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

Sarnak, M. J. et al. American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure research, Clinical Cardiology, and epidemiology and Prevention. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure research, Clinical Cardiology, and epidemiology and Prevention. Circulation 108, 2154–2169 (2003).
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Garg, A. X., Kiberd, B. A., Clark, W. F., Haynes, r. B. & Clase, C. M. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANes iii. Kidney Int. 61, 2165–2175 (2002).
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).
Weir, M. R. Microalbuminuria and cardiovascular disease. Clin. J. Am. Soc. Nephrol. 2, 581–590 (2007).
Boulware, L. E., Jaar, B. G., Tarver-Carr, M. e., Brancati, F. L. & Powe, N. r. screening for proteinuria in Us adults: a cost-effectiveness analysis. JAMA 290, 3101–3114 (2003).
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Agarwal, R., Bunaye, Z., Bekele, D. M. & Light, R. P. Competing risk factor analysis of end-stage renal disease and mortality in chronic kidney disease. Am. J. Nephrol. 28, 569–575 (2008).
de Zeeuw, D. et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110, 921–927 (2004).
Maschio, G. et al. effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-enzyme inhibition in Progressive renal insufficiency study Group. N. Engl. J. Med. 334, 939–945 (1996).
[No authors listed.] randomised placebocontrolled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GiseN Group (Gruppo italiano di studi epidemiologici in Nefrologia). Lancet 349, 1857–1863 (1997).
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Liu, J. E., Robbins, D. C., Palmieri, V., Bella, J. N., Roman, M. J., Fabsitz, R., Howard, B. V., Welty, T. K., Lee, E. T., Devereux, R. B. Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: the strong Heart Study. J. Am. Coll. Cardiol. 41, 2022–2028 (2003).
Miettinen, H., Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., Laakso, M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke 27, 2033–2039 (1996).
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Eddy, A. A. Proteinuria and interstitial injury. Nephrol. Dial. Transplant. 19, 277–281 (2004).
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Ridao, N. et al. Prevalence of hypertension in renal disease. Nephrol. Dial. Transplant. 16 (Suppl. 1), 70–73 (2001).
Inoue, T. et al. Proteinuria as a significant determinant of hypertension in a normotensive screened cohort in Okinawa, Japan. Hypertens. Res. 29, 687–693 (2006).
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Lee, T. M., su, s. F. & Tsai, C. H. effect of pravastatin on proteinuria in patients with wellcontrolled hypertension. Hypertension 40, 67–73 (2002).
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Bianchi, S., Bigazzi, R., Caiazza, A. & Campese, V. M. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am. J. Kidney Dis. 41, 565–570 (2003).
Hommel, E. et al. Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy. Diabetologia 35, 447–451 (1992).
Thomas, M. E. et al. simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria. Kidney Int. 44, 1124–1129 (1993).
Rabelink, A. J., Hené, r. J., erkelens, D. w., Joles, J. A. & Koomans, H. A. effects of simvastatin and cholestyramine on lipoprotein profile in hyperlipidaemia of nephrotic syndrome. Lancet 2, 1335–1338 (1988).
Strippoli, G. F. et al. effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ 336, 645–651 (2008).
Agarwal, R. statin induced proteinuria: renal injury or renoprotection? J. Am. Soc. Nephrol. 15, 2502–2503 (2004).
Brunzell, J. D. et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 31, 811–822 (2008).
Myers, G. L. et al. CDC/AHA workshop on Markers of inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: report from the laboratory science discussion group. Circulation 110, 545–549 (2004).
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).
Blum, M. S. et al. Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines. Am. J. Physiol. 273, H286-H294 (1997).
Michel, C. C. Transport of macromolecules through microvascular walls. Cardiovasc. Res. 32, 644-653 (1996).
Vogel, S. M. et al. evidence of transcellular permeability pathway in microvessels. Microvasc. Res. 61, 87-101 (2001).
Stocker, R. & Keaney, J. F. Jr role of oxidative modifications in atherosclerosis. Physiol. Rev. 84, 1381–1478 (2004).
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).
Stroes, E. S., Koomans, H. A., de Bruin, T. W. & Rabelink, T. J. vascular function in the forearm of hypercholesterolaemic patients off and on lipidlowering medication. Lancet 346, 467–471 (1995).
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).
Kannel, W. B., Stampfer, M. J., Castelli, W. P. & Verter, J. The prognostic significance of proteinuria: the Framingham study. Am. Heart J. 108, 1347–1352 (1984).
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).
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).
Nakayama, M. et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population—the Ohasama study. Nephrol. Dial. Transplant. 22, 1910–1915 (2007).
MacKinnon, M. et al. Combination therapy with an angiotensin receptor blocker and an ACe inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am. J. Kidney Dis. 48, 8–20 (2006).
Bakris, G. L., Weir, M. R., DeQuattro, v. & McMahon, F. G. effects of an ACe inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int. 54, 1283–1289 (1998).
Hou, F. F. et al. renoprotection of Optimal Antiproteinuric Doses (rOAD) study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J. Am. Soc. Nephrol. 18, 1889–1898 (2007).
Aranda, P. et al. Long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive nondiabetic nephropathies. Am. J. Kidney Dis. 46, 1074–1079 (2005).
Bianchi, S., Bigazzi, R. & Campese, V. M. Longterm effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 70, 2116–2123 (2006).
Schjoedt, K. J. et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 68, 2829–2836 (2005).
Chrysostomou, A., Pedagogos, E., MacGregor, L. & Becker, G. J. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin ii receptor blocker. Clin. J. Am. Soc. Nephrol. 1, 256–262 (2006).
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Varun Agrawal, MD

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

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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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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

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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

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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Measurement of Proteinuria

Measuring the amount of protein in urine allows for identification of persons at increased risk for CVD (discussed later in this review), progression of CKD, and monitoring of the efficacy of therapy aimed at reduction of proteinuria. Routine screening for proteinuria in the general population, however, is not cost-effective.^[6] The Kidney Disease outcomes Quality initiative guidelines^[7] recommend that 'individuals at increased risk of developing chronic kidney disease should undergo testing for markers of kidney damage', such as proteinuria ( Box 2 ).

The gold standard for measuring proteinuria is 24 h urine protein excretion; however, this measurement is cumbersome and subject to error owing to improper collection. Untimed (spot) urine sample is a more practical alternative to detect and measure proteinuria. Although first morning void specimens are preferred, random urine specimens are also acceptable. Kidney Disease outcomes Quality initiative guidelines^[7] recommend screening for proteinuria with standard urine dipsticks. Urine dipstick measurements have high specificity (97–100%) but low sensitivity (32–46%), with the possibility of false negative results from dilute urine.^[8] Patients who test positive on the dipstick should have their result confirmed with a quantitative measurement that includes spot urine protein:creatinine or albumin:creatinine ratios. These spot urine measurements correlate well with the gold-standard, 24 h protein quantitation.^[7] Variability in the level of urine protein in an individual, from diet, activity or time of collection, is a serious limitation of the spot urine tests (standard deviation up to 40–50% of the mean).^[7] Repeat urine studies should thus be performed when abnormal results are obtained.

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Proteinuria and Risk of CVD

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: Measurement of Proteinuria

Measurement of Proteinuria

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: Measurement of Proteinuria

Measurement of Proteinuria

Table of Contents