1. Chronic Renal Insufficiency Catherine M Clase Division of Nephrology McMaster University

2. Objectives Review the epidemiology of CRI Describe progression of CRI Evidence-based strategies to minimize progression Be aware of the interaction between CRI and CVD Describe reasons for referral to nephrologists Discuss rationale/evidence

3. Size of the problem - ESRD New to ESRD Canada 1996: 3332 patients Growing at about 10% annually In CRI in nephrology clinics Rate of loss GFR ~ 6 mL/min/y Initiation of dialysis ~ 8 mL/min

4. Size of the problem - CRI 10% of men and 2% of women have Cr>133 µmol/L 11 million in US Jones et al. Am J Kidney Dis 1998;32:992 ~1 million in Canada

5. Referral is mandatory Diagnostic uncertainty Treatment of specific diseases Rapidly rising creatinine (20% increase over days to months)

6. Optimization of management Prevention of progression Optimization of transition to ESRD Management of metabolic complications of CRI Management of comorbidity cardiac diabetic other

7. Optimization of management Prevention of progression Optimization of transition to ESRD Management of metabolic complications of CRI Management of comorbidity cardiac diabetic other

8. Rates of progression in referred populations are variable

9. Multivariate risks for progression HTN Proteinuria

10. Hypertension Achieved BP control Intensive blood pressure control MDRD 1994 MAP 92 mmHg vs. 107 mmHg; 98 mmHg vs. 113 mmHg renal outcomes: no difference HOT study 1998 DBP <80 mmHg vs. 85 mmHg vs. 90 mmHg CV outcomes: no difference

11. Optimal blood pressure control: diabetics and nondiabetics

12. Hypertension in patients with diabetes UKPDS 1998 150/85 mmHg vs. 180/105 mmHg significant differences death stroke microvascular disease HOT study (subgroup) 1998 DBP <80 mmHg vs. 85 mmHg vs. 90 mmHg significant differences CV events CV death

13. Tight control of blood pressure in patients with diabetes

14. Hypertension Volume control sodium restriction diuretics Drug class HANE 1997 hydrochlorothiazide, atenolol, nitrendipine, enalapril similar efficacy & tolerability Isolated systolic hypertension Proteinuria

15. ACE inhibition Diabetic nephropathy Collaborative Study Group 1993 Any chronic renal failure REIN study 1997, 1998 meta-analysis Giatras 1997 proteinuria increased effectiveness Normotensive normoalbuminaemic type II DM Ravid 1998

16. ARB in DMN New Engl J Med 2001;345:851 & 861 & 870

17. ACE inhibition & ARBs Adverse effects precipitation of ARF monitoring usually reversible hyperkalaemia dietary intervention diuretics K binding resins

18. Dietary protein restriction MDRD 1993 1.3 vs. 0.58 g/kg/day; 0.58 vs. 0.28 g/kg/day (+KA) selected, well-nourished patients intensive dietary counselling nutritional parameters  weight, arm circumference, % body fat  albumin no difference in rate of loss GFR

19. Nutrition Spontaneous reduction in protein intake, independent of dietary advice, with advancing CRI Cross-sectional studies Ikizler et al. J Am Soc Nephrol 1995;6:1386 Pollock et al. J Am Soc Nephrol 1997;8:777

20. Nutrition Malnutrition independent predictor of death in ESRD Bloembergen et al. Kidney Int 1996;50:557 Struijk et al. Perit Dial Int 1994;14:121 Churchill et al. J Am Soc Nephrol 1996;7:198 Blake et al. J Am Soc Nephrol 1993;3:1501 Maiorca et al. Nephrol Dial Transplant 1995;10:2295 Jassal et al. Nephrol Dial Transplant 1996;11:1052

21. Optimization of management Prevention of progression Optimization of transition to ESRD Management of metabolic complications of CRI Management of comorbidity cardiac diabetic other

22. How early are patients referred before ESRD? 39% of HD patients and 27% of PD patients are referred <4 months prior to ESRD USRDS Wave 2. Am J Kidney Dis 1997;30:S67

23. How early are patients referred? Canada, 1998-1999 Consecutive patients new to ESRD Multicentre, N=238 35% first saw a nephrologist within 3 months of starting dialysis Curtis et al. Submitted

24. Referral time Effects on mortality morbidity access: Collins 1997 modality: Bloembergen 1997 quality of life: Jones 1998

26. Survival and referral time

27. How early should patients be referred to observe these benefits?

28. Canadian Clinical Practice Guidelines Creatinine clearance Cockcroft-Gault formula Refer when GFR <30 mL/min Refer when Cr <300 µmol/L Whichever is worse Mendelssohn CMAJ 1999;161:4

29. Referral to nephrologists in Ontario Mailed survey, N=728, 41% response rate Mendelssohn et al. Arch Intern Med 1995;155:2473

30. Modality selection Late referrals less likely to select PD: Bloembergen 1997 Multidisciplinary education  time to requirement of dialysis: Binik 1993 Choice  HRQoL on PD: Szabo 1997

31. Access AVF > PTFE > catheter 25% access at 30 days prior to initiation: USRDS 1997 Woods 1997, Collins 1997 access-related morbidity cost mortality Assessment Preservation of veins Creation of fistula at GFR 15 - 25 mL/min

32. Timing of initiation of dialysis Early dialysis Tattersall 1995 CanUSA 1998 Bonomini 1979 - 1986 Results  morbidity  mortality  rehabilitation

33. Symptoms at initiation in the elderly: Porush & Faubert 1991

34. Optimization of management Prevention of progression Optimization of transition to ESRD Management of metabolic complications of CRI Management of comorbidity cardiac diabetic other

35. Anaemia Progressive relative erythropoietin deficiency and uraemic resistance to erthropoietin Cardiac In ESRD LV dilatation, CHF, death: Foley 1996 hospitalization, LoS, death: Collins 1997 In CRF LVH: Levin 1996 Quality of life SF-36 (ESRD): Merkus 1997 SIP (CRF): Klang 1996

36. Treatment of anaemia Erythropoietin cost regulations monitoring Iron p.o. (timing) or i.v. Benefits quality of life  energy, physical functioning no change in GFR, may  BP Target Hgb

37. Calcium homeostasis Phosphate retention early not necessarily accompanied by  phosphate 1, 25 D 3 deficiency Hypocalcaemia Hyperparathyroidism

38. Management of calcium homeostasis Dietary intervention Phosphate binders Calcium carbonate 1-alphacalcidol decreases  PTH no effect on GFR monitoring

39. Metabolic acidosis Malnutrition Metabolic bone disease Treatment Sodium bicarbonate

40. Malnutrition Progressive spontaneous decline in protein intake MDRD 1994, Ikizler 1995, Pollock 1996 Malnutrition at initiation: CanUSA 1996 morbidity mortality Improves with starting dialysis: CanUSA 1996

41. Malnutrition Management dietary intervention 0.8 - 1.3 g/kg/day protein adequate calories control of acidosis initiation of dialysis

42. Cockcroft-Gault (mL/min)MDRD equation 7 (mL/min/1.73m 2 )Couchoud (mL/min/1.73m 2 ) <20<30<40<20<30<40<30 Any metabolic abnormality * Sensitivity45748770889691 95% CI37-5466-8181-9262-7782-9391-9886-95 Haemoglobin <110 g/L Sensitivity58809078939893 95% CI48-6771-8684-9570-8187-9793-9988-97 Albumin <35 g/L Sensitivity38577661799483 95% CI28-4946-6766-8451-7169-8687-9874-90 Bicarbonate <23 mmol/L Sensitivity55769075879390 95% CI44-6565-8481-9564-8378-9486-9783-96 Calcium <2.15 mmol/L Sensitivity53758479899893 95% CI40-6663-8573-9267-8879-9692-10084-98 Phosphorus >2.1 mmol/L Sensitivity100 95% CI77-100 78-100 79-100 Phosphorus >1.6 mmol/L Sensitivity709110094100 95% CI57-8082-9795-10086-9895-100 PTH >22.8 pmol/L Sensitivity61889985100 95% CI50-7279-9493-10075-9296-100

43. Cockcroft-Gault (mL/min)MDRD equation 7 (mL/min/1.73m 2 )Couchoud (mL/min/1.73m 2 ) <20<30<40<20<30<40<30 Any metabolic abnormality * Specificity95694593543043 95% CI87-9957-7934-5785-9743-6520-4132-55 Haemoglobin <110 g/LSpecificity83593876442036 95% CI77-8753-6632-4470-8137-5015-2530-42 Albumin <35 g/LSpecificity72493265361728 95% CI66-7743-5526-3859-7130-4212-2222-33 Bicarbonate <23 mmol/L Specificity79563670401633 95% CI74-8450-6230-4264-7534-4612-2127-39 Calcium <2.15 mmol/LSpecificity74523365371629 95% CI69-7946-5828-3860-7131-4212-2124-35 Phosphorus >2.1 mmol/L Specificity73503160331426 95% CI68-7844-5526-3655-6628-3811-1822-31 Phosphorus >1.6 mmol/L Specificity80573771401731 95% CI75-8451-6332-4365-7634-4613-2226-37 PTH >22.8 pmol/LSpecificity82553570391831 95% CI76-8748-6328-4363-7732-4713-2525-38

44. Nutrition in unreferred populations National Health and Nutrition Examination Survey III database 5248 participants over 60y Composite definition of malnutrition Adjusted OR for malnutrition GFR 30-60 mL/min 1.2 (0.7 – 2.0) GFR <30 mL/min 3.6 (2.0 – 6.6) Garg et al, submitted

45. Optimization of management Prevention of progression Optimization of transition to ESRD Management of metabolic complications of CRI Management of comorbidity cardiac diabetic other

46. Cardiac comorbidity is common Consecutive prevalent patients with CRI in nephrology clinics, mean GFR 75 mL/min Previous CVD 38.5% CVD associated with severity of CRI 80% hypertension 43% hyperlipidemia 38% had diabetes mellitus 27% were smokers

47. Renal insufficiency is an independent CV risk factor Garg et al. Submitted.

48. Cardiac comorbidity Hypertension control Lipid-lowering agents ACE inhibition Beta-blockers ASA Anticoagulation Smoking cessation

49. Diabetic comorbidity Glycaemic control DCCT 1993 (type I) UKDPS 1998 (type II) Hypertension HOT 1998 (subgroup) UKPDS 1998 ACE inhibitors retinopathy (Euclid 1998)

50. Formalized care of patients with chronic renal failure

51. Referral is mandatory Diagnostic uncertainty Treatment of specific diseases Rapidly rising creatinine (20% increase over days to months)

52. Optimization of management Prevention of progression Optimization of transition to ESRD Management of metabolic complications of CRI Management of comorbidity cardiac diabetic other

53. Role of non-nephrologist Diagnosis Establish chronicity/progression rate Manage HTN Use ACE, ARB Manage comorbidity Monitor progression Consider referral

54. When to Refer: Role of Nephrologist Diagnostic uncertainty Rapid progression GFR < 30mL/min Management of complications Preparation for dialysis

55. Objectives Review the epidemiology of CRI Describe progression of CRI Evidence-based strategies to minimize progression Be aware of the interaction between CRI and CVD Describe reasons for referral to nephrologists Discuss rationale/evidence