Table 1.

Studies Evaluating the Association Between Proteinuria and Cardiovascular Disease

Table 2.

Therapeutic Strategies for Reduction of Cardiovascular and Renal Risk in Patients With Proteinuria Based on the KDOQI Guidelines

Box 1.

Classification of Proteinuria

Box 2.

Screening for Proteinuria

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Caglar, K. et al. ADMA, proteinuria, and insulin resistance in non-diabetic stage i chronic kidney disease. Kidney Int. 70, 781–787 (2006).
Yilmaz, M. I. et al. ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction. J. Am. Soc. Nephrol. 19, 388–395 (2008).
Stehouwer, C. D. et al. increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 51, 1157–1165 (2002).
Jaffa, A. A. et al. Plasma prekallikrein: a risk marker for hypertension and nephropathy in type 1 diabetes. Diabetes 52, 1215–1221 (2003).
Takebayashi, K., Matsumoto, s., Aso, Y. & inukai, T. Association between circulating monocyte chemoattractant protein-1 and urinary albumin excretion in nonobese type 2 diabetic patients. J. Diabetes Complications 20, 98–104 (2006).
Hirano, T., Kashiwazaki, K., Moritomo, Y., Nagano, s. & Adachi, M. Albuminuria is directly associated with increased plasma PAi-1 and factor vii levels in NiDDM patients. Diabetes Res. Clin. Pract. 36, 11–18 (1997).
Zimmermann, J. et al. Hemorheology, plasma protein composition and von willebrand factor in type i diabetic nephropathy. Clin. Nephrol. 46, 230–236 (1996).
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Parving, H. H. et al. Macro-microangiopathy and endothelial dysfunction in NiDDM patients with and without diabetic nephropathy. Diabetologia 39, 1590–1597 (1996).
Paisley, K. E. et al. endothelial dysfunction and inflammation in asymptomatic proteinuria. Kidney Int. 63, 624–633 (2003).
Wever, R. M., Lüscher, T. F., Cosentino, F. & rabelink, T. J. Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 97, 108–12 (1998).
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Vuong, T. D. et al. Hypoalbuminemia increases lysophosphatidylcholine in low-density lipoprotein of normocholesterolemic subjects. Kidney Int. 55, 1005–1010 (1999).
Kougias, P. et al. Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis. Med. Sci. Monit. 12, rA5–rA16 (2006).
Zhu, X., Wu, S., Dahut, W. L. & Parikh, C. R. risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am. J. Kidney Dis. 49, 186–193 (2007).
Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).
Stokes, M. B., Erazo, M. C. & D´agati, V. D. Glomerular disease related to anti-VEGF therapy. Kidney Int. 74, 1487–1491 (2008).
Anavekar, N. S. et al. Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria. Kidney Int. Suppl. 92, s50–s55 (2004).
Halbesma, N. et al. Macroalbuminuria is a better risk marker than low estimated GFR to identify individuals at risk for accelerated GFR loss in population screening. J. Am. Soc. Nephrol. 17, 2582–2590 (2006).
Borch-Johnsen, K., Andersen, P. K. & Deckert, T. The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 28, 590–596 (1985).
Cardoso, C. R. & Salles, G. F. Gross proteinuria is a strong risk predictor for cardiovascular mortality in Brazilian type 2 diabetic patients. Braz. J. Med. Biol. Res. 41, 674–680 (2008).
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Astor, B. C., Hallan, S. I., Miller, E. R. 3rd, Yeung, e. & Coresh, J. Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the Us population. Am. J. Epidemiol. 167, 1226–1234 (2008).
Hillege, H. L. et al. Prevention of renal and vascular end stage Disease (PreveND) study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106, 1777–1782 (2002).
Howard, B. V. et al. rising tide of cardiovascular disease in American indians. The strong Heart study. Circulation 99, 2389–2395 (1999).
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Yuyun, M. F. et al. A prospective study of microalbuminuria and incident coronary heart disease and its prognostic significance in a British population: the ePiC-Norfolk study. Am. J. Epidemiol. 159, 284–293 (2004).
Wang, Z. & Hoy, W. E. Albuminuria and incident coronary heart disease in Australian Aboriginal people. Kidney Int. 68, 1289–1293 (2005).
Valmadrid, C. T., Klein, R., Moss, S. E. & Klein, B. E. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch. Intern. Med. 160, 1093–1100 (2000).
Culleton, B. F., Larson, M. G., Parfrey, P. s., Kannel, w. B. & Levy, D. Proteinuria as a risk factor for cardiovascular disease and mortality in older people: a prospective study. Am. J. Med. 109, 1–8 (2000).
Irie, F. et al. The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population. Kidney Int. 69, 1264–1271 (2006).
Madison, J. R. et al. Proteinuria and risk for stroke and coronary heart disease during 27 years of follow-up. Arch. Int. Med. 166, 884–889 (2006).
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Varun Agrawal, MD

Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan

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Disclosure: Varun Agrawal, MD, has disclosed no relevant financial relationships.

Victor Marinescu, MD, PhD

Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan

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Disclosure: Victor Marinescu, MD, PhD, has disclosed no relevant financial relationships.

Mohit Agarwal, MD

Department of Hospitalist Medicine, Marion General Hospital, Marion, Ohio

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Disclosure: Mohit Agarwal, MD, has disclosed no relevant financial relationships.

Peter A. McCullough, MD, MPH, FACC, FACP, FCCP

Divisions of Cardiology, Nutrition, and Preventive Medicine, William Beaumont Hospital, Royal Oak, Michigan

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Disclosure: Peter A. McCullough, MD, MPH, FACC, FACP, FCCP, has disclosed no relevant financial relationships.

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Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

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Disclosure: Charles P. Vega, MD, FAAFP, has disclosed that he has served as an advisor or consultant to Novartis, Inc.

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Bryony Mearns, PhD

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CME

Cardiovascular Implications of Proteinuria: An Indicator of Chronic Kidney Disease

Authors: Varun Agrawal, MD; Victor Marinescu, MD, PhD; Mohit Agarwal, MD; Peter A. McCullough, MD, MPH, FACC, FACP, FCCP
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Target Audience and Goal Statement

This activity is intended for primary care physicians, nephrologists, endocrinologists, cardiologists, and other physicians who care for patients with proteinuria.

The goal of this activity is to describe the relationship between proteinuria and cardiovascular disease.

Upon completion of this activity, participants will be able to:

Describe the procedure of screening for proteinuria
Identify the effect of inhibitors of the renin-angiotensin-aldosterone system on cardiovascular outcomes among patients with proteinuria
Describe the relationship between proteinuria and dyslipidemia
List treatment goals for patients with proteinuria

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Author(s)

Varun Agrawal, MD

Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan

Disclosures

Disclosure: Varun Agrawal, MD, has disclosed no relevant financial relationships.

Victor Marinescu, MD, PhD

Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan

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Disclosure: Victor Marinescu, MD, PhD, has disclosed no relevant financial relationships.

Mohit Agarwal, MD

Department of Hospitalist Medicine, Marion General Hospital, Marion, Ohio

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Disclosure: Mohit Agarwal, MD, has disclosed no relevant financial relationships.

Peter A. McCullough, MD, MPH, FACC, FACP, FCCP

Divisions of Cardiology, Nutrition, and Preventive Medicine, William Beaumont Hospital, Royal Oak, Michigan

Disclosures

Disclosure: Peter A. McCullough, MD, MPH, FACC, FACP, FCCP, has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, FAAFP, has disclosed that he has served as an advisor or consultant to Novartis, Inc.

Editor

Bryony Mearns, PhD

Editor, Nature Reviews Cardiology

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Disclosure: Bryony Mearns, PhD, has disclosed no relevant financial relationships.

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Abstract and Introduction

Abstract

Proteinuria, defined as urine protein excretion greater than 300 mg over 24 h, is a strong and independent predictor of increased risk for all-cause and cardiovascular mortality in patients with and without diabetes. Proteinuria is a sign of persistent dysfunction of the glomerular barrier and often precedes any detectable decline in renal filtration function. Measurement of proteinuria is important in stratifying the risk for cardiovascular disease and chronic kidney disease progression. A variety of basic pathophysiologic mechanisms that can partially explain simultaneous renal and cardiac disease will be discussed in this review. In addition to being a prognostic marker, proteinuria is being considered as a therapeutic target in cardiovascular medicine. Therapeutic strategies for amelioration of proteinuria by achieving blood pressure targets, glycemic control in diabetes, treatment of hyperlipidemia, and reducing dietary salt and protein intake are also reviewed in this paper. Future clinical studies are needed to assess if proteinuria reduction should be a target of treatment to reduce the burden of end-stage renal disease, cardiovascular disease, and improve survival in this high-risk population.

Introduction

AHA guidelines recommend that patients with chronic kidney disease (CKD) be considered at very high risk for cardiovascular disease (CVD).^[1] CKD is defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m², or presence of markers of kidney damage for ≥3 months.^[2] Proteinuria and microalbuminuria are markers of renal injury that can be detected in early stages of CKD and predict rapid decline in renal filtration function. The NHANES III (Third National Health AND Nutrition Examination Survey study 1988-1994)^[3] showed proteinuria to be present in 1% of the general population, 3.3% of patients with eGFR 30.60 ml/min/1.73 m², and 26.0% of patients with eGFR <30 ml/min/1.73 m². Another study found the prevalence of proteinuria to be 10.2% in patients with hypertension and eGFR <60 ml/min/1.73 m².^[4]

Proteinuria usually refers to the presence of an abnormal amount of protein (albumin and nonselective proteins) in the urine, owing to defects in the glomerular barrier; urine measurements that define proteinuria are described in Box 1 . Macroalbuminuria is defined as more than 300 mg urine albumin over 24 h and will be referred to as proteinuria in this paper. Microalbuminuria—urine albumin secretion of 30–300 mg over 24 h—has been extensively reviewed elsewhere,^[5] and will not be discussed in this paper unless there are inferences relevant to proteinuria.

In this review, we will present the current data that shows an association of proteinuria with CVD, and highlight the probable mechanisms responsible for this association. Finally, we will present practical strategies for management of patients with proteinuria to decrease their risk of CVD.

Page 1 of 6

Measurement of Proteinuria

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Table 1.

Table 2.

Box 1.

Box 2.

References

Faculty and Disclosures

Author(s)

Varun Agrawal, MD

Victor Marinescu, MD, PhD

Mohit Agarwal, MD

Peter A. McCullough, MD, MPH, FACC, FACP, FCCP

CME Author(s)

Charles P. Vega, MD

Editor

Bryony Mearns, PhD

CME

Cardiovascular Implications of Proteinuria: An Indicator of Chronic Kidney Disease

Target Audience and Goal Statement

Disclosures

Author(s)

Varun Agrawal, MD

Victor Marinescu, MD, PhD

Mohit Agarwal, MD

Peter A. McCullough, MD, MPH, FACC, FACP, FCCP

CME Author(s)

Charles P. Vega, MD

Editor

Bryony Mearns, PhD

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Cardiovascular Implications of Proteinuria: An Indicator of Chronic Kidney Disease

Abstract and Introduction

Abstract

Introduction

Table of Contents