Concepts of Renal Injury & CKD Prevention

1. Concepts of Renal Injury & CKD Prevention Dhavee Sirivongs, M.D. September 15, 2005 Lecture Hall 1 Faculty of Medicine, KKU

2. Early Stage CKD has been neglected? • High compensatory kidneys • No annual check up • Clinical presentation appears at CKD V • Patients are high tolerant • No doctor concern, no GFR calculation • No public awareness • Etc.

3. Concepts • Critical mass of the kidney • Genetic factor • Environmental insults, include. drugs • In-body factors: Ht • Progressive nature of kidney disease & kidney

4. CKD: pathophysiology • original insult destroyed most nephron • The rest of nephron was hypertrophyas compensatory process • Non-immunological insults destroy glomeruli & tubules • Immunological insults destroy glomeruli & tubules • Proteinuria destroys the tubule via oxidation • Obstructive nephropathy induces glomerular and intersitium invasion of wbc

5. Acute process Unrecovery ARF Trauma Surgical Nephron Loss to Critical number Immunological (SLE) Metabolic (DM) Mechanical (OU) Chronic process

6. Mechanisms of Renal Injury • Immunological insults (direct) & proteinuria (indirect): SLE, NS • Non-immuno insults (direct) & proteinuria (indirect): DM, acetaminophen, pregnancy related • Obstructive nephropathy (tubular dilatation, jncreased luminal pressure, glomerulosclerosis

7. Collagen type IV

8. Lupus nephritis

9. Lupus nephritis

10. Lupus nephritis

11. Lupus nephritis

12. Obstructive nephropathy

15. Nephron Loss to Critical number Progressive nephron loss CKD V ESRD Wear & Tear Hemodynamic Hypertrophy Fibrotic changes Etc. Factors: Hypertension, Smoking, Drugs, Pre-renal

16. Markers of renal injury • Microalbuminuria/Proteinuria • Urinary sediments: hematuria, pyuria • Clinical index: Nocturia (poor concentrating ability), Hypertension • FEMg ?

17. Brenner, Meyer, Hostetter, N Engl J Med, 1982 A unifying hypothesis for the progressive nature of renal disease Renal injury Reduced number of nephrons Systemic hypertension Autoregulation* Glomerular hypertension SCARRING * Lost in diabetes

18. Proteinuria/MicroalbuminuriaThe current number one marker for renal injury(also the marker for CVS morbidity/mortality)

19. Proteinuria Hypertension

20. PODOCYTE DYSFUNCTION IN RESPONSE TO PROTEIN LOAD Ang II ACEi / AIIRA Increased glomerular permeability to proteins Proteinuria Podocyte protein accumulation Loss of differentiated phenotype Cytoskeleton rearrangement Gene activation TGF-b Slit diaphragm dysfunction Prosclerosing activation of mesangial cells Podocyte detachment Foot process effacement Permselective dysfunction Permselective dysfunction GLOMERULOSCLEROSIS Abbate et al., Am J Pathol, 2002

22. Mechanism of Proteinuria

23. Renal Injury Tubular injury Glomerular injury Albuminuria Hypertension Renal deterioration

24. Conclusive concept Known cause Unknown cause Treatable cause Diseased kidney CKD 1 CKD 2 CKD 3 CKD 4 CKD 5 Normal kidney Markers of Kidney damage

25. Life style modification • Adequate fluid intake • Low salt diet • Proper protein diet • Adequate rest • Stop smoking • Exercise • Etc.

26. Pharmacological approach Angiotensin converting enzyme inhibitor (ACE-I) Angiotensin receptor blocker (ARB)

27. Concept of ACE-I/ARB Usage ใช้แนวคิด “เศรษฐกิจพอเพียง ลดความฟุ้งเฟ้อ”

28. Ramipril Conventional therapy REIN: ACE-I IS MORE RENOPROTECTIVE THAN CONVENTIONAL THERAPY IN NON-DIABETIC RENAL DISEASE 100 % of patients without doubling of baseline creatinine or ESRF 80 60 P=0.02 40 20 0 • 100 – • 90 – • 80 – • 70 – • 60 – • 40 – • - 20 – • 0 – • 20 – • 40 – • 60 – 0 6 12 18 24 30 36 Follow-up Diastolic Blood Pressure (mm Hg) % Reduction in Proteinuria Gisen group; Lancet 1997

29. 3 MONTHS PROTEINURIA REDUCTION PREDICTS LONG-TERM GFR DECLINE The REIN study Ramipril Overall Conventional - 0.9 > 3 gr/24 h - 0.8 - 0.7 • GFR (ml/min/month) 3 years - 0.6 -0.5 - 0.4 -0.3 -0.2 - 20 0 20 40 D proteinuria * ( percent change vs .baseline) 3 months * Corrected for GFR Perna et al., J Am Soc Nephrol, 2000

30. Ramipril Ramipril 4 5 D GFR = -0.44 ± 0.54 4 0 D GFR = -0.10 ± 0.50 GFR (ml/min/month) 3 5 3 0 D GFR = -0.81 ± 1.12 D GFR = -0.14 ± 0.87 2 5 Conventional Ramipril FOLLOW-UP CORE Ruggenenti et al., Lancet, 1998

32. 0 Losartan Conventional therapy 25 50 75 100 0 1 2 3 4 RENAAL: ARB IS BETTER THAN CONVENTIONAL THERAPY IN TYPE 2 DIABETIC NEPHROPATHY % with Doubling of Baseline Creatinine + ESRD + death • + 2 – • 0 – • - 2 – • - 4 – • 6 – • 8 – • 9 – • 10 – • + 40 – • + 20 – • 0 – • - 20 – • 40 – • 60 – p <.001 + 19 Decrease in Mean Blood Pressure (mm Hg) % Reduction in Proteinuria -9.2 -9.6 - 45 NS Brenner et al, N Engl J Med., 2001.

33. 6 MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS RENAL AND CARDIOVASCULAR EVENTS The RENAAL study Hazard ratio (95 % C.I.) ESRD CV events Heart failure Increased risk Decreased risk 1 0.8 1.2 0.4 0.6 0.2 RENAAL Study group, 2002

34. Prevention of progression and remission strategies for chronic kideny diseases • Stop activities of the insult(s) • Save the the rest of nephrons • Life style modification eg. Stop smoking • Pharmacological approach, to control hypertension, intraglomerular pressure, protein/microalbuminuria Ideal drugs: ACEI, ARB

35. ISN: Activities on CKD prevention • Canada: Symposium on CKD prevention yearly since 2002 • Mexico 2003: The Ensenada Conference on Renal Disease in Minorities Groups, with Emphasis on the Americas • Italy 2004: Bellago conference: Prevention of Renal Disease in the Emerging World: Toward global Health Equity • Hong Kong 2004: CKD Prevention • Pre-congress WCN 2005, Singapore

36. ISN: Prevention strategies • Detecting those at risk of developing CKD • Preventing the onset of CKD in susceptible individuals by altering lifestyle • Detecting those with early stage CKD • Preventing progression of CKD by intervention • Developing and applying diagnostic guidelines including albuminuria and estimated GFR as well as therapeutic guidelines • Raising awareness with the general public, policymakers and physicians • Creating funds and facilities for global assistances

37. กิจกรรม CKD prevention ในไทย • คณะอนุกรรมการป้องกันไตวายเรื้อรัง สมาคมโรคไตฯ • แผนงานป้องกันภาวะไตวายแบบบูรณาการ • สัมมนาอายุรแพทย์โรคไต • แนวปฏิบัติเพื่อชะลอการเสื่อมของไต • อบรมวิทยากรพยาบาล • โครงการศึกษาอัตราการเสื่อมของไต • อบรมแพทย์และพยาบาลใน 5 พื้นที่ใน 5 ภาค 22-23 กย. 48 • เผยแพร่ความรู้ให้กับประชาชน 5 ธค. 48 กลุ่มวิจัยโรคไตเรื้อรัง คณะแพทยศาสตร์ ม.ขอนแก่น ก่อตั้งตั้งแต่ ปี พ.ศ. 2544

38. End of the session

39. Loss of Kidney Mass

40. A META-ANALYSIS IN 840 TYPE 1 AND TYPE 2 DIABETIC PATIENTS WITH INCIPIENT AND OVERT NEPHROPATHY AND PRESERVED RENAL FUNCTION Change in proteinuria (%) Change in GFR (%/year) Modified from Weidmann et al., Nephrol Dial Transpl, 1995

43. Cause/Etiology Pre-clinical evidences Clinical evidences Lab. evidences

44. NEPHRON NUMBER IN 10 MIDDLE-AGED WHITE HYPERTENSIVES AND 10 MATCHED NORMOTENSIVES Nephron number per kidney 2,500 1,429 (1,130-1,627) 2,000 * 1,500 (x 1,000) 706 (626-802) 1,000 500 0 HP N Mean glomerular volume (10-3/mm3) 2.8 6.5 p < 0.001 * Keller et al., N Engl J Med, 2003

45. HALTING THE PROGRESSION OF CHRONIC NEPHROPATHIES: The negleted issue of residual proteinuria 1.00 Residual proteinuria (6 months) 0.75 DGFR (ml/min/month) 3 years 0.50 0.25 0 Tertiles Proteinuria Lowest < 1.5 g/24 h Middle 1.5 - 3.5 g/24 h Highest ≥3.5 g/24 h Ruggenenti et al., J Am Soc Neph, 2000