Proteinuria as a Cardiovascular Risk Factor

Scheme

• Proteinuria pathophysiology.

• Normal Values and Diagnosis.

• Relation with Cardiovascular disease.

• Relation with Kidney disease.

• Management significance.

• Conclusion.

Pathophysiology

Glomeruli light microscopy schemeWilhelm Kriz, Marlies Elger. Essential Renal Anatomy and Pathology

Glomerular capillary electron microscopy image: Wilhelm Kriz, Marlies Elger. Essential Renal Anatomy and Pathology

Glomerular filtration barrierWilhelm Kriz, Marlies Elger. Essential Renal Anatomy and Pathology

Endothelium

Podocytes

GBM

Glomerular Filtration BarrierMolecule kDa g/mol Na 0.02 22.9 Mg 0.02 24.3 Cl 0.03 35.4 K 0.03 39 Ca 0.04 40 Urea 0.06 60 HCO3 0.06 61 PO4 0.09 94.7 Cr 0.113 113.1 Vit. B12 1.355 1355 Inulin 5 5000 B2 Microglubulin. 11,8 11,800 Albumin 66 66,000

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Protein Composition

Plasma Protein Excretion (mg/day)

Plasma Proteins:

• Albumin 12

• IgG 3

• IgA 1

• IgM 0.3

Light Chain

• Kappa 2.3

• Lambda 1.4

Beta-Microglobulin. 0.12

Other Plasma Prot. 20

All Plasma Prot. 40

Nonplasma Prot.

• Tamm-Horsfall prot. 40

• Other non-renal-derived prot. <1

All nonplasma protein 40

Total Proteins 80

11From Glassock R: Proteinuria. In Massry SG. Glassock RJ. Textbook of Nephroloyg 3rd ed. Baltimore, Willias & Williams, 1995

Proteomics correlation with histopathology in Chronic allograft Nephropathy

CM 10-2200-63CM10-8324-86CM10-4574-7CM10-16528-4Q10-4161-17IMAC30-13913-6

CM10-3463-48CM10-10003-9CM10-15870-9CM10-50159-6

IMAC30-10823

CM10-11673-1CM10-132999Q10-33612-1Q10-66882-9IMAC30-123657IMAC30-147781H50-2511-86H50-486654H50-6449-4

CM10-5874-54CM10-8565-69CM10-11980-5IMAC30-5863-98IMAC-11905-1

IMAC30-3620-96IMAC30-3751-83H50-5026-14

Interstitial Fibrosis

Chronic vascular injuryTubular Atrophy

Michael S. Goligorsky. Diagnostic Potential of Urine Proteome: A broken mirror of renal disease J Am Society of Neph 18: 2233-2239, 2007

14

Urine Dip Stick

CrNational Kidney Foundation. K/DOQi clinical practice guidelines for chronic kidney disease: evaluation, classification, and

stratification. Am. J. Kidney Dis. 39 (2 Suppl. 1), s1–s266 (2002).

Kashif, W., Siddiqi, N., Dincer, A. P., Dincer, H. E. & Hirsch, S. Proteinuria: how to evaluate an important finding. Cleve. Clin. J.

Med. 70, 535–537, 541–544, 546–547 (2003).

Biology.stackexchange.com

Measurement of Proteinuria

Spot Alb/Cr

mg/gm

24h Alb

mg/24hr

Spot Prot./Cr

mg/gm

24 h Prot.

mg/24hr

Normal <30 <30 150 150

Microalbuminuria 30-300 30-300 150-300 150-300

Macroalbuminuria 300-3500 300-3500 300-3500 300-3500

Nephrotic Range >3500 >3500 >3500 >3500

Micoralbuminuria Controversies

Unless the patient is diabetic it does not confirm kidney damage.

It could be due to: • Obesity.

• Inflammation.

• Cancer.

• Diurnal or posture variation.

• Exercise.

• Healthy individual.

Jones CA, Francis ME, Eberhardt MS, Chavers B, Coresh J; Microalbuminuria in the US population: Third NationalHealth and Nutrition Examination Survey. Am J Kidney Dis 39: 445–459, 2002

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Proteinuria present in:

1% of general population.

3.3% of patients with eGFR 30-60ml/min.

26% of patients with eGFR <30ml/min.

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The NHANES III (Third National Health AND Nutrition Examination Survey study 1988-1994). 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).

Prevalence of 10.2% in patient with HTN and eGFR < 60mlmin.

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).

I. Glomerular Proteinuria

Primary GN.

Minimal change.

IgA Nephropthy.

FSGS.

Membranous.

Membranoproliferative

Fibrillary Disease.

Cresentic GN.

Secondary GN. Mutisystemic Disease: SLE, Vasculitis.

Metabolic: DM,

Neoplastic disease.

Infection.

Drugs.

Familial.

Other: toxemia, transplant, Reflux.

Glomerular Proteinuria: without GN: Exercise, Febrile, Orthostasis

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II. Tubular Proteinuria:*Drugs and Toxins:

Light chain.Lysosomal.Heavy metal.Tetracyclin.

*Tubuloinerstitial Nephritis:.HypersensitivityMultisystemic: SLE, Sjogren, Others: Fanconi.

III. Overflow Proteinuria: Myloma, Amyloidosis, Hemoglobinuria, Myoglobinuria.

IV. Tissue Proteinuria:Acute inflammation of Urinary tract.Uroepithelial tumor.

Jane D. Hematuria and Proteinuria. Primer of Kidney Diseases. Saunders Elsevier. 5th Edition.

Diseases:

DM

HTN

Metabolic syndrome.

Autoimmune Disease.

Urinary Tract Infection.

Urinary tract obstruction.

Neoplasia.

Family History of CKD.

Reduction in Kidney mass.

Nephrotoxins like NSAID.

Low birth Wt.

22

Sociodemographic risk for Protienuria:

• Old Age.

• African American, American Indian and Hispanic.

• Exposure to chemical or environmental hazards

• Low income or education.

Varun Agrawal, MD; Victor Marinescu, MD, PhD; Mohit Agarwal, MD; Peter A. McCullough,, Cardiovascular Implications of Proteinuria: An Indicator of Chronic Kidney Disease. Medscape 3/26/2009.

Proteinuria and Cardiovascular Disease

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39 studies.

N =1,371,990 patient with CKD.

Not on Dialysis.

Result:

CKD have higher all cause and Cardiovascular Mortality.

CKD patients were at higher risk of CV Mortality rather than developing ESRD.

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Tonelli, M. et al. Chronic kidney disease and mortality risk: a systematic review. J. Am. Soc. Nephrol. 17, 2034–

2047 (2006).

26

Proteinuria is associated with increase CV mortality and morbidity.

Patient with proteinuria have increased:

Hazard Ratio

CV event 1.6-5.5

CV mortality 1.7-5.4

All cause mortality 1.4-2.9

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Nat Clin Pract Cardiovasc Med 2009. Natural Publishing Group

Most of the studies were in patients with CKD.

In CKD patients proteinuria could increase CV disease by:

Sympathetic stim.

RAAS activation.

Volume overload.

HTN.

Endothelial dysfunction.

Oxidative stress.

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29

Strong Heart Study:

Patients with DMII and proteinuria.

Had worse LV function.

Impaired LV diastolic filling

30

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 strongHeart Study. J. Am. Coll. Cardiol. 41, 2022–2028 (2003).

The degree of proteinuria was determinant of the presence of High BP > 140/90 in CKD with CKD eGFR < 70ml/min.

Proteinuria in CKD with eGFR <90ml/min. is directly related with degree of systolic BP.

Proteinuria is a predictor of HTN development.

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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).

Agarwal, R. & Andersen, M. J. Correlates of systolic hypertension in patients with chronic kidney disease. Hypertension 46, 514–520 (2005).

Proteinuria patient are associated with:

1.6-3.3 relative risk of incident stroke.

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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).

Zhang, Y. et al. incidence and risk factors for stroke in American indians: the strong Heart study. Circulation 118, 1577–1584 (2008).

Cohort of 302 adults with DMI.

Result Ca score > 400 more prevalent in DM & CKD with proteinuria or S Cr >2mg/dl.

N = 122

DM I with Micro and Macro albuminuria.

Log Alb:Cr ratio was predictor of Coronary Calcification.

33

Olson, J. C., Edmundowicz, D., Becker, D. J., Kuller, L. H. & Orchard, T. J. Coronary calcium in adults with type 1 diabetes: a stronger correlate of clinical coronary artery disease in men than in women. Diabetes 49, 1571–1578 (2000).

Wagenknecht, L. E. et al. Familial aggregation of coronary artery calcium in families with type 2 diabetes. Diabetes 50, 861 –866 (2001).

Hyperlipidemia is common with proteinuria.

among PROETIENURIA patients:

88% with S. Chole. > 240mg/dl.

86% with LDL > 130mg/dl.

62% with HDL < 35mg/dl.

62% with Trig. > 200 mg/dl.

34Kasiske, B. L. Hyperlipidemia in patients with chronic renal disease. Am. J. Kidney Dis. 32 (Suppl. 3), s142–s156 (1998).

Meta-analysis.

6 RCT with Statins in CKD patients.

N=311.

Results:

• Significant reduction in Proteinuria.

• Significant reduction in CV events.

• No change in eGFR.

35

Strippoli, G. F. et al. effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomized controlled trials. BMJ 336, 645–651 (2008).

Inflammation had been associated with endothelial dysfunctional and atherosclerosis.

CRP is associated with Endothelium dysfunction.

High Sensitivity CRP is correlated with cardiometabolic risk with adipose tissue.

High sensitive CRP is related with the degree of proteinuria.

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

Monocyte chemoatractant protein 1 increase in Diabetic with macroalbuminuria.

In DM and proteinuria there was an association with elevation in:

• Factor VII.

• Plasminogen Activator inh. type 1

• Platelet adhesiveness.

• Erythrocyte aggregability.

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).

Decrease and abnormal Nitric Oxide function in patients with Nephroticrange proteinuria leading to:

Increased platelet adhesion.

Increased Leukocytes Adhesion.

Smooth muscle Proliferation.

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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Reduction in Proteinuria by 30% with Losartan for > 6 month was associated with:

Reduction

- 49% Heart failure.

- 23% non heart failure CV.

- 34% composite CV end points.

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de Zeeuw, D. et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110, 921–927 (2004).

• N = 1715.

• DM with HTN and Proteinuria.

• S. Cr 1 – 3 mg/dl.

• Follow up 2.6 years.

Intervention arms:

Irbisartan.

Amlodipine.

Placebo.

Results:

Lower doubling S. Creatinine in Irbisartan group.

No significant difference in CV events.

CV mortality.

non fatal MI.

HF, stroke.

lower limb amputation.

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Reduction in proteinuria in each:33%6%10%

Lewis, E. J. et al. Collaborative study Group. renoprotective effect of the angiotensin receptor antagonist Irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).

• N = 4912.

• DM with Albuminuria & intact kidney function.

• S. Cr < 150micmol/l.

• RCT.

• Intervention: Ramipril 1.25mg versus placebo.

Results:• 14 % relative risk reduction in Albuminuria.

• No significant difference in CV outcome death, non fatal MI, Stroke, Heart failure.

49

Marre, M. et al. DIABHYCAR study investigators. effects of low dose ramipril on cardiovascular and renal outcomesin patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebocontrolled trial (the DIABHYCAR study). BMJ 328, 495 (2004).

• Chinese Cohort.

• N= 3773

• DMII with varying degree albuminuria.

• 16.8% with Macroalbuminuria.

• 6.8% with Cr > 150micmol/l.

Intervention: ACE inh versus placebo.

Results: Deceased all cause mortality. HR 0.41

No significant reduction in CV hospitalization.

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So, W. Y. et al. effect of angiotensin-converting enzyme inhibition on survival in 3773 Chinese type 2 diabetic patients. Hypertension 44, 294–299 (2004).

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• N= 1448.• RCT.• Median Follow up 2.2 years. • DM II.• Alb/Cr >300mg/gm.

Intervention:• Losartan 100mg with /without Lisinopril 10-40mg.

Primary end point: decline in eGFR of >30% for eGFR >60 or >50% if eGFR <60. ESRD. Death.

Safety outcome: Mortality, hyperkalemia and AKI.

Linda F. Fried, Nicholas Emanuele, Jane H. Zhang et. al. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy, Ph.D.,N Eng J Med 369;20 nejm.org november 14, 2013

53

Results: No difference.

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STOPPED premature because of Safety:

Aim: Aggressive BP lowering and alteration in GFR.N= of 1094. 647 finished the trial.

- African American.- Having HTN renal disease.

Drugs: ACE inh. or ARB, or others (Ca-channel blocker or Betablocker).

Intervention: lowering BP:- MAP of <92mmHg . <125/75mmHg- Versus 102-107mmHg. <140/90mmHg

Outcome: Doubling of S. Cr. / ESRD / Death. From 2002 till 2007.

1. Progression to renal end point over 10 years was 54%.

2. No difference detected in both arms.

3. Patient on ACE inh had less Proteinuria.

Appel LJ , Wright Jt, Green T Kusek JU. Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans. - - Arch Intern Med - 28-APR-2008; 168(8): 832-9 55

Aim: ARB (Telmisartan) is not inferior to ACE inh.(Ramapril).

Dual Blockade with ACEinh and ARB are superior.

Primary out come: Death from CVD. MI. Stroke. hospitalization for heart failure.

ONTARGET investigators. Telmisartan, Ramipril, or both in patients at high risk for vascular events. N ENG J MED 358;15.1547-59

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Methodology:•N = 25620

•High Cardiovascular risk patients.

•Randomized Controlled Trial.

ONTARGET investigators. Telmisartan, Ramipril, or both in patients at high risk for vascular events. N ENG J MED 358;15.1547-59

Sub analysis:

Primary renal outcome: Doubling S. Cr.

Dialysis.

Death.

Results: Less Proteinuria with combination.

Worsen renal outcome with combination.

Conclusion: Separation of Proteinuria and renal outcome.

Mann JF, Schmieder RE, McQueen M, et al.: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): A multicentre, randomized, double-blind, controlled trial. Lancet 372: 547–553, 2008 58

Population:

High CV risk patient & Intolerant to ACE inh. (cough, hypotension, renal dysfunctionor angioneurotic edema).

Aim: Benefit of ARB in reducing the major CV events in high risk patients.

Randomized controlled trial on Telmisartan 80mg/d or Placebo.

Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P: Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: A randomised controlled trial. Lancet 372: 1174–1183, 2008

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Results:N= 5926.Telmisartan 80mg 2954Placebo 2972

Median Follow up: 56 month.

There was a moderate and significant benefit of Telmisartan on the CV end point: CV death, MI, or stoke.

Conclusion: Telmisartan was as good as ACE inh. in providing CV benefit.

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N = 5927. High risk CV patients.

Patient with CVD or DM.

No Macroalbuminuria or heart failure.

Randomized controlled on Telmisartan 80mg Versus Placebo.

Renal outcome: Dialysis or doubling S. Cr.

Results:Telmisartan Placebo

Renal outcome (58)1.96 (46)1.55% P 0.2Increase Albuminuria 32% 41% P <0.001Decrease GFR -3.2ml/min -0.26ml/min. P < 0.001

Mann JF, Schmieder RE, Dyal L, McQueen MJ, Schumacher H, et. al.: Effect of Telmisartan on renal outcomes: A randomized trial. Ann Intern Med 151: 1–2,2009 62

Aim:Prevention of Microalbuminuria in HTN and DM II. With AT1 receptor blocker.

Randomized controlled.

N= 2200. follow up 3.2 years.

Intervention arm: Olmesartan 40 mg.

Primary endpoint:time to first onset of persistent microalbuminuria (spot Prot/Cr.)

Secondary endpoint: CV event, morbidity, mortality, ESRD, and microvascular morbidity.

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Lower BP in the Olmisartan group.

Lower Microalbuminuria in the intervention.

Slightly higher mortality in the intervention group.

Haller HG, ROADMAP study group: Prevention of Albuminuria and Cardiovascular Morbidity with Olmesartan: TheROADMAP Trial. Presented at the annual meeting of the American Society of Nephrology; October 27 throughNovember 1, 2009; San Diego, CA

65

Hans-Henrick; Cardiorenal End Points in a Trail of Aliskiren. N Engl J Med 2012;367:2204-13.

Aim: effectiveness and safety of Aliskiren in combination with ACE inh. or ARB.

N =8561. DMII. On ACE inh or ARB RCT. Intervention: Aliskiren 300mg.

Primary endpoint: Time to CV death, cardiac arrest, Non fatal MI. Non fatal stroke, death due to renal failure, ESRD. Need for renal replacement.

66Hans-Henrick; Cardiorenal End Points in a Trail of Aliskiren. N Engl J Med 2012;367:2204-13.

67

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Event Aliskiren Placebo P

Decrease eGFR 2.45ml/min 1.29ml/min <0.001

Hyperkalemia 39.1% 29% <0.001

Hypotension 12.1% 8.3% <0.001

Terminated Prematurely because of safety

Hans-Henrick; Cardiorenal End Points in a Trail of Aliskiren. N Engl J Med 2012;367:2204-13.

Separation between Albuminuria and CV outcome.

Further studies to address the renal and CV outcome in different Albuminuria subjects.

Look more into major CV outcome rather than looking into minor factors as Microalbuminuria.

In renal disease microalbuminuria is one among many factors that reflect target organ damage.

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NEPHSAP, CKD 2009.

70

The kidney prevent protein from leaking.

Proteinuria is an indication of renal disease.

Measurement could be done by simple prot./Cr. Or Alb./Cr ratios.

Association with CV end points were found.

Proteinuria was Associated with increased CV disease.

Decreased proteinuria did not decrease CV mortality.

It was associated with increased CV mortality.

PROTEINURIA is not a therapeutic target.

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PROTEINURIA is not a therapeutic target to decrease Cardiovascular Mortality.

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