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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

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:

  1. Describe the procedure of screening for proteinuria
  2. Identify the effect of inhibitors of the renin-angiotensin-aldosterone system on cardiovascular outcomes among patients with proteinuria
  3. Describe the relationship between proteinuria and dyslipidemia
  4. 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

    Disclosures

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


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CME

Cardiovascular Implications of Proteinuria: An Indicator of Chronic Kidney Disease: Potential Mechanisms for CVD Risk

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Potential Mechanisms for CVD Risk

Defects in the glomerular capillary endothelium, basement membrane or podocytes is manifested as proteinuria. The proteins, hormones, growth factors (insulin-like growth factor), lipoproteins and transferrin that leak into the urinary space and flow to the tubules have been postulated to cause tubulointerstitial injury and inflammation.[20] Eventually, this injury pathway leads to parenchymal damage, renal fibrosis and progressive decline in eGFR.[21] This mechanism partly explains the specific association between proteinuria and progression to ESRD and death related to renal disease, and suggests that the protein in the urinary space is a potential renoprotective treatment target.

Here, we review probable mechanisms that link proteinuria with increased CVD risk. Notably, the described mechanistic links only represent associations: they are not yet coupled with definitive data that shows a causal relationship. Indeed, patients with CKD and with eGFR <60 ml/min/1.73 m2 often have proteinuria and much of the evidence for mechanisms described in this section was found in patients with reduced renal filtration function. Numerous pathways in CKD—including extracellular fluid volume overload, hypertension, abnormal calcium and phosphorus metabolism resulting in vascular calcification, endothelial dysfunction, systemic inflammation, oxidative stress and activation of sympathetic system and renin–angiotensin–aldosterone system (RAAS)—have been implicated to increase CVD risk.[22] CVD risk factors associated with proteinuria are discussed below.

Hypertension

Proteinuria is also associated with hypertension—an established cardiovascular risk factor. A study of patients with CKD (creatinine clearance <70 ml/min) in a renal clinic revealed a high prevalence of blood pressure >140/90 mmHg (60.5%), and the degree of proteinuria was found to be a significant determinant of the presence of hypertension in the study population.[23] Proteinuria is also a predictor for future development of hyper tension among normotensive individuals.[24] A cross-sectional study of 232 veterans affairs patients with CKD (eGFR <90 ml/min/1.73 m2) showed degree of proteinuria to be the most significant correlate for systolic blood pressure.[25] Furthermore, increased arterial stiffness, as assessed by pulse wave velocity, was shown to be associated with presence of dipstick-positive proteinuria, creatinine clearance and systolic blood pressure in the general population of Okinawa, Japan (n = 3,387).[26]

Targeting the RAAS with ACEIs or angiotensin II receptor blockers (ARBs) is an effective strategy to reduce proteinuria ( Table 2 ). Improvement in CVD outcomes with RAAS blockers, however, is limited. In the RENAAL trial, 1,513 patients with type 2 diabetes and nephropathy (serum creatinine 1.3–3.0 mg/dl) were randomly assigned to receive treatment with losartan or placebo for 3.4 years;[27] morbidity and mortality from cardiovascular causes was similar in both groups, though the rate of first hospitalization for heart failure was significantly lower in the losartan group (11.9%) than in the placebo group (16.7%, P = 0.005). A posthoc analysis from the RENAAL trial showed that proteinuria reduction by 30% or more after 6 months of losartan was associated with significant adjusted relative risk reductions of 49%, 23% and 34% over the length of the study for heart failure, non-heart-failure CVD and composite CVD end points, respectively, compared with no proteinuria reduction (Figure 2).[13] Every 50% reduction in proteinuria reduced the risk for heart failure and CVD end points by 27% and 18%, respectively.[13] Given the variability in proteinuria measurements, however, it is also possible that a 30% or greater reduction in proteinuria is in part a result of regression to the mean. Furthermore, results of posthoc analyzes are well known to be far from definitive.

Figure 2.

Enlarge

Relationship between change in albuminuria after 6 months of losartan therapy and CV and heart failure end points in the RENAAL (reduction in endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan) trial.[13] Kaplan-Meier curves stratified by the change in albuminuria after 6 months of losartan are shown for a | CV and b | heart failure end points. Hazard ratios as functions of percentage change in albuminuria after 6 months of losartan therapy are also shown for c | CV and d | heart failure end points. The relationship is corrected for multiple risk factors (history of cardiovascular disease and heart failure, age, sex, ethnicity, hemoglobin, sitting diastolic and systolic blood pressure, estimated glomerular filtration rate, weight and hemoglobin A1C) at baseline and 6-month changes and log-changes in sitting diastolic and systolic blood pressure, estimated glomerular filtration rate, weight and hemoglobin A1C from baseline. a n = 393. b n = 631. c n = 489. Abbreviation: CV, cardiovascular. Permission obtained from Lippincott Williams & Wilkins © de Zeeuw, D. et al. Circulation. 110, 921-927 (2004).

In the Irbesartan Diabetic nephropathy trial, 1,715 patients with diabetes, hypertension and proteinuria (serum creatinine 1–3 mg/dl in men and 1.2–3 mg/dl in women) were randomly assigned to treatment with irbesartan, amlodipine or placebo.[28] After a follow-up of 2.6 years, no significant differences in the rates of cardiovascular events (cardiovascular deaths, nonfatal myocardial infarction, heart failure, stroke, lower limb amputation) were observed between the three groups, while proteinuria was reduced by 33%, 6% and 10% in the irbesartan, amlodipine and placebo group, respectively. A prospective cohort study in 3,773 Chinese patients with type 2 diabetes and varying degrees of albuminuria (n for macroalbuminuria = 634) and renal function (plasma creatinine ≥150 µmol/l in 6.8% of patients) showed reduction in all-cause mortality in the entire group (HR 0.41) with ACEI administration; however, no significant improvement in hospitalization for CVD events were seen in the various albuminuria subgroups (HR 1.21, P = 0.53 for patients with macroalbuminuria).[29] The DIABHYCAR (non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril) study included 4,912 patients with diabetes with albuminuria (n = 1,285 for proteinuria) and intact renal function (serum creatinine <150 µmol/l) who were randomly assigned to treatment with ramipril 1.25 mg/d or placebo.[30] No effect on the combined and individual CVD outcomes of death, nonfatal myocardial infarction, stroke and heart failure were observed (HR 1.03, P = 0.65), compared with those on placebo, while a 14% relative risk reduction in albuminuria was observed with ramipril.[30]

The combination of ACEI and ARB for more complete blockade of the RAAS was evaluated in the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial); the effect of combined ACEI and ARB (ramipril 10 mg/d and telmisartan 80 mg/d) on CVD events, versus ACEI or ARB monotherapy, was evaluated in patients at high cardiovascular risk (n = 25,620). The primary outcome of death from CVD, myocardial infarction, stroke, or hospitalization for heart failure was similar in the combination ACEI–ARB therapy versus monotherapy study groups.[31] Another report of the same trial revealed that combination ACEI–ARB might increase risk of renal outcomes (composite of dialysis, doubling of creatinine and death) after 56 months of follow-up;[32] however, the effect of these results needs to be tempered by the fact that only a small subset of the patients had proteinuria (4% had macro albuminuria) and the ONTARGET renal end points were secondary end points of the main study. A large study that examines the long-term effect of combination ACEI and ARB on CVD and CKD progression is needed. One such study that is currently starting enrollment is the veterans affairs NEPHRON-D (Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy, NCT00555217) study, which is a prospective, randomized, double-blind, multicenter trial that will assess the effect of the combination of losartan 100 mg/d and lisinopril 10–40 mg/d (as tolerated), versus losartan alone, on renal end points (eGFR reduction by 50% or >30 ml/min/1.73 m2 or ESRD) or CVD events in patients with type 2 diabetes and CKD (30–90 ml/min/1.73 m2 and urine albumin:creatinine ratio >300 mg/g). Triple blockade of RAAS—using ACEI, ARB and the aldosterone antagonist spironolactone—is currently also being studied for more complete inhibition of the RAAS, and additional proteinuria reduction.[33]

Coronary Artery Calcification

Coronary artery calcification, as assessed by electron beam CT and cardiac CT angiography, identifies subclinical atherosclerotic plaque burden in all layers of the vessel wall, but its reliability in patients with CKD is inadequate.[34,35] In the Pittsburgh epidemiology of Diabetic Complications cohort of 302 adults with type 1 diabetes, patients with coronary artery calcification score >400 had significantly greater prevalence of diabetic CKD (proteinuria >200 µg/min or serum creatinine >2 mg/dl).[36] In another study of 122 patients with type 2 diabetes (including patients with microalbuminuria and macro albuminuria), log albumin:creatinine ratio was a significant predictor of the extent of coronary artery calcification.[37] A cross-sectional study that compared coronary artery calcification in 90 patients with diabetic nephropathy (urine protein:creatinine ratio >0.5 g/g), with 30 patients with diabetes and normoalbuminuria, found a greater prevalence of calcification (93% versus 63%, P <0.001), as well as an increased degree of calcification (calcification score 66 versus 4, P <0.001), in patients with proteinuria. Though the mean eGFR was 39 ± 4 ml/min/1.73 m2 among patients with diabetic nephropathy, no difference in the presence or extent of calcification across the various CKD stages was noted. Interestingly, greater coronary artery calcification score in patients with diabetic nephropathy was associated with the presence of severe hypertension (as studied by the number of antihypertensive medications used), female gender and age <60 years, which suggests that these factors further accelerate coronary calcification in patients with diabetic nephropathy.[38]

Hyperlipidemia

Hyperlipidemia is another risk factor for increased cardiovascular mortality, and an abnormal lipid profile is commonly observed in individuals with proteinuria. Among individuals with proteinuria, the prevalence of total cholesterol >6.22 mmol/l (240 mg/dl), LDL >3.37 mmol/l (130 mg/dl), HDL <0.91 mmol/l (35 mg/dl), and triglyceride >2.26 mmol/l (200 mg/dl) has been reported to be 88%, 86%, 62%, 62%, respectively.[39] In addition, lipoprotein(a), a prothrombotic protein attached to apolipoprotein B100 on LDL particles, has been reported to be elevated (>1.07 µmol/l [30 mg/dl]) in 60% of patients with proteinuria.[39] In general, the severity of the dyslipidemia correlates with the severity of proteinuria.[39]

Some small studies have shown reduction in proteinuria with statin therapy over a limited follow-up period, although others have not. Furthermore, clear evidence for improved CVD and CKD outcomes with use of statins in patients with proteinuria is lacking. In a prospective, double-blind study of 63 patients with proteinuria (with serum creatinine <1.5 mg/dl), normolipemia (total cholesterol <6.22 mmol/l) and controlled hypertension (<140/90 mmHg), participants were randomly assigned to treatment with pravastatin or placebo;[40] after 6 months of treatment, patients on statin therapy demonstrated reduced proteinuria that correlated with reduction in urinary endothelin 1, but not with change in lipid profile, and creatinine clearance remained stable. In a similar study, the research group reported further improvement in proteinuria in patients on statins and losartan therapy, which was lost with withdrawal of statin.[41] Another prospective, controlled, open-label study in 56 patients with proteinuria (secondary to idiopathic glomerulo nephritis, baseline creatinine clearance 50 ml/min) and hyperlipidemia, demonstrated significant proteinuria reduction and slower decline in creatinine clearance with atorvastatin after one year of ACEI–ARB antihypertensive therapy.[42] However, these effects on albuminuria and GFR were not seen in three other studies, which included 26 patients with type 1 diabetes with nephropathy who were treated with simvastatin,[43] 30 adults with nephrotic syndrome or proteinuria >1 g daily who were randomly assigned to simvastatin or placebo,[44] and, despite improvement in hyperlipidemia, in 10 patients with nephrotic syndrome who were treated with simvastatin and cholestyramine.[45] A meta-analysis of randomized, placebo-controlled trials of statins in patients with CKD (presence of proteinuria or eGFR <60 ml/min/1.73 m2) showed an overall significant reduction in proteinuria (n = 311 patients, 6 studies), unchanged GFR, and an interesting significant reduction in CVD events.[46]

Questions still remain as to whether there is a dose-dependent response of statin therapy on urine protein and if different statins cause varying beneficial effect on proteinuria. It is also unclear if the tubular proteinuria from reduced receptor mediated endocytosis at the proximal tubule observed with use of statin (rosuvastatin 80 mg daily) is injurious or protective to the kidney.[47]

Nevertheless, the National Cholesterol Education Project Adult Treatment Panel 4 guideline recommendations on use of statins for goal LDL <1.81 mmol/l and non-HDL <2.59 mmol/l should be adhered to in patients with CKD (proteinuria or eGFR<60 ml/min/1.73 m2) ( Table 2 ). American Diabetic Association/ACC recommendations published in 200848 include a third lipid goal—an apolipoprotein B100 level <0.8 g/l—which addresses the problem of residual risk related to increases in LDL particle number in the setting of low HDL and high triglycerides.

Inflammation

Inflammatory biomarkers of vascular changes and endothelial dysfunction are being actively studied to define their role as markers of atherosclerotic burden, mediators of vascular damage, or both. C-reactive protein (CRP) is a large pentameric protein produced by the liver in response to adipokine signals from intra-abdominal fat stores; this protein is probably not pathogenic itself, but has been associated with impaired endothelial function.[49] CRP measured by high sensitivity CRP (hs-CRP) testing correlates with the degree of global cardiometabolic risk associated with adipose tissue.[49] Hs-CRP measures are elevated in asymptomatic patients with nephroticrange proteinuria and are associated with impaired microvascular endothelial function as assessed by acetylcholine iontophoresis.[25] Moreover, significant correlation between the severity of proteinuria and level of hs-CRP has been demonstrated.[50] Proteinuria is also associated with asymmetric dimethylarginine, another inflammatory biomarker that inhibits production of nitric oxide (NO), and thus causes endothelial dysfunction and atherosclerosis.[51]

Thrombotic Mechanisms

Thrombogenic factors and blood viscosity might predict CVD events in patients with proteinuria. In a prospective study of 328 individuals, von Willebrand factor, tissue type plasminogen activator, soluble vascular cell adhesion molecule, soluble eselectin and fibrinogen were found to correlate with increased urinary albumin excretion.[52] Plasma prekallikrein, a modulator of vascular tone and structure, was found to be high in patients with diabetes with macroalbuminuria.[53] Monocyte chemoattractant protein 1, a chemokine that recruits monocytes into atherosclerotic plaques and produces a local inflammatory response, was also found to be elevated in patients with diabetes with macroalbuminuria.[54] Finally, elevated factor VII, plasminogen activator inhibitor type 1, platelet adhesiveness, and erythrocyte aggregability in patients with diabetes and proteinuria[55,56] could be indicative of high thrombosis risk in the setting of plaque rupture, and the development of thrombi as a result of stasis in the arterial system.

Endothelial Dysfunction and Nitric Oxide

Proteinuria might reflect not only renal injury but also a systemic increase in endothelial permeability, though clear evidence is lacking for this hypothesis. The vascular endothelium has an important role in regulating transport of proteins across microvascular walls through intercellular clefts,[57] transcellular holes,[58] and, possibly, caveolae.[59] Endothelial dysfunction is an attractive mechanism that might link proteinuria with the pathogenesis of atherosclerosis, as endothelial dysfunction, in response to sheer stress and the deposition of lipoproteins in the subendothelial space, is an early event in atherogenesis and is hypothesized to accelerate atherosclerotic plaque formation.[60] Increased transvascular leakage as a result of endothelial permeability could allow the gradient-dependent entry of apolipoprotein B100 containing lipoproteins into the vessel wall, where they would become trapped. In addition, injury to the endothelium results in increased cell and platelet adhesiveness, greater permeability to proteins and inflammatory cells, and altered production of vasoactive mediators, specifically NO.

Against the hypothesis that proteinuria is a marker of increased systemic permeability, transcapillary escape rate of albumin was observed to be increased among patients with diabetes, compared with control participants, to a similar extent in patients with and without proteinuria (urine albumin >300 mg/day).[61] However, macrovascular endothelial function, as assessed by flow-associated dilation, has been shown to be impaired in individuals with nephroticrange proteinuria.[62] This process is thought to occur though the loss of vasoregulatory effects of NO. In addition to maintaining vasodilatory tone, NO also prevents platelet adhesion and aggregation, inhibits vascular smooth muscle proliferation and leukocyte adhesion, antagonizes lipoprotein flux into the subendothelium, and attenuates the oxidative modification of the trapped cholesterol. Indeed, decreased NO activity in individuals with nephrotic syndrome is thought to be responsible for their atherosclerosis.[63]

Nephroticrange proteinuria is associated with deranged NO activity through indirect mechanisms. Dyslipidemia is commonly seen in individuals with nephrotic syndrome, and increases in very low-density lipoprotein, and LDL is believed to further worsen NO-mediated vasodilation (endothelial dysfunction).[64] An interesting hypothesis to explain this link involves lysophosphatidylcholine. In patients with nephrotic syndrome, abnormally low serum albumin levels results in diminished binding of lysophosphatidylcholine to albumin, thus leading to sequestration and increased levels of lysophosphatidylcholine in LDL cholesterol.[65] The lysophosphatidylcholine probably affects endothelial function through NO dependent and independent pathways, in addition to its proinflammatory and oxidative effects.[66] There is a lack of evidence for endothelial dysfunction in patients with milder degree of proteinuria, but it is possible that the aforementioned mechanism occurs in nonnephrotic proteinuria.

Vascular Endothelial Growth Factor

Another interesting potential mechanism that links proteinuria and hypertension is being studied in patients receiving vascular endothelial growth factor (VEGF) inhibitors for treatment of cancer. In a meta-analysis of 7 trials (1,850 patients), use of a VEGF antagonist (bevacizumab) was associated with an increased incidence of proteinuria and hypertension.[67] These adverse effects were reversed when the anti-VEGF therapy was stopped.[68] The pathogenesis of proteinuria that results from VEGF antagonism is not clear, but endothelial dysfunction is a potential cause. VEGF is expressed by the podocytes and is important in glomerular development (angiogenesis), maintenance of endothelial function and endothelial repair after injury.[69] Increased hemodynamic stress from the associated hypertension might also be implicated in the proteinuria. Studies have not assessed whether anti-VEGF-associated endothelial dysfunction occurs only at the glomerular level, or also at a systemic level to result in increased atherosclerosis and cardiovascular risk.

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