1. Canadian Diabetes Association Clinical Practice Guidelines Chronic Kidney Disease in Diabetes Chapter 29 Phil McFarlane, Richard E. Gilbert, Lori MacCallum, Peter Senior

2. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association SCREEN regularly with random urine albumin creatinine ratio (ACR) and serum creatinine for estimated glomerular filtration rate (eGFR) DIAGNOSE with repeat confirmed ACR ≥2.0 mg/mmol and/or eGFR <60 mL/min DELAY onset and/or progression with glycemic and blood pressure control and ACE-inhibitor or Angiotensin Receptor Blocker (ARB) PREVENT complications with “sick day management” counselling and referral when appropriate 2013 Chronic Kidney Disease (CKD) Checklist

3. Patients with DM 6-12X more likely to be hospitalized for CKD or End-stage renal disease (ESRD) Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

4. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Diabetes is #1 Cause of New Cases of ESRD Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

5. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association CKD in Diabetes ACR ≥2.0 mg/mmol and / or eGFR <60 mL/min 2013

6. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Diabetic Nephropathy “ Progressive increase in proteinuria in people with longstanding diabetes, followed by declining function which can eventually lead to End-Stage Renal Disease (ESRD)”

7. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Stages of Diabetic Nephropathy Note: change in definition of microalbuminuria ACR ≥2.0 mg/mmol 2013

8. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

9. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Screening and Diagnosis of CKD in Diabetes

10. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

11. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Beware of Transient Albuminuria

12. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

13. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

14. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 2013

15. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

16. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

17. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 2

18. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Beware of Other Causes of CKD

19. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association When to Consider Other Causes of CKD

20. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 2

21. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Care Gap Still Exists for Screening Canadian Institute of Health Information – Diabetes Care Gap 2009

22. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Optimal glycemic control in type 1 and type 2 diabetes has been shown to reduce the development and progression of nephropathy Prevention of Diabetic Nephropathy

23. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. 34% RRR (p<0.04) 43% RRR (p=0.001) 56% RRR (p=0.01) Primary PreventionSecondary Intervention Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria DCCT: Reduction in Albuminuria RRR = relative risk reduction CI = confidence interval guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

24. deBoer IH et al. Arch Intern Med 2011;171(5):412-420. HR 1.92 (p<0.05) HR 0.64 (95% CI 0.40-1.02) Return to normoalbuminuria Macroalbuminuria HR = hazard ratio CI = confidence interval guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association EDIC: Continued Reduction in Albuminuria

25. EDIC: Early Glycemic Control Reduces Long-term Risk of Impaired GFR Risk reduction with intensive therapy 50% (95% CI 18-69; p=0.006) DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-76.

26. After median 8.5 years post-trial follow-up Aggregate Endpoint 19972007 Any diabetes related endpoint RRR: 12%9% P: 0.029 0.040 Microvascular disease RRR: 25%24% P: 0.00990.001 Myocardial infarction RRR: 16%15% P: 0.0520.014 All-cause mortality RRR: 6%13% P: 0.440.007 Holman R, et al. N Engl J Med 2008;359. UKPDS: Post-trial Monitoring “Legacy Effect” guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

27. New/worsening nephropathy, retinopathy 66 Cumulative incidence (%) Follow-up (months) HR 0.86 (0.77-0.97) p = 0.01 Standard control Intensive control 25 20 15 10 5 0 06121824303642485460 Adapted from: ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72. ADVANCE Collaborative Group. N Engl J Med 2008;358:24. ADVANCE: Primary Microvascular Outcomes

28. Reducing Progression of Diabetic Nephropathy Optimal glycemic control (as shown) Optimal blood pressure control ACE-inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB) guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

29. ACE-inhibitor in T1DM with MAU Reduces Progression to Clinical Proteinuria Laffel LM et al. Am J Med 1995;99(5):497-504. Months of Therapy Proportion with Event guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

30. Lewis EJ et al. N Engl J Med 1993;329:1456-62. ACE-inhibitor in T1DM with Macroalbuminuria Reduces Renal Outcomes guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

31. ARB in T2DM with MAU reduces progression Parving et al. N Engl J Med 2001;345:870-8 Primary endpoint: Time to onset of diabetic nephropathy* (n=590) *defined by persistent albuminuria in overnight specimens, with urinary albumin excretion rate <200 μg/min and ≥30% higher than baseline level Placebo Irbesartan 150mg Irbesartan 300mg guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

32. Brenner et al. N Engl J Med 2001;345:861-9 Cumulative % of patients with event Months 240123648 Placebo Losartan Risk reduction = 16% p=0.02 0 10 20 30 40 50 Primary endpoint: Time to doubling of serum creatinine, ESRD, or death (n=1513) ARB in T2DM with Macroalbuminuria Reduces Renal Outcomes guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

33. Lewis et al. N Engl J Med 2001;345:851-60 Primary endpoint: Time to doubling of serum creatinine, ESRD, or death (n=1,715) Patients (%) 0 61218243036424854 Follow-up (mo) 60 0 10 20 30 40 50 60 70 Irbesartan Amlodipine Placebo RRR 20% p=0.02 p=NS RRR 23% p=0.006 ARB in T2DM with Macroalbuminuria Reduces Renal Outcomes

34. Safe use of treatments in kidney disease…..

35. Check serum K + and Cr – Baseline – Within 1-2 weeks of initiation or titration – During acute illness If K + becomes elevated or Cr >30% increase Review therapy Recheck serum K + and Cr Practical Tips: Potassium (K+) and Creatinine (Cr) guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

36. Mild to moderate stable hyperkalemia – Counsel on a low potassium diet – If persistent, consider adding non-potassium sparing diuretics and/or oral sodium bicarbonate (in those with metabolic acidosis) – Consider temporarily holding or discontinuing ACEi, ARB or Direct Renin Inhibitor (DRI) Severe hyperkalemia – Hold or discontinue ACEi, ARB or DRI – Emergency management strategies guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Practical Tips: Potassium (K+) and Creatinine (Cr)

37. Counsel all Patients About Sick Day Medication List 2013

38. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association See CPG Appendix 6 for therapeutic considerations for renal impairment 2013

39. Chronic, progressive loss of kidney function ACR persistently >60 mg/mmol eGFR <30 mL/min Unable to remain on renal-protective therapies due to adverse effects such as hyperkalemia or a >30% increase in serum Cr within 3 months of starting ACEi or ARB Unable to achieve target BP (could be referred to any specialist in hypertension) When to Refer….. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

40. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 1.In adults, screening for CKD in diabetes should be conducted using a random urine ACR and a serum creatinine converted into an eGFR [Grade D, Consensus]. Screening should commence at diagnosis of diabetes in individuals with type 2 diabetes and 5 years after diagnosis in adults with type 1 diabetes and repeated yearly thereafter. Recommendation 1: Screening

41. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association A diagnosis of chronic kidney disease should be made in patients with a random urine ACR ≥2.0 mg/mmol and/or an eGFR<60 mL/min on at least two out of three samples over a three month period [Grade D, Consensus]. 2013 Recommendation 1: Screening (continued)

42. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 2: Vascular Protection 2.All patients with diabetes and chronic kidney disease should receive a comprehensive, multifaceted approach to reduce cardiovascular risk (see Vascular Protection, CPG Chapter 22) [Grade A, Level 1A].

43. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 3: Treatment 3.Adults with diabetes and CKD with either hypertension or albuminuria should receive an ACE inhibitor or an ARB to delay progression of CKD [Grade A, Level 1A for ACE-inhibitor use in type 1 and type 2 diabetes, and for ARB use in type 2 diabetes; Grade D, Consensus, for ARB use in type 1 diabetes].

44. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 4.People with diabetes on an ACE inhibitor or an ARB should have their serum creatinine and potassium levels checked at baseline and within 1 to 2 weeks of initiation or titration of therapy and during times of acute illness [Grade D, Consensus]. 5.Adults with diabetes and CKD should be given a “sick day” medication list that outlines which medications should be held during times of acute illness (see CPG Appendix) [Grade D, Consensus]. 2013 Recommendation 4 and 5

45. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 6 6.Combination of agents that block the renin- angiotensin-aldosterone system (ACE-inhibitor, ARB, DRI) should not be routinely used in the management of diabetes and CKD [Grade A, Level 1]. 2013

46. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 7: When to Refer 7.People with diabetes should be referred to a nephrologist or internist with an expertise in chronic kidney disease in the following situations: – Chronic, progressive loss of kidney function – ACR persistently >60 mg/mmol – eGFR<30 mL/min – Unable to remain on renal-protective therapies due to adverse effects such as hyperkalemia or a >30% increase in serum creatinine within 3 months of starting an ACE-inhibitor or ARB – Unable to achieve target BP (could be referred to any specialist in hypertension) [Grade D, Consensus]

47. CDA Clinical Practice Guidelines www.guidelines.diabetes.cawww.guidelines.diabetes.ca – for professionals 1-800-BANTING (226-8464) www.diabetes.ca www.diabetes.ca – for patients