Circulation. 2004;110:921-927
Published online before print August 9, 2004, doi: 10.1161/01.CIR.0000139860.33974.28
Published online before print August 9, 2004, doi: 10.1161/01.CIR.0000139860.33974.28
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(Circulation. 2004;110:921-927.)
© 2004 American Heart Association, Inc.
Original Articles |
Albuminuria, a Therapeutic Target for Cardiovascular Protection in Type 2 Diabetic Patients With Nephropathy
From the Department of Clinical Pharmacology, Groningen University Medical Center, the Netherlands (D.d.Z.); Mario Negri Institute for Pharmacological Research, Bergamo, Italy (G.R.); Steno Diabetes Center Gentofte and Faculty of Health Science, Aarhus University, Denmark (H.-H.P.); Merck Research Laboratories, Merck & Co, Inc, Whitehouse Station, NJ (W.F.K., Z.Z., S. Shahinfar, S. Snapinn); Baker Medical Research Institute, Melbourne, Australia (M.E.C.); Department of Medicine, University of Texas, Medical Branch, Galveston (W.E.M.); and Department of Medicine, Renal Division, Brigham and Women’s Hospital and Harvard School of Medicine, Boston, Mass (B.M.B.).
Correspondence to Prof Dr D. de Zeeuw, Department of Clinical Pharmacology, Groningen University Medical Center, Ant Deusinglaan 1, 9713 AV Groningen, Netherlands. E-mail d.de.zeeuw{at}med.rug.nl
Received July 22, 2003; de novo received November 17, 2003; revision received April 20, 2004; accepted April 22, 2004.
Background— Albuminuria is an established risk marker for both cardiovascular and renal outcomes. Albuminuria can be reduced with drugs that block the renin-angiotensin system (RAS). We questioned whether the short-term drug-induced change in albuminuria would predict the long-term cardioprotective efficacy of RAS intervention.
Methods and Results— We analyzed data from Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL), a double-blind, randomized trial in 1513 type 2 diabetic patients with nephropathy, focusing on the relationship between the prespecified cardiovascular end point (composite) or hospitalization for heart failure and baseline or reduction in albuminuria. Patients with high baseline albuminuria (
3 g/g creatinine) had a 1.92-fold (95% CI, 1.54 to 2.38) higher risk for the cardiovascular end point and a 2.70-fold (95% CI, 1.94 to 3.75) higher risk for heart failure compared with patients with low albuminuria (<1.5 g/g). Among all available baseline risk markers, albuminuria was the strongest predictor of cardiovascular outcome. The association between albuminuria and cardiovascular outcome was driven by those patients who also had a renal event. Modeling of the initial 6-month change in risk parameters showed that albuminuria reduction was the only predictor for cardiovascular outcome: 18% reduction in cardiovascular risk for every 50% reduction in albuminuria and a 27% reduction in heart failure risk for every 50% reduction in albuminuria.
Conclusions— Albuminuria is an important factor predicting cardiovascular risk in patients with type 2 diabetic nephropathy. Reducing albuminuria in the first 6 months appears to afford cardiovascular protection in these patients.
Key Words: proteinuria • albuminuria • cardiovascular disease • angiotensin • diabetes
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|
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|
|
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|
|
|
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|
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|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
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|
|
|
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|
|
|
|
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|
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|
|
|
|
 |
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 M. Rodriguez-Yanez, M. Castellanos, M. Blanco, M. Millan, F. Nombela, T. Sobrino, I. Lizasoain, R. Leira, J. Serena, A. Davalos, et al. Micro- and macroalbuminuria predict hemorrhagic transformation in acute ischemic stroke. Neurology, October 10, 2006; 67(7): 1172 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 J. J. Wang, S. X. Zhang, R. Mott, R. R. Knapp, W. Cao, K. Lau, and J.-x. Ma Salutary Effect of Pigment Epithelium-Derived Factor in Diabetic Nephropathy: Evidence for Antifibrogenic Activities Diabetes, June 1, 2006; 55(6): 1678 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Miyata and C. van Ypersele de Strihou Renoprotection of angiotensin receptor blockers: beyond blood pressure lowering Nephrol. Dial. Transplant., April 1, 2006; 21(4): 846 - 849. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
R. E. Gilbert, K. Connelly, D. J. Kelly, C. A. Pollock, and H. Krum Heart Failure and Nephropathy: Catastrophic and Interrelated Complications of Diabetes Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 193 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Berl and W. Henrich Kidney-Heart Interactions: Epidemiology, Pathogenesis, and Treatment Clin. J. Am. Soc. Nephrol., January 1, 2006; 1(1): 8 - 18. [Full Text] [PDF]
|
|
|
|
|
|
M. Shlipak and C. Stehman-Breen Observational Research Databases in Renal Disease J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3477 - 3484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Mancia and G. Grassi Efficacy of antihypertensive treatment: which endpoints should be considered? Nephrol. Dial. Transplant., November 1, 2005; 20(11): 2301 - 2303. [Full Text] [PDF]
|
|
|
|
|
|
K. R. Tuttle, G. L. Bakris, R. D. Toto, J. B. McGill, K. Hu, and P. W. Anderson The Effect of Ruboxistaurin on Nephropathy in Type 2 Diabetes Diabetes Care, November 1, 2005; 28(11): 2686 - 2690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Weir Blood pressure salt sensitivity: a biomeasure of kidney disease susceptibility in diabetics? Nephrol. Dial. Transplant., October 1, 2005; 20(10): 2022 - 2024. [Full Text] [PDF]
|
|
|
|
|
|
R. E. Schmieder, A. U. Klingbeil, E. H. Fleischmann, R. Veelken, and C. Delles Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan: A Double-Blind, Randomized, Prospective Study J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3038 - 3045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rossing, K. J. Schjoedt, U. M. Smidt, F. Boomsma, and H.-H. Parving Beneficial Effects of Adding Spironolactone to Recommended Antihypertensive Treatment in Diabetic Nephropathy: A randomized, double-masked, cross-over study Diabetes Care, September 1, 2005; 28(9): 2106 - 2112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. J, L. G, W. P, V. H, Y. X, L. Y, W. Y, P. A, C. S, D. GV, et al. Kidney and Blood Pressure--The Story Unfolds: Renalase Is a Novel, Soluble Monoamine Oxidase That Regulates Cardiac Function and Blood Pressure. J Clin Invest J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2521 - 2527. [Full Text] [PDF]
|
|
|
|
|
|
R. Agarwal and M. J. Andersen Correlates of Systolic Hypertension in Patients With Chronic Kidney Disease Hypertension, September 1, 2005; 46(3): 514 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Arnlov, J. C. Evans, J. B. Meigs, T. J. Wang, C. S. Fox, D. Levy, E. J. Benjamin, R. B. D'Agostino, and R. S. Vasan Low-Grade Albuminuria and Incidence of Cardiovascular Disease Events in Nonhypertensive and Nondiabetic Individuals: The Framingham Heart Study Circulation, August 16, 2005; 112(7): 969 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W, Y. PX, L. BM, C. RD, M. DL, M. RH, I. H, O. MH, W. K, B.-J. K, et al. Anorexia and Cachexia in Renal Failure--Is Leptin the Culprit?: Role of Leptin and Melanocortin Signaling in Uremia-Associated Cachexia. J Clin Invest 115: 1659-1665, 2005 J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2245 - 2250. [Full Text] [PDF]
|
|
|
|
|
|
D. de Zeeuw Albuminuria, Just a Marker for Cardiovascular Disease, Or Is It More? J. Am. Soc. Nephrol., July 1, 2005; 16(7): 1883 - 1885. [Full Text] [PDF]
|
|
|
|
|
|
J. Redon Urinary Albumin Excretion: Lowering the Threshold of Risk in Hypertension Hypertension, July 1, 2005; 46(1): 19 - 20. [Full Text] [PDF]
|
|
|
|
|
|
F. Togel, Z. Hu, K. Weiss, J. Isaac, C. Lange, C. Westenfelder, T. Stasko, M.D. Brown, J.A. Carucci, S. Euvrard, et al. Amelioration of Acute Renal Failure by Stem Cell Therapy--Paracrine Secretion Versus Transdifferentiation into Resident Cells: Administered Mesenchymal Stem Cells Protect against Ischemic Acute Renal Failure through Differentiation-Independent Mechanisms. Am J Physiol Renal Physiol E-pub February 15, 2005 J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1153 - 1163. [Full Text] [PDF]
|
|
|
|
 |
|
 Other articles noted Evid. Based Med., April 1, 2005; 10(2): 63 - 64. [Full Text] [PDF]
|
|
|
|
|
|
A. Smith, J. Karalliedde, L. De Angelis, D. Goldsmith, and G. Viberti Aortic Pulse Wave Velocity and Albuminuria in Patients with Type 2 Diabetes J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1069 - 1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Weir Reduction in Microalbuminuria: A Biomeasure of Therapeutic Success? Hypertension, February 1, 2005; 45(2): 181 - 182. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|