Proteinuria and Cardiovascular risk is it a cause and effect or only association?

1. ProteinuriaasaCardiovascular
RiskFactor

2. Scheme
• Proteinuria pathophysiology.
• NormalValues and Diagnosis.
• Relation with Cardiovascular disease.
• Relation with Kidney disease.
• Management significance.
• Conclusion.

3. Pathophysiology

4. Glomeruli light microscopy scheme
Wilhelm Kriz, Marlies Elger. Essential Renal Anatomy and Pathology

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

6. Glomerular filtration barrier
Wilhelm Kriz, Marlies Elger. Essential Renal Anatomy and Pathology
Endothelium
Podocytes
GBM

7. Glomerular Filtration Barrier
Molecule 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
Small
<0.5KD
Middle
0.5-
60KD
Large
>60KD
-ve-ve-ve-ve
--ve-ve-ve-ve
BLOOD
URINE
60
Cyberound.s.com

8. Protein Composition

9. 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
11
From Glassock R: Proteinuria. In Massry SG. Glassock RJ. Textbook of Nephroloyg 3rd ed. Baltimore, Willias & Williams, 1995

10. Proteomics correlation with histopathology in Chronic allograft Nephropathy
CM 10-2200-63
CM10-8324-86
CM10-4574-7
CM10-16528-4
Q10-4161-17
IMAC30-13913-6
CM10-3463-48
CM10-10003-9
CM10-15870-9
CM10-50159-6
IMAC30-10823
CM10-11673-1
CM10-132999
Q10-33612-1
Q10-66882-9
IMAC30-123657
IMAC30-147781
H50-2511-86
H50-486654
H50-6449-4
CM10-5874-54
CM10-8565-69
CM10-11980-5
IMAC30-5863-98
IMAC-11905-1
IMAC30-3620-96
IMAC30-3751-83
H50-5026-14
Interstitial Fibrosis
Chronic vascular injuryTubularAtrophy
Michael S. Goligorsky. Diagnostic Potential of Urine Proteome: A broken mirror of renal disease J Am Society of Neph 18: 2233-2239, 2007

12. 14

13. Urine Dip Stick
Cr
National 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

14. 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

15. 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 National
Health and Nutrition Examination Survey. Am J Kidney Dis 39: 445–459, 2002

16. 19

17. Proteinuria present in:
 1% of general population.
 3.3% of patients with eGFR 30-60ml/min.
 26% of patients with eGFR <30ml/min.
20
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).

18. 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
21
II. Tubular Proteinuria:
*Drugs and Toxins:
Light chain.
Lysosomal.
Heavy metal.
Tetracyclin.
*Tubuloinerstitial Nephritis:.
Hypersensitivity
Multisystemic: 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.

19. 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.

20. Proteinuria and Cardiovascular Disease

21. 24

22. 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.
25
Tonelli, M. et al. Chronic kidney disease and mortality risk: a systematic review. J. Am. Soc. Nephrol. 17, 2034–
2047 (2006).

23. 26

24. 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
27
Nat Clin Pract Cardiovasc Med 2009. Natural Publishing Group

25. 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.
28

26. 29

27. 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 strong
Heart Study. J. Am. Coll. Cardiol. 41, 2022–2028 (2003).

28. 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.
31
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).

29. Proteinuria patient are associated with:
 1.6-3.3 relative risk of incident stroke.
32
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).

30. 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).

31.  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.
34
Kasiske, B. L. Hyperlipidemia in patients with chronic renal disease. Am. J. Kidney Dis. 32 (Suppl. 3), s142–s156 (1998).

32. 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).

33.  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

34. 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).

35. Decrease and abnormal Nitric Oxide function in patients with Nephrotic
range 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).

36. 42

37. 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.
45
de Zeeuw, D. et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with
nephropathy. Circulation 110, 921–927 (2004).

38. • 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.
48
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).

39. • 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 outcomes
in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo
controlled trial (the DIABHYCAR study). BMJ 328, 495 (2004).

40. • 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.
50
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).

41. 51

42. • 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

43. 53
Results: No difference.

44. 54
STOPPED premature because of Safety:

45. 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

46. 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
56

47. 57
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

48. 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

49. Population:
High CV risk patient & Intolerant to ACE inh. (cough, hypotension, renal dysfunction
or 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
60

50. Results:
N= 5926.
Telmisartan 80mg 2954
Placebo 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.
61

51. 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 0.2
Increase Albuminuria 32% 41% P <0.001
Decrease 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

52. 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.
63

53. 64
 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: The
ROADMAP Trial. Presented at the annual meeting of the American Society of Nephrology; October 27 through
November 1, 2009; San Diego, CA

54. 65
Hans-Henrick; Cardiorenal End Points in a Trail of Aliskiren. N Engl J Med 2012;367:2204-13.

55.  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.
66
Hans-Henrick; Cardiorenal End Points in a Trail of Aliskiren. N Engl J Med 2012;367:2204-13.

56. 67

57. 68
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.

58. 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.
69
NEPHSAP, CKD 2009.

59. 70

60.  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.
71

61. PROTEINURIA is not a therapeutic target to
decrease Cardiovascular Mortality.
72