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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Segura, J., Campo, C. & Ruilope, L. M. effect of proteinuria and glomerular filtration rate on cardiovascular risk in essential hypertension. Kidney Int. Suppl. 92, s45–s49 (2004).
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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).
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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).
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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).
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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).
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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).
Xu, J. et al. Association of albuminuria with all-cause and cardiovascular disease mortality in diabetes: the strong Heart study. Br. J. Diabetes Vasc. Dis. 5, 334–340 (2005).
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).
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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).
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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

Disclosures

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

Mohit Agarwal, MD

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

Disclosures

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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Management of Patients

In patients with proteinuria, reduction of cardiovascular risk is aimed at both the reduction in degree of proteinuria and control of associated clinical risk factors including hypertension, diabetes, hyperlipidemia, obesity and smoking. This multifactorial intervention offers benefit in reducing the global cardiovascular risk. A summary of therapeutic strategies is presented in Table 2.

Is proteinuria a target for cardiovascular protection? Despite an approach aimed at reduction in degree of proteinuria often being included in the therapeutic strategy for the reduction of cardiovascular risk in patients with proteinuria, to date no completed, randomized, controlled trials have proved that reducing urinary protein excretion lowers CVD risk. Clearly, the presence of proteinuria is associated with an increased risk for CVD mortality, and its presence is as good a predictor of CVD mortality as CKD or previous myocardial infarction.^[56] CKD itself is a cardiovascular risk marker owing to a high prevalence of traditional and nontraditional cardiovascular risk factors, including proteinuria; the concurrent presence of proteinuria might further amplify the increased cardiovascular risk observed with decreased GFR. Clear dissociation of the exaggerated cardiovascular risk imposed by the concurrent presence of these two important risk factors is challenging. Clinical trials studying the effect of different proteinuria targets on cardiovascular outcomes are strongly needed, but are difficult to plan and implement for a variety of practical reasons—including variability in measures of proteinuria, difference among class and dosage of medications that reduce proteinuria, baseline levels of proteinuria that predict varying outcomes and responses to RAAS blockade, difficulty achieving target blood pressure, patient adherence to diet and therapy, careful monitoring of medication complications, and long term follow-up needed to demonstrate benefit in clinical outcomes.

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Table 1.

Table 2.

Box 1.

Box 2.

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: Management of Patients

Management of Patients

Table of Contents

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: Management of Patients

Management of Patients

Table of Contents