Microalbuminuria pathogenesis and clinical implications Eberhard Ritz Heidelberg

Microalbuminuria – pathogenesis and clinical implications

Eberhard Ritz Heidelberg (Germany)

Jan Steen 1626 -1679 Pisskijker

Microalbuminuria • 30 – 300 mg / day albumin excretion or • 20 – 200 µg / min or µg/ml respectively (1 day = 1440 min = 1500 ml urine ~ 1 ml/min) - high day-to-day variability (VC 30%) diagnosis of MA : 2/3 urine samples positive exclude : renal causes (microhematuria, bacteriuria) comorbidity (uncontrolled hyperglycemia, hypertension, cardiac failure)

normo Comparison albumin measurement using HPLC vs nephelometry in the ranges normo-, microand macroalbuminuria micro Brinkman, Kidn. Intern. (2004) 92: (S 92) S 69 macro

Are albumin excretion rates in the upper normal range innocuous ?

Progressive increase of renal and CV risk with albuminuria within the normal range in type 2 diabetes albuminuria (mg/day) 0 -10 10 -20 20 -30 relative risk progression to microalbuminuria CV endpoint 1 2. 34 12. 4 1 1. 9 9. 8 Rachmani, Diab. Res. (2000) 49: 187

In non-diabetics more frequent development of microalbuminuria if at baseline urinary albumin high-normal odds ratio (95%CI) urinary albumin 15 -30 vs 0 -15 mg/24 h 23, 7 ( 11, 7 -47, 9) age (per 1 year) 1, 03 ( 1, 0 -1, 06 ) smoking vs nonsmoking 3, 9 (1, 1 -6, 5) hypertension (± treatment) 2, 4 (1, 0 -5, 7) Stuveling, J. Am. Soc. Nephrol. (2003) 14: 679 a

Increasing cardiovascular risk above median of urinary albumin – HOPE - study Gerstein, JAMA (2001) 268: 421

Increased cardiovascular risk above the median of urine albumin excretion LIFE - study no threshold, no plateau Deciles of albumin-creatinine ratio Wachtell, Ann Intern Med (2003) 139: 244

Nord Tröndelag Health Study 2, 089 apparently healthy individuals 4. 4 years follow-up percentile 95 th 90 th 80 th 60 th crude mortality albumin/creatinine rel. risk ratio µg/mg) (multivariate adjusted) 22. 0 14. 5 9. 7 6. 7 8. 6 5. 1 4. 5 2. 3 Romundstad, Am. J. Kid. Dis. (2003) 42: 466

Is the renal risk identical in microalbuminuria of diabetic and nondiabetic individuals ?

Gross, Kidn Intern (2002) 62: 51

Glycation renders albumin more nephrotoxic Scores protein droplets peritubular fibrosis Na. Cl 1. 23 ± 0. 5 0. 40 ± 0. 05 albumin 2. 74 ± 0. 4 2. 87 ± 0. 7 glycated albumin 3. 70 ± 0. 4 3. 30 ± 0. 6 Gross et al, submitted

How frequent is microalbuminuria ? Which factors predispose to microalbuminuria ?

Albumin excretion rates in 40, 619 citizens of Groningen (7. 2%) (0. 7%) microalbuminuria macroproteinuria >200 mg/l 20 -200 mg/l (16. 6%) high-normal albuminuria 10 -20 mg/l n=40, 856 normal 0 -10 mg/l Hillege, J. Intern. Med. (2001) 249: 519

Risk of microalbuminuria fasting glycemia UAE (mg/24 h) 13 12 Male Female 11 10 9 8 7 6 3 4 5 6 7 8 plasma glucose (mmol/l) Verhave, JASN (2003) 14: 1330

Nondiabetic subjects – insulin resistance associated with microalbuminuria • • • 982 nondiabetic subjects insulin sensitivity with frequently sampled iv glucose tolerance test (HOMA) subjects with microalbuminuria : lower insulin sensitivity ( 1. 70 ± 0. 11 vs 2. 25 ± 0. 07 ) and higher IRI ( 17. 4 ± 1. 1 vs 15. 7 ± 0. 5 m. U/L ) Mykkanen, Diabetes(1998) 47: 793

Male type 2 diabetics – insulin resistance associated with microalbuminuria • 712 type 2 diabetic patients • 61 years, diabetes duration 11 years, Hb. A 1 c 8. 6% HOMA index # significant correlation to albuminuria in male, but not in female patients (pinteraction 0. 04) # male pat. with HOMA index above median (insulin resistance) odds ratio for microalbuminuria 2. 2 De. Cosmo, Diabetes Care (2005) 28: 910

Albuminuria predicts new onset diabetes (Prevend study, 4. 2 year follow-up) New onset Diabetes (%) 14 11. 8 12 10 7. 9 8 6 4. 3 4 2 2. 2 0 0 - 14 15 – 29 30 - 300 >300 Albuminuria (mg/day) Brantsma ; Diaberes Care (2005) 28: 2525

Early onset of insulin resistance in renal disease (renal insulin resistance syndrome) control >90 GFR (ml/min/1. 73 m 2) 45 -90 <45 Becker, J. Am. Soc. Nephrol(2005) 16: 1091

Adiponectin predicts cardiovascular events in patients with renal failure Becker, J. Am. Soc. Nephrol(2005) e-pub

Risk of microalbuminuria metabolic syndrome prevalence CKD (%) metabolic syndrome risk factors : metabolic syndrome risk factors waist > 102 cm/men fasting glucose>110 mg/dl HDL-C <40 mg/dl/men triglycerides >140 mg/dl blood pressure >130/85 mm. Hg prevalence microalbuminuria (%) metabolic syndrome risk factors Chen, Ann. Int. Med. (2004) 140: 167

Microalbuminuria correlated to indices of metabolic syndrome In nondiabetic patients albumin excretion rate related to : • 24 h blood pressure • Left ventricular mass • body weight • fasting insulin • reduced insulin sensitivity (HOMA) • higher creatinine clearance Del’Omo, Am. J. Kid. Dis. (2002) 40: 1

Risk of microalbuminuria hereditary factors 662 diabetics from 310 families, 422 of whom siblings concordant for diabetes 10. 8 years H 2 (adjusted) = 0, 46 ± 0, 12 (p< 0, 0001) Langefeld, Am. J. Kid. Dis. (2004) 43: 796

Offspring of type 2 diabetic parents with nephropathy – higher albuminuria offspring of type 2 diabetic parents - with nephropathy (n=26) - without nephropathy (n=30) controls (n=30) albumin (mg/24 h) increase with treadmill 7. 8 x 16 4. 8 x 6. 3 4. 4 x 4. 8 Strojek, Kidn. Intern. (1997) 51: 1602

What are the consequences of microalbuminuria ? Does microalbuminuria matter for CV endpoints and survival ?

Albuminuria predicts development of moderate chronic kidney disease (Prevend study) 70 58 Stage 3 CKD (%) 60 50 40 30 22 20 10 9 13 0 0 - 14 15 – 29 30 - 300 >300 Albuminuria (mg/day) Verhave, Kidney Int (2004) Suppl. 92, S 18

Albuminuria predicts CV death in the general population (Prevend study, 3 year follow up) CV death (% per 1000 pj) 35 29. 1 30 25 20 15 11. 2 10 5 3. 5 4. 5 0 0 - 14 15 – 29 30 - 300 >300 Albuminuria (mg/day) Hillege; Circulation (2002); 106 : 1777

Same correlation albuminuria and cardiovascular mortality in type 2 diabetes Valmadrid, Arch. Int. Med. (2000) 160: 1093

Microalbuminuria and ischemic heart disease without microalbuminnuria with microalbuminuria Borch-Johnsen, Arter. Thromb. Vasc. Biol. (1999)19: 1992

Microalbuminuria – coronary heart disease and death Copenhagen City Heart study Klausen, Circulation(2004) 110: 32

Albuminuria - predictor of cardiovascular risk (Hoorn study) adjusted rel. risk smoking diabetes type 2 history CV events microalbuminuria 2. 8 3. 7 3. 6 3. 3 significant risk even when corrected for GFR Stehouwer and Jager

Change of albuminuria translates into change of cardiovascular endpoints (CEP) high baseline/ high year 1 high baseline/ low year 1 low baseline/ high year 1 low baseline/ low year 1 Ibsen, Hypertension(2005) 45: 198

Does treatment of microalbuminuria matter ?

Pravastatin vs Placebo PREVEND IT study– effect on cardiovascular endpoints Asselbergs, Circulation (2004) 110: 2809

Fosinopril vs Placebo PREVEND IT study reduction of CV cardiovascular events Asselbergs, Circulation (2004) 110: 2809

Treat the kidney to cure your heart ! de Zeeuw, 2004

Progression from microalbuminuria to proteinuria – effect of ACE inhibitor and ARB treatment Hollenberg, Arch. Int, Med. (2004) 164: 125

Regression from microalbuminuria to normoalbuminuria – effect of ACE inhibitor and ARB treatment Hollenberg, Arch. Int, Med. (2004) 164: 125

Reduction of microalbuminuria in type 2 diabetic patients albuminuria Placebo Rosiglitazone 117± 31. 1 40. 4± 12. 3 140± 3. 7 137± 3. 3 (mg/24 h) systolic BP (mm. Hg) Pistrosch, Diabetes (2005) 54: 2206

ARB and prevention of onset of microalbuminuria in diabetic patients – LIFE study • 1195 patient type 2 diabetes • de novo microalbuminuria • Losartan 7 % Atenolol 13 % p< 0. 01 Lindholm, Lancet (2002) 359: 1004

Why does microalbuminuria cause cardio-vascular complications ?

Urinary albumin excretion (UAE) in diabetics correlates with retina thickness and transcapillary albumin escape rate (TER) retinal thickness transcapillary escaoe Knudsen, Diabetes Care (2002) 25: 2328

What did he say? • microalbuminuria frequent • indicator (causal factor for? ) renal and cardiovascular risk • routine determination in high risk patients recommended by ESH and ASH • treatment with RAS blockade reduces CV events • RAS blockade and glitazones reduce existing albuminuria