Cardiovascular complications in CKD - Dr. Mohamed Mamdouh AbdAlBary

Cardiovascular
complications
in CKD
Mohamed Mamdouh AbdAlBary
Assistant Lecturer of Internal Medicine
(Nephrology)

• CVD represents leading
cause of mortality in CKD
patients, 50% of ESRD die
from a CV cause.
• CV mortality : 15 to 30 times
higher than the age-related
general population. - in
younger even 500-fold
greater.
• 40% of patients who started
dialysis have CAD - 85% of
them have cardiac structural
abnormalities.

Cardiovascular
risk according
to CKD stage
• Edwards NC, Moody WE, Chue CD, Ferro CJ, Townend JN,
Steeds RP (2014) Defining the natural history of uremic cardiomyopathy in chronic kidney disease: the role
of cardiovascular magnetic resonance. JACC Cardiovasc Image 7(7):703–714
Cardiovascular Disease Is Present Before the Start of RRT

Risk
Factors for
CV Disease
in CKD

• CKD stage 2 or 3: traditional factors are major
contributors to CV mortality.
• CKD stage 4 : traditional and novel risk factors.
• HD : novel risk factors are more prevalent.
• CV events is higher in first weeks after (HD),
dialysis procedure per se may trigger CV
events.
• majority of increased risk is attributable to
non-atherosclerotic pathologies
• MI is the most common CV death in general
population, in ESRD arrhythmia and HF.

Traditional Risk Factors
HTN
HF
ArrythmiaACS
Dyslipidemia

Hypertension
High prevalence in CKD (87–90%).
Major risk factor for CAD, LVH, and
mortality.
Good control in CKD stages 1e4 associated
with possible benefits for CVD.
Once on dialysis, the relationship with outcomes is
less clear; ‘J’-shape, reflecting ‘reverse causality’
Patients with co-morbid diseases may have low blood
pressure, reflecting underlying cardiac dysfunction.

 Lifestyle modification:
Healthy weight (BMI 20 to 25).
Lower salt intake to (2 g) per day of Na (corresponding to 5 g of NaCl)
Exercise program compatible with health and tolerance, at least 30 minutes 5 times per week.
Limit alcohol intake
 ARB or ACE-I first-line therapy in DM and non-DM with CKD ND and with
proteinuria > 30 mg per 24 hours.
 Individualize BP targets and agents.
 Inquire about postural dizziness and check for postural hypotension.
 Tailor treatment regimens in elderly CKD BP measured on non-dialysis days
better than intra-dialytic, linear relationship with mortality
Summary from KDIGO Recommendation :

 Develop early in CKD and increases with progression, 75% at time of dialysis
initiation.
 Strong predictor of CV morbidity and mortality.
 Hypertension and calcific valvular disease >> LVH >> pressure overload.
 CKD secondary anemia and sodium and water retention, which may be
worsened by vascular access in those with limited myocardial function reserve
>> Volume overload.
 Impaired heart function leads to (RAAS) and (SNS) activation with consequent
worsening of blood pressure and volume overload.

 Dialytic cycle of volume accumulation between sessions and intra-dialytic
UF mask clinical presentation of underlying heart disease.
 To differentiate between patients with DD and those with pure volume
overload assess right atrial pressures by IVC imaging before and after UF.
 High UF rates associated with higher mortality despite treatment of
congestion >> rapid fluid removal acutely reduce the ECV and cause transient
myocardial ischemia and myocardial stunning.

In addition to
hemodynamic
mechanisms,
Neurohormonal activation
Chronic inflammation
Malnutrition
Endothelial dysfunction
Hyperphosphatemia leads to increase (FGF-23) promote
LVH and cardiac remodeling.
CKD-MBD induce cardiac vessels and valves calcification
Uremic toxins such as indoxyl sulfate and p-cresol
contribute to cardiac fibrosis.

Patho-
physiological
pathways of 4
-Chronic CRS

 Beneficial effects of RAAS and SNS blockade are consistent in the literature
 Use of BB and ACEI or ARBs is associated with
Better CV and renal outcomes.
Improvement of heart failure symptoms, EF, but in some mild increase of create with ACE
and hyperkalemia.
 Treatment of severe anemia is associated with reduction in left ventricular
mass and increasing of ejection fraction. But higher hemoglobin levels are
associated with worse outcomes.

 Half of CV deaths in ERSD may be related to arrhythmia.
 CKD patients more prone to develop arrhythmias dt many Risk factors:
electrolytes abnormalities and shifts with HD, high rates of CAD, HTN, HF, changes of blood
pressure/volume in intra- and inter-dialytic periods.
 Sudden cardiac arrest was associated with:
Low potassium dialysate (<2 meq/l)
Low pre-dialysis serum potassium
Increased ultrafiltration volumes : rapid volume shifts lead to atrial and ventricular stretch ,
hypotension.
Low calcium dialysate < 2.5 mmol/l

 (ICDs) recommended in non-CKD patients with severely reduced EF for
prevention of SCD. Evidence is lacking in HD. However, use of ICDs is increasing
in US , especially for primary prevention
 β-blockers : Although beneficial in general population, not associated with
reduced incidence of SCD, small RCT carvedilol in HD with HF did detect a
reduction in CV deaths and a trend toward reduction in SCD.
 Other modifiable practices: dialysate potassium (>2.5 mmol/l), dialysis
prescription (treatment time ≥ 210 min, Kt/V ≥ 1.2), UF (≤5.7%), and
amiodarone avoidance.

 AF common In dialysis patients with prevalence 10.7%.
 Even more common but underdiagnosed 40% of ERSD
without known AF at baseline had AF detected with an
implantable loop recorder
 AHA and ACC guideline for the management of patients
with AF still recommends warfarin for dialysis patients
with a CHA2DS2-VASc score >1.
 Routine anticoagulation of all dialysis patients with atrial
fibrillation cannot be unequivocally recommended.

 Efficacy and safety of (NOACs) versus warfarin patients with moderate CKD
from RCT.
 All RCT with NOAC excluded ESRD. However, given apixaban, and potentially
edoxaban, could be considered with dose adjustment, as they are not primarily
renally excreted.

Acute Coronary Syndromes
 17% of deaths in ESRD are attributable to
ACS.
 60% of new HD may have evidence of
coronary atherosclerosis.
 Pathophysiology is quite different from
general population.
 Systemic persistent inflammation the
main factor in risk in ESRD.
 VC key factor to explain the higher rates
of cardiovascular morbidity and mortality

 Symptomatic angina may occur with normal coronary , dt sub-endocardial
ischaemia, capillary/myocyte mismatch in the presence of LVH and
microvascular dysfunction
 Non-STEMI is the most common, unusual to see typical STEMI in HD.
 Challenging in Diagnosis:
Chest pain absent in more than 50% of HD due to autonomic and/or uremic neuropathy
Troponin values problematic, patients have elevated troponin levels in the absence of clinical
ischemia
Nevertheless, elevated troponin associated with higher CV events.
Dynamic increase in troponin levels of >20% within 9 hours and at least one value
exceeding the 99th percentile is D.
 High index of suspicion necessary to avoid missing diagnosis.

 Although, many confounders but treat ACS according to the standard guidelines
for non-dialysis patients.
 Challenging in Management:
PCI underutilized in CKD, to avoid CI-AKI.
Secondary preventive measures such as aspirin, (ACEIs), β-blockers, or statins, are
not applied in the majority of dialysis patients.
 Only one RCT compared CABG and PCI to medical ttt – and no trial compare both.
 The ISCHEMIA-CKD Trial may provide answers about the optimal strategy for
treatment of atherosclerotic CAD in patients with advanced CKD. Start 2014 -
Completion Date : December 2019

 Regular Assessment
 Cardiac function : NT-proBNP serum levels
 KDIGO recommend an ECG at dialysis initiation and then annually.
 KDOQI recommend echocardiography in all dialysis patients after they
achieve “dry weight” targets, preferably 1-3 months after HD initiation on an
interdialytic day for HD patients and at 3-year intervals thereafter.
 cardiac magnetic resonance (CMR).
 3-D echocardiography demonstrates an accuracy quite close to CMRI.
 Cardiac CT : detect and quantify vascular and cardiac valve calcifications.
 planar X-ray, ultrasound and echocardiography, are appropriate alternatives
 Screen for CVD before Tx

 Healthy lifestyle recommended for all CKD patients
 Prescribe secondary preventive ttt in CKD who experience an
atherosclerotic cardiac event.
no evidence to suggest aspirin or clopidogrel for primary prevention of
CVD in CKD.
 Maintain HB bet 10 and 12 g/dl in CKD patients requiring ESAs.
 Avoid ‘therapeutic nihilism’ undertreatment of CKD : following
myocardial infarction or coronary revascularization.
 Hyperphosphataemia and elevated PTH are associated with increased
mortality. However, no specific phosphate binder has been shown to
reduce cardiovascular mortality.

• Neither pattern of dyslipidemia nor the relationships with outcome are
the same as general pop.
• ESRD, low total cholesterol is associated with poorer outcome
• The overall relationship having a J shape resembling that seen for
hypertension

Summary From KDIGO recommendations
 Rule out causes of secondary dyslipidemia: NS , hypothyroid, alcohol, drugs ,
etc,
 Establish indication of ttt based on underlying cardiovascular risk and select
agent and dose.
 Treat according to ‘‘FIRE-AND-FORGET’’ strategy : in newly CKD evaluate with a
lipid profile.
 ‘‘TREAT-TO-TARGET’’ strategy not recommended : follow-up measurement not
required for majority. never been proven beneficial - higher doses not safe in the
setting of CKD.
 Follow-up measurement in patients only when measurements influence
treatment

Situations in which measuring cholesterol level might or might not change
the management

 Age more or equal 50 years CKDND : recommend treatment with statin.
 Age 18–49 not treated HD or Tx, suggest statin in people with 1 or more of:
known coronary disease (myocardial infarction or coronary revascularization)
diabetes mellitus
prior ischemic stroke
estimated 10-year incidence of coronary death or non-fatal myocardial infarction >10%
 CKD5D, statins not be initiated but continued if already receiving them.
 In Tx, suggest treatment with a statin.
 In adults with CKD (including HD or Tx) and hypertriglyceridemia, we suggest that
therapeutic lifestyle changes.
 Fibric acid derivatives not recommended as Evidence supporting the safety and efficacy
is extremely weak, and statins appear to prevent pancreatitis with mildly elevated TG

Non-Traditional Risk Factors
CKD-MBD
Endothelial Dysfunction
Protein Carbamylation
Oxidative Stress
Uraemic Toxins
Gut Dysbiosis

CKD-MBD
 (VCs) are a well-known CV risk factor in HD patients
 Not simple deposition of calcium phosphate crystals.
 These cells down-regulate the production of specific genes and up-regulate
osteochondrogenesis markers, losing their contractile competence and forming
calcium–phosphorus-rich vesicles able to start the mineralization process
 Increase the incidence of arrhythmias, SCD.
lead to ischaemic CVD and increased pulse pressure contributing to the reduction
of diastolic coronary perfusion and to LVH, Aortic stenosis,
 Detection of valve calcification is fundamental for risk stratification of dialysis

Femoral arteries
Brain
Coronaries
Lung Abdominal >> SI
Abdominal Aorta
Calciphylaxis
Cardiac Valves

Due to its mesenchymal origin VSMCs under stress undergo osteogenic differentiation

Calcification
Promoters
Calcification
Inhibitors
The uremic milieu is a hostile environment reduces the levels of physiologic inhibitors .

Uraemic toxins
 Increase with decline of renal function.
 Detrimental effect on the CV system, mediated by their impact on cells in
myocardial and vessel functions
 Compromise infection response and trigger a condition of micro-inflammation
and atherosclerosis.

 P-cresol :
Accumulate dt gut dysbiosis and inability of kidney to excrete it.
Strongly associate to CV risk and predictive of mortality
Difficult to removed by dialysis, gut microbiota could be a future target
 Indoxyl sulphate (IS)
Increase up to 50-fold compared with healthy.
Pro-oxidative and pro-inflammatory activity, triggers immune response
High concentrations progression of vascular damage and VC of VSMC
High-affinity binding to albumins, hinders its removal by HD.
 Both inhibit (NO) production
 (AGEs) : interactions with their receptors trigger intracellular events, such as
oxidative stress and inflammation >> CV complications.

Endothelial Dysfunction and Oxidative Stress

 ED >> atherosclerosis and contribute to CV events and mortality.
 Reduced bioavailability of (NO) : one of the main factors involved in ED.
 ADMA (competitive inhibitor of NO synthase) mainly cleared by the
kidney.
One of the strongest markers of atherosclerosis and endothelial dysfunction
Predictor of CV morbidity and mortality.
Increases IL-6 and (TNF-a) expression.
 High levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6) -
strong predictors of CV mortality in dialysis patients

 Imbalance in ROS production to degradation
ratio.
 Kidney important source of antioxidant
enzymes – OS increases along with renal
impairment
 Uremia pro-oxidant condition
 HD : loss of antioxidants during procedures
and accumulation of oxidative products. >
prominent dysfunction of the mitochondrial
respiratory system.
 OS cause accelerated atherosclerosis of RF
and increase in inflammatory biomarkers

Protein Carbamylation
 Irreversible (PTM) results from interaction between isocyanic acid and amino
groups of proteins.
 Increased by chronically high levels of urea
 Linked to an increased CV risk in ESRD patients.
 Protein carbamylation alter the structure and function of proteins;
LDL > CV atherosclerosis
Albumin > renal fibrosis
Erythropoietin > anaemia
 Intensification of HD therapy help in controlling low levels of plasma urea and
reducing carbamylate protein concentrations by reducing CV risk.

Gut Microbiome a Potential Source Of Uraemic Toxins
 GM : metabolically active endogenous organ
 Uremia cause Dysbiosis (alteration of microbiota) ,
Breaking of the intestinal barrier (epithelial tight
junctions).
 HD itself may induce intestinal ischemia during
hypotension with alteration of intestinal wall integrity.
 Translocation of bacteria and endotoxins in the circulatory
system, stimulate pro-inflammatory cytokine production
and produce excessive uraemic toxins such as p-cresol
sulphate, IS >> CVD

ACIDOSIS AND CVD
 Associated with the existence of both peripheral vascular disease and diastolic
dysfunction
Significant positive association of metabolic acidosis status with high-sensitivity
CRP
Changes in serum bicarbonate levels produced by a dialysis session are sometimes
too abrupt and tempestuous, producing adverse consequences
These variations can increase vascular stiffness, vascular calcification and, in
general, CV risk.

Conclusion
Encourage Life Style Modification.
Detect before it is too Late.
Don’t under-treat.
Consider treatment Complications.
Don’t be too happy and be-aware of paradoxical observation with
low LDL, hypotension, low BMI esp in late stages.

References
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Cardiovascular complications in CKD - Dr. Mohamed Mamdouh AbdAlBary

Cardiovascular complications in CKD - Dr. Mohamed Mamdouh AbdAlBary

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