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Diabetes, Metabolic Disorders & Control

Mini Review Volume 5 Issue 6

Proteinuria, a marker of cardiovascular risks

Anuj Maheshwari

Babu Banarasi Das University, India

Correspondence: Anuj Maheshwari, Babu Banarasi Das University, India, Tel +91 9918116016

Received: November 18, 2017 | Published: November 15, 2018

Citation: Maheshwari A. Proteinuria, a marker of cardiovascular risks. J Diabetes Metab Disord Control. 2018;5(6):208-210. DOI: 10.15406/jdmdc.2018.05.00167

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Introduction

The association between chronic kidney disease (CKD) and cardiovascular disease has long been recognized and current guidelines recommend that patients with CKD be considered to be at particularly high cardiovascular risk.1 Although often transient and benign, the persistent presence of protein or albumin in the urine has marked clinical significance as an early indicator of underlying renal pathology, preceding tangible decline in renal filtration function. In addition to its role as a marker for CKD risk, it is now widely accepted that proteinuria is an independent predictor of cardiovascular morbidity and mortality across divergent populations.

The presence of CKD is a powerful predictor of adverse clinical outcomes.2,3 cardiovascular disease is by far the most common cause of death in dialysis-dependent and renal transplant patients. Only a small minority of the CKD population progress to endstage renal disease requiring renal replacement therapy (RRT), with death prior to RRT being far more common. A 2010 meta-analysis with data for over 1 million subjects reported that stage 3 CKD (eGFR<60mL/minute/1.73m2) was associated with both cardiovascular and all-cause mortality.4 In a systematic review of associations between non-dialysis-dependent CKD and mortality, Tonelli et al reported that the absolute risk of death increased exponentially with declining renal function.5 Even the earliest, clinically silent stages of CKD have been associated with major cardiovascular disease. In addition to reduced eGFR, ACR and dipstick positive proteinuria have also been associated with graded cardiovascular and all-cause mortality, acting as risk multipliers across all levels of renal function.6,7 In a large Canadian study, Hemmelgarn et al found that heavy proteinuria independently increased risk of death, myocardial infarction (MI) and progression of CKD in particular patient groups.8

Evidence now suggests that proteinuria has implications for all-cause mortality and cardiovascular outcomes at a general population level, not only in individuals with CKD. Population based cohort studies have shown that multivariable relative risks of cardiovascular disease mortality for proteinuria range from 1.2–2.9.9 The Prevention of Renal and Vascular Endstage Disease (PREVEND) study included over 40,000 individuals and found that a 2-fold increase in ACR equated to close to a 30% increase in risk for cardiovascular mortality.10 Moreover, this relationship is constant across distinct ethnic groups,11‒13 and in elderly populations.14 In terms of cardiovascular morbidity, dipstick positive proteinuria and ACR have emerged as predictors of cardiovascular diseases including ischemic heart disease, stroke, and hypertension in the general population, with some sources suggesting that proteinuria is a stronger predictor of outcome than traditional risk factors such as blood pressure and cholesterol.15,16 Indeed, the Heart Outcomes Prevention Evaluation (HOPE) study found that proteinuria was associated with adverse outcome independently of traditional cardiovascular risk factors.17 Furthermore, cardiovascular risk appears to be increased even at levels of urinary protein excretion that are not considered to be pathological,17 and in fact there is no distinct threshold level that confers increased cardiovascular risk; rather, increasing albuminuria is associated with a graded increase in risk.18 Proteinuria has also been associated with increased risk of atherosclerotic events affecting the peripheral vasculature. Patients with proteinuria have been shown to have increased risk of incident stroke. A 2010 meta-analysis of studies totalling 48,000 participants reported that the presence of Microalbuminuria was associated with a future stroke risk 90% greater than that of normoalbuminuric individuals.19 The impact of Microalbuminuria was greatest on ischemic stroke incidence in those with a prior history of cerebrovascular disease and found to be relatively modest within the diabetic population.20 a further meta-analysis of the relationship between proteinuria and stroke has suggested that risk rises with degree of urinary protein excretion.21,22

In the hypertensive population, studies suggest that Microalbuminuria confers a 4 times greater risk of subsequent ischemic heart disease than in normoalbuminuric individuals.23,24 this effect appears to be independent of conventional atherosclerotic risk factors. In addition, albuminuria has been associated with the presence of left ventricular hypertrophy in patients with hypertension and diabetes.25‒27 It has also been demonstrated that in individuals with stable underlying coronary artery disease, proteinuria confers increased risks of all-cause and cardiovascular mortality, even at lower levels within the defined “normal range”.28‒31 This has also been shown in individuals who have recently suffered a coronary event.32,33 The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) study showed that macro- rather than Microalbuminuria was a better predictor of mortality in this group.34

Mechanisms underlying cardiovascular consequences of proteinuria

The Steno hypothesis suggested that urinary protein excretion not only reflects localized subclinical renal disease but also a more generalized vascular endothelial dysfunction.35 High-sensitivity troponin T (hs-TnT) as a marker of vascular micro necrosis has been found to independently predict transitions in albuminuria grade.36 Microalbuminuria is also accompanied by a fall in adiponectin levels and elevated C-reactive protein (CRP),37 and there appears to be a significant correlation between degree of proteinuria and CRP level. Evidence has also linked proteinuria with asymmetric dimethylarginine (ADMA), an inflammatory biomarker which causes endothelial dysfunction through inhibition of nitric oxide production.38 Circulating von Willebrand Factor (vWF) antigen is released in greater concentrations in response to endothelial cell damage. Levels of vWF have been shown to be higher in patients with Microalbuminuria compared to control subject.39 Macro vascular endothelial dysfunction assessed by flow-mediated dilatation has been shown to be impaired in individuals with proteinuria. Vascular endothelial growth factor (VEGF) is another interesting potential mechanistic link between proteinuria and endothelial dysfunction. Use of VEGF-antagonists as angiogenesis inhibitors for the treatment of patients with cancers have been associated with increased incidence of proteinuria and hypertension, an effect which was reversed on withdrawal of therapy.40

As well as inflammation and endothelial dysfunction, thrombogenic factors have been implicated as potential mechanisms underlying the relationship between proteinuria and cardiovascular disease. In addition to vWF, soluble vascular cell adhesion molecule, fibrinogen, and tissue plasminogen activator have been found to correlate with urinary albumin excretion.41 A variety of hemostatic abnormalities have been described in patients with diabete,42 and it has been suggested that high platelet adhesiveness and erythrocyte aggregation demonstrated in diabetic patients with proteinuria could indicate increased thrombosis risk.

Both insulin resistance and proteinuria have been associated with atherogenesis. The Insulin Resistance Atherosclerosis Study involving 982 no diabetic participants found that Microalbuminuria subjects had lower insulin sensitivity and higher plasma insulin levels compared to normal albumin uric participants, leading the authors to propose that insulin resistance has a role to play in the increased cardiovascular risk conferred by proteinuria. Hyperinsulinemia has been shown to cause renal vasodilatation and increased glomerular filtration rate in rats, with some suggesting that this localized elevated pressure is involved in regulating urinary albumin excretion.29 As well as demonstrating association between insulin resistance and Microalbuminuria, Bianchi et al noted that in patients with essential hypertension, Microalbuminuria was associated with altered lipid profile and an abnormal circadian blood pressure pattern, thus forming part of a cluster with potential to modify cardiovascular risk in these individuals.

Conclusion

The significant burden on health services posed by cardiovascular disease has prompted investigation of prognostic markers and therapeutic targets. There is a clear association between proteinuria and cardiovascular outcomes despite marked heterogeneity in the literature when considering the method of detection used and classification of degree of proteinuria. This association has been demonstrated both in disease population including hypertensives, diabetic patients, and those with CKD, as well as in otherwise healthy individuals. Proteinuria has evolved into a surrogate marker of cardiovascular risk and it seems intuitive that earlier detection and more aggressive intervention may serve to reduce risk in affected individuals. Several publications have considered the cost-effectiveness of population screening. In 2003 Boulware et al concluded that population screening for dipstick proteinuria was not cost-effective in terms of CKD morbidity and mortality unless specifically targeted towards higher risk groups such as hypertensive or elderly patients and done at less frequent intervals. When considering prevention of cardiovascular events, an analysis of the PREVEND-IT study was more favourable. RAAS inhibition, together with control of additional cardiovascular risk factors, remains the mainstay of treatment for individuals with proteinuria. Studies of earlier and more aggressive intervention with two or more RAAS blocking agents have demonstrated reduction in proteinuria but this has not yet translated into reduction in hard clinical cardiovascular endpoints and these studies have also reported a greater degree of side effects and adverse events.

Acknowledgements

None.

Conflict of interest

Author declares there is no conflict of interest.

References

  1. Sarnak MJ, Levey AS, Schoolwerth AC, et al. 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. 2003;108(17):2154–2169.
  2. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–1305.
  3. Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med.2004;164(6):659–663.
  4. Matsushita K, Velde M, Astor BC, et al. Chronic Kidney Disease Prognosis Consortium Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–2081.
  5. Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol. 2006;17(7):2034–2047.
  6. Angelantonio DE, Chowdhury R, Sarwar N, et al. Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. BMJ. 2010;341:4986.
  7. Herzog CA. Kidney disease in cardiology. Nephrol Dial Transplant. 2009;24(1):34–37
  8. Nagata M, Ninomiya T, Kiyohara Y, et al. EPOCH-JAPAN Research Group Prediction of cardiovascular disease mortality by proteinuria and reduced kidney function: pooled analysis of 39,000 individuals from 7 cohort studies in Japan. Am J Epidemiol. 2013;178(1):1–11.
  9. Hemmelgarn BR, Manns BJ, Lloyd A, et al. Alberta Kidney Disease Network Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303(5):423–429.
  10. Kannel WB, Stampfer MJ, Castelli WP, et al. The prognostic significance of proteinuria: the Framingham study. Am Heart J. 1984;108(5):1347–1352.
  11. Matsushita K, Velde M, Astor BC, et al. Chronic Kidney Disease Prognosis Consortium Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–2081.
  12. Hillege HL, Fidler V, Diercks GF, 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. 2002;106(14):1777–1782.
  13. Irie F, Iso H, Sairenchi T, et al. The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population. Kidney Int. 2006;69(7):1264–1271.
  14. Inoue T, Iseki K, Higashiuesato Y, et al. Proteinuria as a significant determinant of hypertension in a normotensive screened cohort in Okinawa, Japan. Hypertens Res. 2006;29(9):687–693.
  15. Wang Z, Hoy WE. Albuminuria and incident coronary heart disease in Australian Aboriginal people. Kidney Int. 2005;68(3):1289–1293.
  16. Damsgaard EM, Froland A, Jorgensen OD, et al. Microalbuminuria as predictor of increased mortality in elderly people. BMJ. 1990;300(6720):297–300.
  17. Bello AK, Hemmelgarn B, Lloyd A, et al. Alberta Kidney Disease Network Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes. Clin J Am SocNephrol. 2011;6(6):1418–1426.
  18. Perkovic V, Verdon C, Ninomiya T, et al. The relationship between proteinuria and coronary risk: a systematic review and meta-analysis. PLoS Med. 2008;5(10):207.
  19. Gerstein HC, Mann JF, Yi Q, et al. HOPE Study Investigators Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286(4):421–426.
  20. Hillege HL, Janssen WM, Bak AA, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249(6):519–526.
  21. Wachtell K, Ibsen H, Olsen MH, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med. 2003;139(11):901–906.
  22. Wachtell K, Olsen MH, Dahlof B, et al. Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. J Hypertens. 2002;20(3):405–412.
  23. Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Impact of microalbuminuria on incident stroke: a meta-analysis. Stroke. 2010;41(11):2625–2631.
  24. Ninomiya T, Perkovic V, Verdon C, et al. Proteinuria and stroke: a meta-analysis of cohort studies. Am J Kidney Dis. 2009;53(3):417–425.
  25. Jensen JS, Feldt-Rasmussen B, Strandgaard S, et al. Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension. 2000;35(4):898–903.
  26. Nobakhthaghighi N, Kamgar M, Bekheirnia MR, et al. Relationship between urinary albumin excretion and left ventricular mass with mortality in patients with type 2 diabetes. Clin J Am SocNephrol. 2006;1(6):1187–1190.
  27. Post WS, Blumenthal RS, Weiss JL, et al. Spot urinary albumin-creatinine ratio predicts left ventricular hypertrophy in young hypertensive African-American men. Am J Hypertens. 2000;13(11):1168–1172.
  28. Dell’omo G, Giorgi D, Di Bello V, et al. Blood pressure independent association of microalbuminuria and left ventricular hypertrophy in hypertensive men. J Intern Med. 2003;254(1):76–84.
  29. Solomon SD, Lin J, Solomon CG, et al. Prevention of Events With ACE Inhibition (PEACE) Investigators Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease. Circulation. 2007;116(23):2687–2693.
  30. Jose P, Skali H, Anavekar N, et al. Increase in creatinine and cardiovascular risk in patients with systolic dysfunction after myocardial infarction. J Am Soc Nephrol. 2006;17(10):2886–2891.
  31. Nazer B, Ray KK, Murphy SA, et al. Urinary albumin concentration and long-term cardiovascular risk in acute coronary syndrome patients: a PROVE IT-TIMI 22 substudy. J Thromb Thrombolysis. 2013;36(3):233–239.
  32. Deckert T, Feldt RB, Borch JK, et al. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989;32(4):219–226.
  33. Hellemons ME, LambersHeerspink HJ, Gansevoort RT, de Zeeuw D, Bakker SJ. High-sensitivity troponin T predicts worsening of albuminuria in hypertension; results of a nested case-control study with confirmation in diabetes. J Hypertens. 2013;31(4):805–812.
  34. Tsioufis C, Dimitriadis K, Chatzis D, et al. Relation of microalbuminuria to adiponectin and augmented C-reactive protein levels in men with essential hypertension. Am J Cardiol. 2005;96(7):946–951.
  35. Yilmaz MI, Sonmez A, Saglam M, et al. ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction. J Am SocNephrol. 2008;19(2):388–395.
  36. Pedrinelli R, Giampietro O, Carmassi F, et al. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet. 1994;344(8914):14–18.
  37. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49(2):186–193.
  38. Stehouwer CD, Gall MA, Twisk JW, 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. 2002;51(4):1157–1165.
  39. Knobl P, Schernthaner G, Schnack C, et al. Thrombogenic factors are related to urinary albumin excretion rate in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36(10):1045–1050.
  40. Hirano T, Kashiwazaki K, Moritomo Y, et al. Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients. Diabetes Res Clin Pract. 1997;36(1):11–18.
  41. Mykkanen L, Zaccaro DJ, Wagenknecht LE, et al. Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the insulin resistance atherosclerosis study. Diabetes. 1998;47(5):793–800.
  42. Bianchi S, Bigazzi R, Valtriani C, et al. Elevated serum insulin levels in patients with essential hypertension and microalbuminuria. Hypertension. 1994;23(1):681–687.
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