerular filtration rate measurement and estimation in chronic kidney disease. • Pediatr Nephrol. 2007 Nov;22(11):1839-48. • Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study. • Clin J Am Soc Nephrol. 2006 Sep;1(5):1006- • Validation of creatinine assays utilizing HPLC and IDMS traceable standards in sera of children. • Pediatr Nephrol. 2009 Jan;24(1):113-9. • New Equations to Estimate GFR in Children with CKD. • J Am Soc Nephrol. 2009 Mar;20(3):629-37.

30. Specific Aims • Identify risk factors for the progression of CKD • Characterize the impact of CKD on neurodevelopment, cognitive abilities, and behavior • Identify the prevalence and the evolution of CV disease risk factors in children with CKD • Examine the effects of declining GFR on growth

31. Recruit CKD stage 2&3 • Prospective cohort study • 540 children

32. CKiD Study Organization

37. Italkid: Started in 1990 • Urea percentiles in children with chronic renal failure. Data from the ItalKid project. • Pediatr Nephrol. 2003 Mar;18(3):261-5. • Epidemiology of chronic renal failure in children: data from the ItalKid project. • Pediatrics. 2003 Apr;111(4 Pt 1):e382-7. • The probability of ESRD by age 20 years was 68% (eGFR<75=CKD stage 2B-5) • Severe vesicoureteral reflux and chronic renal failure: a condition peculiar to male gender? • J Pediatr. 2004 May;144(5):677-81.

38. Italkid • Proteinuria as a predictor of disease progression in children with hypodysplastic nephropathy. Data from the Ital Kid Project. • Pediatr Nephrol. 2004 Feb;19(2):172-7. • Long-term outcome of VUR associated chronic renal failure in children. Data from the ItalKid Project. • The probability of ESRD by age 20 years was 56% (eGFR<75=CKD stage 2B-5) • J Urol. 2004 Jul;172(1):305-10.

39. Italkid • Prescription of drugs blocking the renin-angiotensin system in Italian children. • Pediatr Nephrol. 2007 Jan;22(1):144-8. • No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy--report from the ItalKid. • Nephrol Dial Transplant. 2007 Sep;22(9):2525-30.

40. Prevention of CKD in Children Vijayakumar et al., Indian J Nephrol, 2007 • Primary • Reduce exposure to factors that cause renal disease • Reduce antenatal exposure to infections, drugs • Prevention of inheritable renal disease by genetic counseling • Prevention of obesity, dyslipidemia • Early detection/management of hypertension and DM • Secondary • Appropriate measures at various stages of CKD • Tertiary • Reduction of complications impairments or disabilities • Requiring RRT

41. 三段五級的預防工作 初段預防 次段預防 末段預防

42. 疾病自然史與三段五級預防工作

43. Outlines • Cr-based eGFR • Questionnaire design • Which phenotype: High risk group • CKD screen: which parameter(s) • Global status of CKD prevention programs in children • Intervention: ACEi, ARB, OR? • CVD in CKD • Sub-committee OR interesting topic • 林: FGF-23, Ghrelin • 邱: Solitary kidney outcome/LN/Cystic kidney • 田: ADMA and SDMA

44. Final Common Pathway for Progression of Chronic Kidney Disease Brenner BM, JCI, 2002

45. Prevention of CKD progression by ACEI/ARB www.eguidelines.co.uk/.../clark_angiotensin.gif

46. Surrogate end-point of CKD Progression: Proteinuria &Hypertension Hypertension Risk factors CKD progression Proteinuria Hypertension Proteinuria Risk factors CKD progression CKD

47. End-point: Hypertension • The use of ACEI/ARB in children with diabetes and microalbuminuria or proteinuric renal disease. • The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents , Pediatrics, 2004

48. ACEI/ARB for Hypertension in Children The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents , Pediatrics, 2004

49. Rate of cough as a side effect of ACE inhibitor and ARB therapy Matchar DB et al. Ann Intern Med 2008; 148:16-29.

50. Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals Kunz R et al. Ann Intern Med 2008; 148:30-48.