Dick de Zeeuw Department of Clinical Pharmacology University Medical Center Groningen The Netherlands Albuminuria; a tool for measuring non-blood pressure related renal protection. Data from the RENAAL trial

RENAAL  Trial design: Rand control trial, double dummy intervention placebo vs losartan with conventional therapy background (without ACEi or ARB)  Population: 1513 type 2 diabetic nephropathy n Serum creatinine: 1.3 to 3 mg/dl n Albuminuria: > 300 mg/g  Dosing: 50 mg losartan or 100 mg if blood pressure >140/90  Measurements: n Albuminuria: morning void ACR; 24 hour Albumin and ACR in subgroup (n=710) n Proteinuria: 24 hour proteinuria, in subgroup (n=710)  Change in albuminuria: n Individual ACR change comparing baseline to 6 months  End-points: n Combined endpoint: Doubling serum creatinine, ESRD, Death n Single of each

RENAAL; AII-antagonist more renal protective than placebo in type 2 diabetes; similar blood pressure, different albuminuria % with event p=0.024 Risk Reduction: 16% Placebo Losartan Systolic Diastolic MAP Mo Pulse Pressure Blood Pressure (mmHg) P L Brenner et al; New Engl J Med 2001 Albuminuria (Change,%) p=< % Overall Reduction Mo P L

Questions  Is Albuminuria a predictor of outcome?  Is it independent from other risk markers?  Is proteinuria different than albuminuria  Is spot sampling different than 24 hour  Is Albuminuria lowering predictive of outcome?  Is it independent from blood pressure lowering?  Is residual albuminuria predicting outcome?  Is Albuminuria a predictor of outcome?  Is it independent from other risk markers?  Is proteinuria different than albuminuria  Is spot sampling different than 24 hour  Is Albuminuria lowering predictive of outcome?  Is it independent from blood pressure lowering?  Is residual albuminuria predicting outcome?

RENAAL; Baseline proteinuria as a determinant for renal events in type 2 diabetic nephropathy De Zeeuw et al; Kidney Int 2004 Primary composite Endpoint Hazard ratio <  5.25  Baseline Albuminuria (g/g) 0 < ESRD  Hazard ratio

= Hemoglobin (g/dL) < Serum albumin (per 0.5 g/dL) < – Serum creatinine (mg/dL) < Urine albumin:creatinine (log, mg/g) p-Value 95% Conf Interval Hazard Ratio* RENAAL; Model for independent renal risk factors during (optimal) blood pressure treatment in type 2 diabetic nephropathy (n=1300) Keane et al, Kidney Int 2003; and Keane et al, Clin J Am Soc Nephrol 2006 RENAAL RISK SCORE: (1.96 log [urinary albumin:creatinine ratio]) * (0.78 serum albumin [g/dl]) * (1.28 serum creatinine [mg/dl]) * (0.11 hemoglobin [g/dl]).

Questions  Is Albuminuria a predictor of outcome?  Is it independent from other risk markers?  Is proteinuria different than albuminuria  Is spot sampling different than 24 hour  Is Albuminuria lowering predictive of outcome?  Is it independent from blood pressure lowering?  Is residual albuminuria predicting outcome?  Is Albuminuria a predictor of outcome?  Is it independent from other risk markers?  Is proteinuria different than albuminuria  Is spot sampling different than 24 hour  Is Albuminuria lowering predictive of outcome?  Is it independent from blood pressure lowering?  Is residual albuminuria predicting outcome?

RENAAL; Albuminuria Reduction ( 30%) at Month 6 determines the renal outcome De Zeeuw et al; Kidney Int 2004 Renal Endpoint ESRD Month % with composite endpoint >30% <0% Month % with ESRD <0% >30%

RENAAL; Initial anti-albuminuric response predicts renal outcome Albuminuria reduction (%) Albuminuria reduction (%) Hazard ratio Renal Endpoint ESRD De Zeeuw et al; Kidney Int 2004

RENAAL; Antialbuminuric effect of losartan expIains the renal protective effect Outcome adjusted for albuminuria RR (97%CI)P valueRR (97%CI)P value Primary Composite 16.1 ( ) ( ) ESRD 28.6 ( ) ( ) De Zeeuw et al; Kidney Int 2004

RENAAL; Response variability discordant for blood pressure and albuminuria Losartan N=715 Increased blood pressure (systolic) Decreased blood pressure (systolic) > +15 mmHg+15 to 0 mmHg0 to -15 mmHg > -15 mmHg Increased albuminuria >+30% 4.6%4.3%5.7%3.2% 0 to +30% 2.0%3.8%4.1%3.4% Decreased Albuminuria -30 to 0% 3.2%5.0%9.0%5.3% >-30% 5.6%8.5%15.9%16.6% Eijkelkamp et al; JASN

RENAAL; Differential effect of antihypertensive treatment on albuminuria and BP has differential effect on ESRD Eijkelkamp et al; JASN 2007

Questions  Is Albuminuria a predictor of outcome? n Is it independent from other risk markers? n Is proteinuria different than albuminuria n Is spot sampling different than 24 hour  Is Albuminuria lowering predictive of outcome? n Is it independent from blood pressure lowering?  Is residual albuminuria predicting outcome?

RENAAL; High residual albuminuria levels De Zeeuw et al; Kidney Int < >5.0 Losartan 0 mo (n=751) Losartan 6 mo (n=751) < >5.0 Placebo 0 mo (n=762) Placebo 6 mo (n=762)

RENAAL: Residual high albuminuria and not residual high blood pressure determines risk for ESRD Eijkelkamp et al; JASN 2007

Summary  Is Albuminuria a predictor of outcome?YES n Is it independent from other risk markers?YES n Is proteinuria different than albuminuriaNO n Is spot sampling different than 24 hourNO  Is Albuminuria lowering predictive of outcome?YES n Is it independent from blood pressure lowering?YES  Is residual albuminuria predicting outcome? YES