1. Slides current until 2008 Diabetic nephropathy

2. Curriculum Module III-7b Slide 2 of 37 Slides current until 2008 Risk factors Poor glycaemic control Hyperlipidaemia Hypertension Genetic predisposition Glomerular hyper-filtration during early period Ethnicity Long disease duration Smoking

3. Diabetic nephropathy Curriculum Module III-7b Slide 3 of 37 Slides current until 2008 Diabetic nephropathy About 20% to 30% of people with diabetes In type 2 diabetes, a smaller fraction of these progress to CKD People with type 2 diabetes – over half of those with diabetes starting on dialysis

4. Diabetic nephropathy Curriculum Module III-7b Slide 4 of 37 Slides current until 2008 Type 1 diabetes Decreasing incidence over past 35 years Overall incidence –2.2% at 20 years duration –7.8% at 30 years duration Finne 2005

5. Diabetic nephropathy Curriculum Module III-7b Slide 5 of 37 Slides current until 2008 Microalbuminuria (incipient diabetic nephropathy) Acute renal hypertrophy-hyperfunction Normoalbuminuria Proteinuria (clinical overt diabetic nephropathy) Chronic renal failure 10 to 15 years Natural history of diabetic nephropathy

6. Diabetic nephropathy Curriculum Module III-7b Slide 6 of 37 Slides current until 2008 Protein Albumin Albumin Excretion Rate Microalbuminuria: 30-300 mg/24 hr 20-200 µg/min 2.5-25 mg/mmol (men) 3.5-35 mg/mmol (women) Macroalbuminuria: >300 mg/24 hr or >200 µg/min >25 mg/mmol (men) >35 mg/mmol (women) Protein, microalbuminuria and macroalbuminuria

7. Diabetic nephropathy Curriculum Module III-7b Slide 7 of 37 Slides current until 2008 Transient increases in albumin excretion Exercise Menstruation Pregnancy Poor glycaemic control Urinary tract infection Hypertension Cardiac failure Factors affecting albumin excretion

8. Diabetic nephropathy Curriculum Module III-7b Slide 8 of 37 Slides current until 2008 Transient microalbuminuria 2/874/879/871/882/884/885/888/882/897/89 10/89 1/905/907/90 10/90 2/92 6/91 10/91 4/92 1 2 5 10 50 100 200 1 2 5 10 20 50 100 200 20 µg/min 15 µg/min AER (µg/min x 1,73m²) Age: 15 years diabetes duration: 5 years Girl >2 consecutive measurements >20 µg/min therafter 3 measurements normal Example:

9. Diabetic nephropathy Curriculum Module III-7b Slide 9 of 37 Slides current until 2008 Permanent microalbuminuria 8/87 10/8811/8812/88 4/891/907/909/90 10/9012/90 9/91 11/9212/93 6/947/95 1 2 5 10 50 100 200 1 2 5 10 20 50 100 200 20 µg/min 15 µg/min Age: 21 years diabetes duration: 10 years Girl AER (µg/min x 1,73m²) 278253 3 consecutive measurements >20 µg/min Example:

10. Diabetic nephropathy Curriculum Module III-7b Slide 10 of 37 Slides current until 2008 Diabetic renal assessment Urinalysis for proteinuria Spot urine for microalbuminuria –morning and resting or –preferably with albumin/creatinine ratio (normal <2.5 mg/mmol in men and <3.5 mg/mmol in women) Serum creatinine; preferably with adjustment of body size Calculated glomerular filtration rate Repeat the tests at about yearly intervals if normal If GFR <60 ml/min test 3-6 monthly

11. Diabetic nephropathy Curriculum Module III-7b Slide 11 of 37 Slides current until 2008 Microalbuminuria Type 1 diabetes –indicates incipient nephropathy Type 2 diabetes –marker of increased cardiovascular morbidity and mortality Presence of microalbuminuria is an indication for screening of vascular disease and intensive intervention

12. Diabetic nephropathy Curriculum Module III-7b Slide 12 of 37 Slides current until 2008 Interventions: glycaemic control Diabetes Control and Complications Trial (DCCT) – occurrence of microalbuminuria by 40% – occurrence of macroalbuminuria by 50% United Kingdom Prospective Diabetes Study (UKPDS) – overall microvascular complication rate by 25%

13. Diabetic nephropathy Curriculum Module III-7b Slide 13 of 37 Slides current until 2008 Institution of tight metabolic control after onset of overt proteinuria or renal insufficiency is important for general health but not all that helpful in preventing chronic kidney disease.

14. Diabetic nephropathy Curriculum Module III-7b Slide 14 of 37 Slides current until 2008 Diabetic nephropathy Treatment –intensive treatment of blood pressure target <130/80 mmHg –reduce salt in diet –reduce alcohol Sacks, 2001

15. Diabetic nephropathy Curriculum Module III-7b Slide 15 of 37 Slides current until 2008 Interventions: hypertension control Type 1 diabetes Lewis Study (Collaborative Study Group) –proteinuria –captopril  albumin excretion rate – in rate of decline of kidney function by 30% ACE inhibitors have independent effect Lewis et al 1993

16. Diabetic nephropathy Curriculum Module III-7b Slide 16 of 37 Slides current until 2008 Interventions: hypertension control Type 2 diabetes IRMA 2 –(microalbuminuria) IDNT –(proteinuria) IRMA 2 + IDNT = PRIME –angiotensin-2 receptor blockers (Irbesartan) –reduced progression by 30%

17. Diabetic nephropathy Curriculum Module III-7b Slide 17 of 37 Slides current until 2008 Interventions: hypertension control Any blood pressure-reducing medication can be used Often need at least three agents

18. Diabetic nephropathy Curriculum Module III-7b Slide 18 of 37 Slides current until 2008 Management of people with elevated creatinine Caution should be taken when using the following: –metformin –non-steroidal anti-inflammatory drugs –glibenclamide –radiographic contrast

19. Diabetic nephropathy Curriculum Module III-7b Slide 19 of 37 Slides current until 2008 Management of people with elevated creatinine Insulin dosage may need adjustment due to change in insulin half life and dialysis Anaemia is common and may need treatment – measure haemoglobin every 6 months if eGFR is <60 ml/min/1.73 m 2 Refer to nephrologist when eGFR <30 ml/min/1.73m 2

20. Diabetic nephropathy Curriculum Module III-7b Slide 20 of 37 Slides current until 2008 CKD – clinical features Nausea Poor appetite and weight loss Fatigue Dry, itchy skin Oedema Anaemia Dyspnea   serum creatinine   GFR

21. Diabetic nephropathy Curriculum Module III-7b Slide 21 of 37 Slides current until 2008 Nutritional needs As renal failure progresses Recommended diet may change over time Fluid restriction at renal failure Evidence base weak for protein restriction in diabetes

22. Diabetic nephropathy Curriculum Module III-7b Slide 22 of 37 Slides current until 2008 Estimated Glomerular Filtration Rate (eGFR) May underestimate actual renal function especially in women, the young and the obese More accurate in lower ranges <60 ml/min If eGFR is <60 ml/min, 30% risk of CVD Most common cause of death in CKD is cardiac arrest (22%)

23. Diabetic nephropathy Curriculum Module III-7b Slide 23 of 37 Slides current until 2008 Estimated Glomerular Filtration Rate (eGFR) <60 ml/min – osteodystrophy – anaemia <30 ml/min – pre-dialysis < 15 ml/min – dialysis and transplant

24. Diabetic nephropathy Curriculum Module III-7b Slide 24 of 37 Slides current until 2008 Treatment of chronic kidney disease (CKD) Prepare for eventual dialysis Peritoneal dialysis Haemodialysis Renal transplantation

25. Diabetic nephropathy Curriculum Module III-7b Slide 25 of 37 Slides current until 2008 Peritoneal (PD) versus haemodialysis (HD) PDHD Time hr/treatment treatment/week 24 hr continuous or >10 hr overnight 7 days per week 3-5 3 Dialysis Solution duration 8-15 l per day (3-5 h) 500-700 ml minutes for treatment Volume Dialysis solution Delivery system 2-3 l per exchangecontinuous flow AccessPD cathetervascular catheter, fistula or graft

26. Diabetic nephropathy Curriculum Module III-7b Slide 26 of 37 Slides current until 2008 Management of hyperglycaemia, CKD and dialysis Blood glucose-lowering agents Subcutaneous insulin Intraperitoneal insulin – more consistent, physiological absorption

27. Diabetic nephropathy Curriculum Module III-7b Slide 27 of 37 Slides current until 2008 Special problems in peritoneal dialysis Catheter-related infection Risk of peritonitis Glucose absorption from peritoneal dialysis fluid may affect glycaemic control WARNING: Check the meter used with peritoneal dialysis

28. Diabetic nephropathy Curriculum Module III-7b Slide 28 of 37 Slides current until 2008 Special problems in hemodialysis Vascular access problem Hypotension Advanced cardiac disease Pre-dialysis hyperkalemia Hypoglycaemia

29. Diabetic nephropathy Curriculum Module III-7b Slide 29 of 37 Slides current until 2008 Renal transplant Discuss the use of renal transplantation in your country. ACTIVITY

30. Diabetic nephropathy Curriculum Module III-7b Slide 30 of 37 Slides current until 2008 Summary Diabetes is a common cause of CKD Various grades of nephropathy The higher the A 1c the higher the risk Control matters Blood pressure

31. Diabetic nephropathy Curriculum Module III-7b Slide 31 of 37 Slides current until 2008 Review question 1.Which of the following statements concerning the development of microalbuminuria and hypertension in people with diabetes is true? a.In type 1 diabetes, hypertension is usually not present until several years after microalbuminuria is detected b.In type 2 diabetes, hypertension is often present on diagnosis but microalbuminuria is usually not detected until 10 to 20 years after diagnosis c.In type 1 diabetes, hypertension and microalbuminuria are often detected at about the same time d.In type 2 diabetes, both hypertension and microalbuminuria tend to appear after insulin therapy is initiated

32. Diabetic nephropathy Curriculum Module III-7b Slide 32 of 37 Slides current until 2008 Review question 2. Which of the following people with diabetes should have a urine screening test for microalbuminuria: a.A man who is newly diagnosed with type 1 diabetes b.A woman with type 1 diabetes for 2 years, who presently has blood glucose levels over 20mmol/L c.A woman with type 2 diabetes who has had macroalbuminuria detected twice on recent routine urinalysis d.A man who is newly diagnosed with type 2 diabetes and has no protein detected on routine urinalysis

33. Diabetic nephropathy Curriculum Module III-7b Slide 33 of 37 Slides current until 2008 Review question 3. In the UKPDS, improving blood glucose levels through intensive diabetes management significantly decreased the risk of: a.Nephropathy b.Hypertension c.Myocardial infarction d.Stroke

34. Diabetic nephropathy Curriculum Module III-7b Slide 34 of 37 Slides current until 2008 Review question 4. When overt nephropathy is approaching ESRD, what information would be accurate regarding insulin requirements? a.Kidney failure often decreases insulin requirements b.Kidney failure has no effect on insulin needs until people are on dialysis c.Kidney failure most often increases the requirement of long-acting insulin d.Kidney failure increases the need for rapid-acting insulin

35. Diabetic nephropathy Curriculum Module III-7b Slide 35 of 37 Slides current until 2008 Answers 1.c 2.d 3.a 4.a

36. Diabetic nephropathy Curriculum Module III-7b Slide 36 of 37 Slides current until 2008 References 1.Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977–86. 2.Clark CM Jr, Lee DA. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 1995; 332: 1210–7. 3.Pirart J. Diabetes mellitus and its degenerative complications: A prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1978; 1: 168–88. 4.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53. 5.UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703-13. 6.International Diabetes Federation - The Kidney Issue. Diabetes Voice 2003; 48: 3-44. 7.Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2003; 27 (Suppl 2): S66-71. 8.The HOPE Study Investigators. The HOPE (Heart Outcomes Prevention Evaluation) study: the design of a large simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients of high risk of cardiovascular events. Can J Cardiol 1996; 12: 127-37.

37. Diabetic nephropathy Curriculum Module III-7b Slide 37 of 37 Slides current until 2008 References 9.Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group (published erratum appears in N Eng J Med 1993; 330: 152). N Eng J Med 1993; 329: 1456-62. 10.Andersen S, Brochner-Morteusen J, Parving H. Kidney Function During and After Withdrawal of Long-Term Irbesartan Treatment in patients with type 2 diabetes and Microalbuminuria. Diabetes Care 2003; 26(12): 3296-302. 11.Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 2005; 294(14): 1782-7. 12.IDF Clinical Guidelines Task Force. Global Guideline for type 2 diabetes. Brussels: International Diabetes Federation 2005. 13.Sacks FM, Svetkey LP, Vollmer WM, et al. DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001; 344(1): 3-10. 14.Berl T, Hunsicker LG, Lewis JB, et al. for the Collaborative Study Group* Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy. Ann Intern Med 2003; 138: 542-549.