- Cardiovascular disease is a major cause of mortality in patients with chronic kidney disease, accounting for around 50% of deaths. - Traditional risk factors do not fully explain the high cardiovascular risk in CKD patients. Emerging non-traditional risk factors include inflammation, oxidative stress, endothelial dysfunction, protein-energy wasting, and accumulation of uremic toxins. - Proteinuria is an important risk factor for cardiovascular disease, even at low levels. It is associated with endothelial dysfunction through mechanisms like increased inflammation, asymmetric dimethylarginine, and vascular cell adhesion molecules. - Uremic toxins play a key role in cardiovascular risk through multiple pathways like oxidative stress, inflammation, epigen

1. By
Hesham Elsayed
Professor of Nephrology
Ain Shams university
CV RISK PUZZLE
IN CKD PATIENTS

2. 50% mortality
Atherosclerotic
Ht.Disease
CHF
Sudden death
CVD
Others
Arrhythmia
Stunning
DATA FROM UNITED STATES RENAL DATA SYSTEM 2016

3. CVD
CKD
CAD
LVH
CHF
volume
SUDDEN
DEATH
Stroke
Vascular occlusion
Cardio-Renal
syndrome
CVD STILL A NOTORIOUS PROBLEM IN PATIENTS
WITH CKD

4. CVR Puzzle
Traditional
Ca x ph
UREMI
A
Uremic
ADMA
P-Cresol
Leptin
Oxidation
Overload
Anemia
Inflammation
PTX3
CIS
ET,DNA,OND
Blood Tubing
Heparin
Vascular
Calc.
Age
Male
DM
Smoking
Lipid
HTN
LVH

5. MICRO-INFLAMMATION
MACRO- CALCIFICATION
Not All
patients have
the same
effect of high
PTH-PH-CA

6. Chronic Kidney Disease and Frailty

8. 40% OF the patients Had Coronary calcification
Afifi ,A , Elsayed H , Elsaied T 2006
RC
A
LA
D
CX
LM
A

9. Volume overload
and water toxicity

11. Volume overload
LVH – HTN Rapid UF
IDH-Stunning

12. Malnutrition + Volume overload synergistic
effect on CVD Kidney International 2014
Multivariate logistic regression model showing the associations of the eGFR, UPCR, and OH with
malnutrition, inflammation, and atherosclerosis syndrome
Malnutrition Inflammation Atherosclerosis
Variable Albumin<3.0g/dl IL-6≥3.0pg/ml CVD
eGFR
(ml/minper1.
73m2)
1.014 (0.986,
1.043)
P=0.319 0.998
(0.982,
1.015)
P=0.824 0.972 (0.952,
0.992)
P=0.006
UPCR (g/g) 2.456 (1.819,
3.316)
P<0.001 1.211
(1.035,
1.416)
P=0.017 0.994 (0.864,
1.143)
P=0.929
OH (%) 1.121 (1.061,
1.184)
P<0.001 1.041
(1.008,
1.075)
P=0.015 1.040 (1.004,
1.077)
P=0.028

13. Fluid Overload “FO”
 severe FO, defined as an expansion of the extracellular fluid
by more than 15% (around 2.5 L in a person weighing 70 kg).
 Fluid overload ( FO ) and Fluid Depletion ( FD ) Both has a
higher risk for mortality ( U shaped )
Data analysis for 8883 patients for 12 months follow up
Kidney International (2017) 91

14. “FO” and “FD” survival Kidney International (2017) 91
Normovolemia
Moderate volemia + > 1.1
Volume depletion - > 1.1 L
severe hypervolemia + > 2.5 L
Extreme hypervolemia + > 5 L

15. Atherosclerosis
Procoagulant
Platelet Activation
Uremic Toxins
Volume overload
Inflammatory reactions
Micro-RNA
Impaired NO
Aged Endothelial Cells
inflammation
Calcification
Atherosclerosis

17. EC
Dysfunction
Cytokines
Vascular
calcifications
Uremic
toxins
LVH Anemia
Volume
load
HD
stunning

18. ABC in Uremia followed By
Calcifications
HD
Uremia
induced
Crosstalk NO
deficient

21. Sieving Coefficient of Molecules Elsayed H etal WCN
2017
100 Patients on High Flux dialysis Aim Shams Research WCN Mexico 2017
27.10%
10%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
IL-1 B RR
IL-1B RR in HF dialysis ( MW 17,000 D )
Platinum H2X FX 400.45
0.28
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
Myoglobin SC
Platinum H2X FX 40

22. Biological Effects of Cytokines in
Atherosclerosis Arteriosclerosis, Thrombosis, and Vascular Biology. 2011
disrupts endothelial
junctions
facilitating leukocyte
transmigration
induce the expression of
chemokines and adhesion
molecules on the vascular
endothelium
inflamed vessel wal
MMP = Matrix metalloproteinase
TIMP = tissue inhibitor
Inflamed vessel wall ready
for calcification

23. single dialysis session leads to evidence of platelet activation,
endothelial injury, inflammatory reaction, and coagulation
activation.

25. MicroRNA-92a Mediates Endothelial
Dysfunction in CKD
MicroRNAs (miRs) have emerged as
crucial regulators in EC function via
their modulation of eNOS-derived
nitric oxide (NO) bioavailability,
angiogenesis, and innate immune
response
JASNNovember 2017 vol. 28

26. Mechanistically, miR-92a targets eNOS-derived NO
JASNNovember 2017 vol. 28
inhibit
eNOS

28. Procalcitonin as an inflammatory marker in
comparison between high-flux and low-flux
hemodialysis in ESRD patients JESN 2017
Hesham Mohammed El Sayed, Hussein Sayed Hussein, Sabah Hammad.
Nephrology Department, Faculty of Medicine, Ain Shams University

29. Procalcitonin as an inflammatory marker in
comparison between high-flux and low-flux
hemodialysis in ESRD patients JESN 2017
0
0.2
0.4
0.6
0.8
1
Group Group II
Group I
Mean PCT ng/ml pre-HD
Group I
Group II
0
0.2
0.4
0.6
0.8
1
GroupGroup I Group II
Mean PCT ng/ml post-HD
Group I
Group II

30. The risk factor profile in this unfortunate patient
group seems to be markedly different from that of
the general population .
CVD RISK IS NON TRADITIONAL IN
CKD PATIENTS
Emerged Non Traditional CVD Risk

31. Schematic presentation of traditional and novel (or uremia-
specific) cardiovascular risk factors in chronic kidney disease.
Stenvinkel P et al. CJASN 2008;3:505-521

32. PARADOX IN PATIENTS UNDER HD

33. PARADOX IN PATIENTS UNDER HD

34. PARADOX IN PATIENTS UNDER HD
ASN 2017
Obesity is a risk factor for CKD
While Obesity confers survival advantage in advanced CKD
THE “Reverse Epidemiology”

35. protein-energy wasting (PEW), which is a condition for
simultaneous loss of systemic body protein and fat mass
(energy reservoir) .
 PEW may debilitate physiologic functions of the various
organs and may affect clinical outcome in addition to a
specific disease itself. In situation of deficiency or
excessive consumption in energy, obesity may potentially
attenuate the magnitude of PEW, resulting in favorable
outcomes in patients with Advanced CKD Kidney Res Clin
Pract. 2017 Mar
OBESITY PARADOX AND PEW

37. Low
Cholesterol
levels may
denote
malnutrition in
patients on HD
JASN January 2007 vol. 18
no. 1 293-303

38. Over the 5-year period (July 2001–June 2006), 164,789 adult subjects received dialysis treatment
Glycemic control in advanced CKD

39. ADVANCED CKD
SPECIFIC FACTORS

40. the term cardio-renal syndrome (CRS) has been used to
define different clinical conditions in which heart and
kidney dysfunction overlap.
CARDIO-RENAL SYNDROME
Type Denomination Description Example
1 Acute cardiorenal Heart failure leading to AKI
Acute coronary syndrome
leading to acute heart and
kidney failure
2 Chronic cardiorenal Chronic heart failure leading to CKD Chronic heart failure
3 Acute nephrocardiac AKD leading to acute heart failure AKI related uremic
4 Chronic nephrocardiac CKD leading to heart failure
Left ventricular hypertrophy
and diastolic heart failure
due to CKD
5 Secondary
Systemic disease leading to heart and kidney
failure
Sepsis, vasculitis, diabetes
mellitus, amyloidosis
Initiated by the Heart
Initiated by the Kidney
Simultaneous Heart and the
Kidney

44. Novel risk and/or uremia-related risk
factors
Markers
Inflammation IL-6 , IL-18 , S-albumin , fibrinogen ,
CRP , PTX3
Oxidative stress oxLDL ,
Endothelial Dysfunction PTX3 , ADMA , tHcys , VCAM
Protein Energy wasting S. Albumin , Pre- Albumin
Classical and New Uremic Toxins P-Cresol ,ADMA
Volume overload ( salt war toxins) BNP - Troponin
NOVEL, AND UREMIA-RELATED BIOCHEMICAL RISK
FACTORS TO PREDICT CVD
CJASN March 2008 vol. 3 no. 2 505-521

45.  Cardiovascular risk starts early
in CKD patients with
Albuminuria.

46. National Health and Nutrition Examination Survey study
(NHANES) data demonstrated that proteinuria is present
in 4% of men and 2% of women between 45 and 74 years
of age in the general population and up to 26% of
patients with estimated glomerular filtration rate (eGFR)
<30 mL/minute/1.73 m
CVR IN CKD

47. A comprehensive evaluation of the independent and
combined associations of estimated glomerular filtration
rate (eGFR) and albuminuria with mortality is required for
assessment of the impact of kidney function on risk in the
general population, with implications for improving the
definition and staging of chronic kidney disease (CKD).
 14 studies (105,872 participants
CVR WITH PROTEINURIA AND GFR

48. META-ANALYSIS OF GENERAL POPULATION COHORTS WAS UNDERTAKEN TO
POOL STANDARDIZED DATA FOR ALL-CAUSE AND CARDIOVASCULAR
MORTALITY.
Lancet. 2010 Jun 12

49. HRs and 95% CIs for all-cause and cardiovascular mortality according to spline eGFR and
categorical albuminuria (ACR: <30 [black], 30-299 [green], and ≥300 [red] mg/g

50. The hypothesis suggested that urinary protein excretion not only
reflects localized subclinical renal disease but also a more generalized
vascular endothelial dysfunction.
Microalbuminuria is also accompanied by a fall in adiponectin levels
and elevated C-reactive protein. Hypertens. 2013 Apr; 31(4):805-12
Evidence has also linked proteinuria with asymmetric dimethylarginine
(ADMA), an inflammatory biomarker which causes endothelial
dysfunction through inhibition of nitric oxide production Nat Rev Cardiol.
2009 Apr;
MECHANISMS UNDERLYING CARDIOVASCULAR
CONSEQUENCES OF PROTEINURIA

51.  Levels of vWF have been shown to be higher in patients with
microalbuminuria compared to control subject
Vascular endothelial growth factor (VEGF) is another interesting
potential mechanistic link between proteinuria and endothelial
dysfunction Am J Kidney Dis. 2007 Feb;
soluble vascular cell adhesion molecule, fibrinogen, and tissue
plasminogen activator have been found to correlate with urinary
albumin excretion
MECHANISMS UNDERLYING CARDIOVASCULAR
CONSEQUENCES OF PROTEINURIA

52. Uremic Toxins

53. Nephrol. Dial. Transplant. (2013) 28 (1):
progressive damage in various vital organs such as bones,
heart and vasculature, which already starts before the onset of
dialysis treatment
biological age is difficult to quantify

54. Aging in
uremia
DNA and mitochondria
damage
Downregulation of
klotho gene
expression by
uremic toxins
Telomere
shortening
Hyperphospahtemia
Persistent
inflammation
Increased reactive
oxygen species
generation
CHRONIC KIDNEY DISEASE: A CLINICAL MODEL OF PREMATURE
AGING
NATURE REVIEWS NEPHROLOGY 10, 732 –742 (2014)
Uremia
Toxins
Retention
Metabolic
Cytotocity

55. Uremic serum
increased ROS
Uremic serum
increased NF-
κB
uremic serum
induce
apoptosis
In Aging Cells
oxidative
stress damage
senescent
cells
Evidences in Uremia to promote Aging
Human umbilical vein endothelial cells (HUVEC) incubated with
uremic serum Experimental Gerontology August 2014

56. UREMIC TOXINS AND MULTI-ORGAN DAMAGE

57. Cytokines and
Adhesion
molecules

59. Focused in Depth the uremic milieu
Uremic Toxins
Epigenetics
Effects are not
caused by changes
in the DNA
sequence
GENETICS ?
changes to
the DNA
sequence
with CKD telomere
length is reduced

60. Uremic Toxins : Effects in Depth
Uremic Toxins
Effect By Accumulations
B2m Amyloidosos
Epigenetics and DNA
Methylation
Gene Dysregulation
Abnormal Cell Life span
KLOTHO Gene and
membrane Correceptor
GUT Metabolomics
Orchestrate the Metabolic
changes and CVD
Endotoxins , PB Toxins
inflammation
KLOTHO

61. The Protein
Bound Uremic
Toxins
Removed By
Tubules not By
filtration !
X

62. PB Toxins
ROS
Through
NOX4 of
NADPH
oxidase
Kidney International (2013) 83

63. Indoxyl Sulfate
IS level is better in patients with Residual
Renal Functions
( Tubular Organiic Anion Transporter )
OATs
PLoS One v.10(3);
2015

64. Indoxyl sulfate (IS)- and p-cresyl
sulfate (PCS)-injected mice had
increased DNA
methyltransferase 1 (DNMT 1)
expression and DNA
hypermethylation of the Klotho
gene
Kidney International (2012) 81, 640–650

65. Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions
through Up-regulation of E-selectin , ICAM , VCAM and TNF α
:Journal of Biological Chemistry ,Dec 2010
Effects of indoxyl sulfate on the TNF-α-induced NF-κB
pathway
Nx: only
water
Nx IS : IS

66. Klotho Protects Against Indoxyl Sulphate-Induced
Myocardial Hypertrophy JASN March 24, 2015
LVH in CKD mice was
attenuated after
Klotho treatment,
which was assessed
by echocardiography

67. Uremic Toxins
induce DNA
methyltransferase
(DNMT) protein
expression,
Hypermethylated
status of KLOTHO
coreceptor
JASN December 4, 2014
ROLE OF UREMIC TOXINS : Effect on KLOTHO Gene

68. Study of the Effects of
Hemodiafiltration versus
Hemodialysis on DNA Methylation
and Indoxyl sulfate Removal
Hesham Elsayeda Magdy Elsharkawya Walid Tahab Hussein Sayeda
Mohammed Kotbb in press 2017

69. Indirect correlation (r= -0.922, P < 0.001)
Hesham Elsayeda Magdy
Elsharkawya Walid Tahab Hussein
Sayeda Mohammed Kotbb in
press 2017

70. Endothelial Damage

71. Vascular calcification

72. Adam M. Zawada et al. Nephrol. Dial. Transplant. 2013
DNA methylation in atherosclerosis
monocytes differentiate into macrophage
gene-specific DNA methylation
suggests alterations and
advanced atherosclerotic lesions
toxic uraemic milieu may exert a crucial impact on epigenetic gene regulation and CKD-associated
accelerated arteriosclerosis

73. CIRCULATING ENDOTHELIAL CELLS (CES) BIOMED
RESEARCH INTERNATIONAL VOLUME 2014
 CEC counts are increased in diseases associated with a high degree of endothelial cell
activation and⁄ or injury
(1) Uremia induces the release of
endothelial microparticles (EMP)
(2) increase in circulating endothelial
cells (CEC)
(3) uremia impairs the survival of
endothelial progenitor cells (EPC)
combination of different surface antigens such as CD146, CD45, and CD31 to detect the endothelial cells

74. ADMA : PB Toxins Retention J Am Soc Nephrol. 2015 Apr
Inhibitor of NOS

75. Increased ADMA Authors
An endogenous inhibitor of NO-synthase Kielstein etal, Am J Kidney Dis46 :186– 202,2005
An independent predictor of endothelial dysfunction Cagler etal, Lancet358 :2113– 2117,2001
Strong and independent risk marker for progression
of CKD
Ravani etal , Am Soc Nephrol16 :2449– 2455,2005
Decreased ADMA levels improve Endothelial
Dysfunction Cubisti etal , Nephrol Dial Transplant22 :229– 234,2007
Chang etal , Am J Nephrol27 :70– 74,2007
ENDOTHELIAL DYSFUNCTION—A COMMON FEATURE OF CKD LINKED TO
ASYMMETRIC DIMETHYLARGININE ADMA AND ALBUMINURIA

76. 
Raymond Vanholder et al. JASN , 2014
NADPH ox excess
ROS
Inhibit eNO
Promote for Cytokine
production
CELL SENSSCENSE
Uremic retention solutes and vascular endothelial damage

77. inflammation
Oxidation
Cytokine
production
Thrombosis
Cracks and
Fissure
Formation
Endothelial
Dysfunction
MECHANISM OF THROMBUS FORMATION

78. VASCULAR CALCIFICATIONS

79. CKD-MBD MANY PLAYERS WITH THE SAME
TARGET
Targeting
Inflamed ET

80. Disordered Mineral Metabolism
 Elevated serum phosphate levels
 Elevated serum calcium levels
 Elevated parathyroid hormone levels
 Changes in vitamin D metabolism
 Elevated FGF23 levels
Inflammation and Oxidative Stress
Osteogenesis Factors
VASCULAR CALCIFICATION IN CKD

81. VASCULAR CALCIFICATION IN CKD

82. Fetuin Level in CKD patients
Elsayed.H etal Actamedica jan 2015
0.125
0.245
0.275
0.33
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Serum Fetuin level g/l
HD with CVD HD without CVD
CKD conserv Healthy control
HD - CVD HD without CVD CKD
CKD on HD and conservative treatment against
Healthy control

83. Nephrology Dialysis
Transplantation,
Volume 27, Issue 8, 1
August 2012,

84. upregulation of
transcription
factors

86. Vascular Calcification Endothelial cells
Molecules
retention
Retention in
CKD
Mediators
Cross Talk
with
Endothelium
Vascular
calcification

87. Calcification follows inflammation in human
atherosclerosis and therefore most likely
represents a secondary phenomenon.
Nephrol. Dial. Transplant. (2015) 30 (3): 352-357.

88. ADDING A THIRD ORGAN TO THE SCENARIO
THE GUT
 A gut Feeling of
New immersed
Uremic Toxins
 Gut source of the
Endotoxins

89. THE GUT
KIDNEY
CARDIAC
AXIS

90. Circulating Endotoxemia:
A Novel Factor in Systemic Inflammation and
Cardiovascular Disease in Chronic Kidney Disease .

91. The colon is responsible for salvage of energy and possibly
nitrogen from carbohydrate (CHO) and protein not digested in the
upper gastrointestinal tract.
Nephrol. Dial. Transplant. 2011; 26:759-761

92. GUT KIDNEY CARDIAC CYCLE
GUT
CVD
Uremic
Toxins
Progress
CKD
ET

93. The serum level of free p-cresol in dialysis patients who have cardiovascular event (n = 34)
and no cardiovascular event (n = 66).
Lin C et al. Nephrol. Dial.
Transplant. 2010;25:3693-3700

94. ENDOTOXEMIA IS A GUT FEELING
ET translocation
Paracellular passage
Tightjunction
Intracellular passage
Cellular signaling
through TLR4

95. BIOLOGICAL SYSTEMS RESPONSIBLE FOR
TRIGGERING INFLAMMATION
Nephron Clin Pract 2011;118:c165–c172
• Viral RNA
TLR 3
• Bacterial LPS
TLR4
• Bacterial
Oligodeoxynucleotides(ODN)
TLR9

96. ENDOTOXEMIA A GUT FEELING
LPS
LPS – LBP protein complex
TLR4
Cell Signaling
MD-2 co-Receptor
CD14 membrane bound Ag

97. Volume
overload
Over UF

98. Endotoxemia
Contamination of Tissues, Fluids
or Foreign Bodies
Sepsis
dialysate
Catheter
AVF
Gut leaking
CHF
Volume overload
Splanchnic
hypoperfusion
IDH
Bacterial overgrowth
Motility disorders
constipation
SOURCES OF ENDOTOXEMIA IN CKD PATIENTS
NEPHRON CLIN PRACT 2011;118:C165–C172

99. ENDOTOXEMIA IS A GUT FEELING
ET translocation
Paracellular passage
Tightjunction
Intracellular passage
Cellular signaling
through TLR4

100. HD
IDH SUDDEN CARDIAC
ARRIST
Myocardial
stunning
Hemodynamic
instability
CRITICAL DMAGE
HD Induced CVD
Patient and
operational Factors

101. HD Induced Cardiac LOAD
Sudden
Cardiac
Arrest
STUNNING
HIBERNATION
FIBROSIS
CAD
CHF
INFLAMMATION
COMORBIDITES
MBF
MULTIFACTORIAL

102. MYOCARDIAL STUNNING DURING HD
CARDIAC
COMPLIACTIONS
MYOCARDIAL
STUNNING
Myocardial
hibernations
adaptive reduction
of myocardial
contractile function
in response to a
reduction of
myocardial blood
flow

103. MYOCARDIAL STUNNING DURING HD
Stunning
Transient dysfunction
hibernation
chronically dysfunctional
myocardium
Myocardial stunning.
functional decline of >20%
during HD compared with rest
with evidence of functional
recovery in the postdialysis
period
reduction in resting systolic
function of >60% within
previously stunned
myocardial segments that
remained fixed during HD
CJASN December 2009 vol. 4 no. 12 1925-1931

104. Myocardial Ischemia
And Reperfusion
Lipid and Protein peroxidation
Inflammatory cells Accumulation
Reactive oxygen species
Sarcoplasmic Reticulum
Dysfunction
Excitation contraction
uncoupling
Decreased Sensitivity to
Ca+
Contractile protein
alterations
Decrease Myocardial
Contractility
Myocardial Stunning
Oxyradical
Hypothesis
Calcuim
Hypothesis
Stunning

105. Mean global myocardial blood flow (MBF) reduced significantly during dialysis from baseline
with partial restoration in the recovery period.
McIntyre C W et al. CJASN 2008;3:19-26
©2008 by American Society of Nephrology

106. Mean MBF during hemodialysis (HD) and biofeedback dialysis (BFD) Hemocontrol .
McIntyre C W et al. CJASN 2008;3:19-26
©2008 by American Society of Nephrology

107. An MBF reduction of ≥30% was associated with a mean reduction in wall motion of −15.2%;
McIntyre C W et al. CJASN 2008;3:19-26
©2008 by American Society of Nephrology
−15.2%

108. CKD is a considered a high risk factor for development of
CVD
CVD starts early with decline in eGFR
Proteinuria is an additional factor for carrying the risk of
CVD
Patients with Advanced CKD have reversed epidemiology
with a “Paradox” pattern
In uremia non traditional risk factors play the major roles
CONCLUSION

109. THANK
YOU