Diabetic Nephropathy

1. Diabetic Nephropathy Dr Peter Andrews Consultant Nephrologist St Helier Hospital, Carshalton, Surrey Frimley Park Hospital, Surrey Farnham HD Unit

2. Topics to be Covered • Demographics of diabetic renal disease • Screening and diagnosis • How can diabetic nephropathy be reduced? • BP control • Glycaemic control • BP targets • Choice of antihypertensive agents • The life of a diabetic nephropath and other aspects of management

3. Treated ESRD Incidence for Selected Countries 1984-95 New Patients/Million Population USA (All) JPN USA (White) CAN AUS FRA UK POL Year of ESRD Incidence

4. Incidence ESRF by Age: USA 1986-95 Median 64 60 Mean

5. Treated ESRD Incidence and Prevalence Rates by Race, 1993-95 Rate per Million Pop./Year Overall Rate=242 Overall Rate=909 Race

6. Causes of Renal Failure Diabetes * 23% Renovascular disease * 21% Chronic interstitial disease 10% Glomerulonephritis 10% Obstructive uropathy * 8% Cystic disease 3% Miscellaneous (amyloid, myeloma) 5% Unknown 20%

7. Diabetes: the Growing Problem • The prevalence of diabetes is 2-3% and on the increase • >50% type II diabetics are hypertensive • 20% of type II diabetics have renal involvement after 20 years • Approximately equal numbers Type I and Type II diabetics currently entering ESRF

8. Topics to be Covered • Demographics of diabetic renal disease • Screening and diagnosis • How can diabetic nephropathy be reduced? • BP control • Glycaemic control • BP targets • Choice of antihypertensive agents • The life of a diabetic nephropath and other aspects of management

9. Screening and Diagnosis • Screening(N Thomas) vs • Opportunistic testing vs • High risk testing vs • Event testing • Serum creatinine • Esp when used with Cr Cl calculators / eGFR • 24 hour urine specimen • Urinary dipstick for protein +/- blood • Assessment for microalbuminuria

10. Type II Diabetic Nephropathy: a progressive disease Clinical type 2 diabetes Functional changes* Structural changes† Rising blood pressure Microalbuminuria Proteinura Rising serum creatinine levels End-stage renal disease Cardiovascular death Onset of diabetes 2 5 10 20 30 Years *Kidney size ­, short-term GFR ­, long-term GFR . †GBM thickening ­, mesangial expansion ­,hypertensive changes +/-.

11. Importance of Microalbuminuria • Technique Albustix Early morning specimen Infection excluded Repeated tests • AER 20-200 mmol/min • Albumin/creatinine ratio >2 mg/mmol • How useful? Pro’s & cons • Should it prompt referral? No!

12. Importance of Microalbuminuria/Proteinuria • Predicts CV mortality in DM and non-DM • Predicts renal disease in DM and non-DM PREVEND - increase in cardiovascular mortality of x1.35 for each doubling of urinary albumin excretion • Predicts morbidity • Predicts end-organ damage in all important systems • If you have one bedside test, dip the urine! • Stratifies risk (not an indication for referral)

13. Serum Creatinine • If it’s raised, its important! • If it’s normal, it may still be abnormal! • Very low threshold for referral / investigation • If only mildly elevated, still a significant predictor of vasculopathy

14. Measuring Renal Impairment - 1 • GFR is ideal measure of renal function. • Plasma creatinine is used as surrogate for GFR • Large changes in GFR correspond to small changes in creatinine until around 40% of GFR is lost In the elderly, women and malnourished >50% of the GFR will be lost before the creatinine rises above the normal hospital range

15. Measuring Renal Impairment - 2 Alternative is to measure creatinine clearance which gives a more accurate measurement in mild renal impairment, BUT • 24 hr urine collections unreliable • Awkward to organise, especially as outpatient, therefore often not done

16. Measuring Renal Impairment - 3 A better alternative is to use a formula to predict GFR from plasma creatinine measurement eg Cockcroft-Gault: Cr Cl ml/min = 1.23 x (140-age) x weight in kg plasma creatinine umol/l • takes body weight into account • takes into account that urinary creatinine excretion decreases with age regardless of renal function • makes allowances for smaller creatinine production in women by replacing 1.23 with 1.04

17. Minor Renal Dysfunction Predicts Risk of Cardiovascular Disease • HOORN Study: • Population based cohort, n=631 • Age 50-75 yrs • Followed 10.2 yrs • 5ml/min drop in GFR increased risk of CV death by 26%

18. Minor Renal Dysfunction Predicts Risk of Cardiovascular Disease P<0.001 P<0.001 22.1% 15.1% 11.4% 6.6% HOPE study : Patients at high risk of cardiovascular events. Mann JF Ann Intern Med 2001 134:629-36

19. NEJM Sept 23rd 2004 • Anavekar et al: VALIANT sub-study • 14500 pts followed 2.14 years • Below 81ml/min, each 10ml/min decrease = 1.1 x risk ratio for death & CV outcomes • The lower the GFR, the lower the use of aspirin, beta blockade, statin, & revascularisation • Go et al: 1.12 million adults followed for 2.84 years (Kaiser) • RR CV death below 60 ml/min x 1.2 • RR 30 - 44 ml/min x 1.8 • RR 15 - 29 ml/min x 3.2 • RR <15 ml/min x 5.9

20. Diagnosis of Diabetic Nephropathy • Usually clinical • Rarely, renal biopsy Indications: Atypical clinical course Absence of retinopathy High grade proteinuria Reasons: Exclude other pathology Aid management Inform prognosis

21. Diabetic Nephrosclerosis

22. Hypertensive Nephropathy

23. Topics to be Covered • Demographics of diabetic renal disease • Screening and diagnosis • How can diabetic nephropathy be reduced? • BP targets • Choice of antihypertensive agents • The life of a diabetic nephropath and other aspects of management

24. How can Diabetic Nephropathy be Reduced? • DM Control NB NICE target 6.5 – 7.5% • BP Control

25. Optimisation of Diabetes • Long established importance in Type I DM (DCCT 1993) • Effectiveness in Type II DM - UKPDS (1998) “The UKPDS has shown that intensive blood glucose control reduces the risk of diabetic complications, the greatest effect being on microvascular complications”

26. Glucose Control Study Summary • The intensive glucose control policy maintained a lower HbA1c by mean 0.9 % over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: • 12% for any diabetes related endpoint p=0.029 • 25% for microvascular endpoints p=0.0099 • 16% for myocardial infarction p=0.052 • 24% for cataract extraction p=0.046 • 21% for retinopathy at twelve years p=0.015 • 33% for albuminuria at twelve years p=0.000054

27. Aggregate Clinical Endpoints

28. risk reduction37% p=0.0092 Effect of BP on Microvascular endpoints - incl ESRFTight control (< 150/85) or less tight control (< 180/105)

29. 250 225 200 175 150 125 100 75 50 25 0 Type II Diabetes and Hypertension: Non-diabetic Diabetic Cardiovascular mortality rate/10,000 person-yr < 120 120–139 140–159 160–179 180–199 ³ 200 Systolic blood pressure (mm Hg) Stamler J et al. Diabetes Care. 1993;16:434-444.

30. HOT Study: 51% RR Reduction of CV Events in DM 25 20 Major cardiovascular events/1,000 patient-years 15 p=0.005 for trend 10 5 0 90 85 80 mm Hg Target Diastolic Blood Pressure Hansson L et al. Lancet. 1998;351:1755-1762.

31. Lower Blood Pressure is Associated with Slower Decline in GFR Mean arterial pressure (mm Hg) 98 100 102 104 106 108 110 0 r = 0.66; p<0.05 -2 GFR decline(mL/min/year) -4 -6 -8 -10 Results of studies ³ 3 years in patients with type 2 diabetic nephropathy. Bakris GL. Diabetes Res Clin Pract. 1998;39(suppl):S35-42.

32. Topics to be Covered • Demographics of diabetic renal disease • Screening and diagnosis • How can diabetic nephropathy be reduced? • BP targets • Choice of antihypertensive agents • The life of a diabetic nephropath and other aspects of management

33. BHS Guidelines 2004: Optimal Targets for Treatment • Most patients • <140 systolic and • <85 diastolic • If high risk(DM, renal disease, organ damage) • <130 systolic and • <80 diastolic • If daytime ABPM or home readings, subtract 10/5 • N.B. Audit target (=minimal standard) is <150/90, or <140/80 if high risk

34. BP Targets • BHS V DM 130/80 140/85 • BHS Audit DM 140/80 150/90 • NICE DM 135/75 140/90 • SIGN DM 135/75 (if nephropathy) • GMS DM 145/85 150/90

35. HOWEVER • Targets attained not = desired • USA - 27% achieve target • Canada - 16% achieve target • UK – 16% achieve target • Reluctance to escalate therapy • cost • therapeutic drift • therapeutic nihilism • Over-use of monotherapy

36. Therapy requirement - UKPDS

37. Topics to be Covered • Demographics of diabetic renal disease • Screening and diagnosis • How can diabetic nephropathy be reduced? • BP targets • Choice of antihypertensive agents • The life of a diabetic nephropath and other aspects of management

38. 0.40 0.20 0.00 -0.20 -0.40 -0.60 Are all agents equal in terms of renoprotection? Proteinuria Albuminuria Log change from baseline † * ACE inhibitors Calcium channel blockers Beta-blockers Control Meta-regression analysis of 100 studies totaling 2494 patients with type 1 and type 2 diabetes. *p<0.05 vs calcium channel blockers. †p<0.05 vs control. Kasiske BL et al. Ann Intern Med. 1993;118:129-138.

39. Use of ACE Inhibitors / ARB in CRF • In diabetics, ACE inhibitors / ARB reduce the progression of microalbuminuria to overt proteinuria, and also slow the decline in GFR • IRMA, RENAL studies • numbers reaching end stage reduced 23% • doubling of serum creatinine reduced by up to 35% in dose-dependent fashion

40. BHS Indications & Contraindications for Drug Treatment

41. Why do ACE / ARB Inhibitors Protect ? • ACE inhibitors / ARBs lower intraglomerular pressure and are more effective at doing this than most other anti-hypertensive agents • Degree of proteinuria varies directly with intraglomerular pressure - ACE inhibitors lower proteinuria by 35%-40%

42. GLOMERULUS Angiotensin Angiotensin afferent arteriole efferent arteriole JGA Capillary loops and mesangial cells Proximal tubule

43. Suggested Protocol • Type I diabetic with any sign of nephropathy should be on an ACE inhibitor/ARB regardless of BP • Type II diabetic with microalbuminuria should be on ACE inhibitor/ARB as first line treatment for BP if > 120/70 • Type II diabetic with overt nephropathy should be on ACE inhibitor/ARB • Anyone with CRF, high BP should be treated with ACE/ARB as first line treatment (goal of 130/80 or lower) • Anyone with CRF and protein > 1g ? ACE/ARB whatever BP

44. ACEI and Decline in Renal Function • Drop in intraglomerular pressure may drop GFR • Rise of 10-20% in serum creatinine is common and should not result in ACE being stopped unless the rise continues • One review found that an initial rise in creatinine correlated with slower rate of long-term renal dysfunction

45. ACE combined with AII antagonists • Until recently, little published experience; no large, long-term outcome trials • 5-7 mmHg reduction in BP with dual therapy • Great care over potassium

46. ACE combined with AII antagonists • CALM study (BMJ 2000;321:1440) • ACE vs AIIRA vs combination • 199 pts, crossover, blinded study, 24 wk study • BP reduction > in combination group than monotherapy(16.3 vs 10.4/10.7 mmHg) • Greater reduction in proteinuria (50% vs 24/39%)

47. ACE combined with AII antagonists • CHARM Lancet Sept 2003 • Additional cardio-protection • Both diabetic and non-diabetic populations • Increased incidence cough (15-20%) Care re K+ ? Spironolactone better alternative • ? Cost-effective to prescribe

48. Topics to be Covered • Demographics of diabetic renal disease • Screening and diagnosis • How can diabetic nephropathy be reduced? • BP control • Glycaemic control • BP targets • Choice of antihypertensive agents • The life of a diabetic nephropath and other aspects of management

49. The Life of a Diabetic Nephropath • 0-10 years Well Hyperfiltration • 10-14 years Microalbuminuria • 14-20 years Proteinuria Pathlogy Deteriorating GFR • ESRF

50. The Life of a Diabetic Nephropath • ESRF Options • PD 5 years • HD 10 years • Cadaveric renal transplant 8-10 years • Living donor renal transplant 12-18 years • Isolated pancreas transplant ? • SKP transplant ?