Download RENAL AND CARDIOVASCULAR INTERACTION

RENAL AND
CARDIOVASCULAR
INTERACTION
Renal blood flow
• Each kidney weights about 150 grs
• Blood flow is 400 ml /100gr /min
(20-25 % of cardiac output)
low oxygen extraction (about 8 %of the
total body oxygen consumption)
CARDIOVASCULAR DISEASE
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Renal hypoperfusion
Prerenal azotemia
Atheroembolism
Septic embolism
Immunologic phenomena
Side effect of drugs
CHRONIC KIDNEY DISEASE
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Accelerates atherosclerosis
Hypertension
Heart failure
Pericardial effusion
Myocardial disease
Valvular disease
Cardiac arrhythmias
Sudden death
Dialysis related problems
CHRONIC KIDNEY DISEASE
• eGFR of less than 60 ml/min/1.73 m2 for
more than 3 months
• serum creatinine (Cr) greater than 1.5
mg/dl
• presence of kidney damage
• microalbuminuria at any level of eGFR
(random urine albumin-to-Cr ratio (ACR) of
30 to 300 mg/gm )
CHRONIC KIDNEY DISEASE
• JNC 7 has recognized CKD as an
independent cardiovascular risk state
Decreasing levels of renal function act
as a major adverse prognostic factor
after a variety of cardiac events
Anemia and CKD
• WHO definition :Hb level less than 13 g/dl
in men and less than 12 g/dl in women
• Anemia caused by CKD in 20 %of patients
with stable CAD and 30 to 60 % of
patients with HF
Anemia and CKD
• Relative deficiency of EPO causes:
impaired vascular repair, progression of
atherosclerosis
Anemia and CKD
• Increased levels of:
• TNF-alpha
• ILs 1 and 6
• Endothelin
• Matrix metalloproteinases
directly reduce RBC production at the level
of the bone marrow and further worsen the
anemia
Anemia and CKD
• 28 of 29 large prospective studies of HF have
found anemia to be an independent predictor of
mortality.
• Among HF patients for each 1 g/dl decrement in
Hb, there is a 13 % increase in risk for all-cause
mortality
• Patients with anemia and CKD are more likely to
progress to ESRD irrespective of their baseline
level of renal function.
• As Hb drops over time, there is a graded
increase in HF hospitalizations and death
EPO
• Increase in coronary flow reserve.
• Preventing endothelial cell apoptosis.
• Enhancing myocardial repair in myocardial
injury that could minimize LV dysfunction
by recruiting vascular progenitor cells,
which can become functional myocardial
cells, thereby increasing the contractile
function of the injured ventricle.
Treatment of anemia with EPO
• Reducing morbidity, particularly that of
cardiovascular origin
• Improving quality of life
• Favorable changes in left ventricular
remodeling
• Improved ejection fraction
• Improved functional classification
• Higher levels of peak O2 consumption with
exercise testing.
Treatment of anemia with EPO
• Increased platelet activity, thrombin
generation, and resultant increased risk of
thrombosis
• Increased endothelin levels, increased
asymmetric dimethylarginine, which
theoretically reduces nitric oxide
availability and results in HTN
• Worsened measures of oxidative stress.
Treatment of anemia with EPO
• Two RCTs in CKD indicate that treatment
with EPO to higher Hb targets resulted in
higher CVD events.
• Until there is clear evidence that the partial
correction of anemia has favorable
outcomes in CVD, this form of treatment is
not recommended for the primary purpose
of improving the natural history of CVD.
ACCELERATION OF VASCULAR
CALCIFICATION
• Coronary artery calcification (CAC) seems to
occur exclusively in atherosclerotic arteries and
is absent in normal vessel walls.
• Patients with ESRD have the greatest absolute
values and rates of accumulation of CAC.
• using CAC as a diagnostic or therapeutic target
in patients with CKD or ESRD is not
recommended.
RENAL DISEASE AND
HYPERTENSION
• An optimal BP can be defined as less
than 120/80 (SBP being more
important).
• Most patients with CKD and HTN
require 3 or more antihypertensive
agents to achieve a goal BP of less
than 130/80 .
RENAL DISEASE AND
HYPERTENSION
• Pharmacological therapy : RAAS
antagonist often in combination with a
thiazide-type diuretic.
• Dihydropyridine CCBs alone, cause
relative afferent arteriolar dilation,
increase intraglomerular pressure and
worsen glomerular injury and thus
should be avoided as singular agents
for BP control.
Antihypertensive Agents in CKD
Type of Kidney
Disease
Preferred
Agents for
CKD, With
(or Without)
Hypertension
Blood
Pressure
Target
(mm Hg)
Other Agents to
Reduce CVD Risk
and Reach Blood
Pressure Target
Diabetic kidney
disease
<130/80
B
ACE inhibitor or
ARB
A Diuretic preferred,
(A) then BB or CCB
A
Nondiabetic kidney
disease with spot
urine total proteinto-creatinine ratio
<130/80
A
ACE inhibitor or
ARB
A Diuretic preferred,
(C) then BB or CCB
A
Nondiabetic kidney
disease with spot
urine total proteinto-creatinine ratio
<200 mg/g
<130/80
B
None preferred
Diuretic preferred,
then ACE
inhibitor, ARB,
BB, or CCB
A
Kidney disease in
the transplant
recipient
<130/80
B
None preferred
CCB, diuretic,
BB, ACE inhibitor,
ARB
B
200 mg/g
ACEI/ARB in CKD
• Elevation in Cr and ARF that are more
likely when the patient is volume depleted
or in the presence of occult bilateral renal
artery stenosis or equivalent.
• Have SBP stable and greater than 90 mm
Hg, euvolemia, and a drug regimen
without concurrent renal toxic agents
ACEI/ARB in CKD
• CKD patients enjoy an improved survival
and reduced rates of ESRD on ACEI/ARB
agents even though the serum Cr is
chronically elevated on these agents
because of reductions in intraglomerular
pressure.
• Discontinuation of ACEI/ARB drugs
because of moderate, asymptomatic rises
in Cr is a common management error.
ACEI/ARB in CKD
• Use ACEI or ARB in patients down to an
eGFR of 15 ml/min/1.73 m2
• Below this level, case reports suggest a
high rate of hyperkalemia and the concern
of accelerating the course to ESRD and
dialysis .
CONTRAST-INDUCED
NEPHROPATHY
CONTRAST-INDUCED
NEPHROPATHY
• A form of acute kidney injury
• definition: rise in serum Cr greater than
25 % or greater than 0.5 mg/dl from
baseline after IV contrast administration
• frequency :13 % in nondiabetics and 20 %
in diabetics undergoing PCI
is related in a curvilinear fashion to the
eGFR
Contrast-Induced Nephropathy
Definition
• New onset or exacerbation of renal
dysfunction after contrast administration in
the absence of other causes:
increase by > 25%
or
absolute  of > 0.5 mg/dL
from baseline
serum creatinine
Occurs 24 to 48 hrs post–contrast exposure, with creatinine
peaking 5 to 7 days later and normalizing within
7 to 10 days in most cases
Epidemiology
 Incidence varies according to the population and risk factor
profile.
 Reports of incidence subject to under-reporting, due to lack of
appropriate follow-up.
 Incidence of 7% reported in the overall population exposed to
radio-contrast agents. Incidence declining.
 Incidence ≥50% in patients with multiple risk factors.
Prognostic Implications
 3rd most common cause of hospital acquired renal
insufficiency (11% of all cases). Behind pre-renal
causes and nephrotoxic medications.
 5.5 fold increase in mortality (in-hospital).
 < 1% risk of Hemodialysis. (19 % 2 yr survival)
 Associated with MI, TVR at 1 year; longer hospital
stay.
 Post-procedural creatinine more powerful predictor of
late events than CK-MB.
Prognostic ImplicationsIncreased In-Hospital mortality.
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Retrospective, 16,248 inpatients
Cases with CIN
(n=183) matched with controls
(n = 174). Adjusted co-morbidity
CIN: > 25% increase in baseline
creatinine.
Percentage In-Hospital Mortality
40
OR 5.5
35
30
25
20
15
10
5
0
CIN
No CIN
Levy EM, et al; JAMA 1996;275(19):1489-94
PATHOPHYSIOLOGY
Pathophysiology of CIN
• (1) direct toxicity of iodinated contrast
material to nephrons related to the ionicity
and osmolality of the contrast media.
• (2) microshowers of atheroemboli to the
kidneys
• (3) contrast material– and atheroemboliinduced intrarenal vasoconstriction.
Pathophysiology of CIN
• The most important predictor of CIN is
underlying renal dysfunction.
Risk Stratification
Patient related
 Pre-existing renal
impairment
 Age
 Diabetes
 Heart failure
 Acute MI
 Cardiogenic shock
 Nephrotoxins
 Hypoalbuminemia
 Anemia
 Volume depletion
Procedural related
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Procedural hypotension
Intra-aortic balloon pump
Cholesterol embolization
Contrast volume and type
Risk Stratification- Risk score
Diabetes - any Tx
Age over 70
Multiple vessels treated
Female
IABP use
% CIN
SVG treated
60
50
40
30
20
10
0
0 or 1
Acute coronary
syndrome
2
3
4
5
6
7 or 8
Risk Score
CrCl < 50 cc/min
•9639 patients
•Multivariate predictors chosen by backward
logistic regression with a entry/leave criteria of 0.1
Mehran et al, JACC 2004
CIN PREVENTION
PREVENTION OF CONTRASTINDUCED NEPHROPATHY
• CIN must be discussed in detail during the
informed consent process of high-risk
patients before use of intravascular
iodinated contrast.
Basic concepts in CIN
prevention
• (1) hydration and volume expansion
• (2) choice and quantity of contrast
material
• (3) pre-, intra-, and postprocedural endorgan protection with pharmacotherapy
• (4) postprocedural monitoring and
expectant care.
CIN Prevention Trials
Agent
Design
Results
Furosemide
Pro-Ran
Worsened CIN
Mannitol
Pro-Ran
Worsened CIN
Hydration with 1/2 NS
Pro-Ran
Benefit vs. furosemide & mannitol
Atrial natriuretic peptide
Pro-Ran
No benefit
Dopamine
Pro
No benefit
Endothelin antagonist
Pro-Ran
No benefit
Adenosine antagonist
Pro-Ran
No benefit
Calcium channel blockade
Pro
Not adequately studied
Low Osmolar contrast
Pro-Ran
Nonionic monomer= Nonionic dimer
Low vs. High Osmolar
n-Acetylcysteine
Fenoldopam
Sodium Bicarbonate
Pro-Ran
Pro-Ran
Pro-Ran
Pro-Ran
Low Osmolar CONTRAST Beneficial
?Benefit (low volume I.V. contrast)
No benefit
?Benefit
HYDRATION
Hydration
Hydration
• Normal saline or isotonic sodium
bicarbonate is reasonable
• Starting 3 to 12 hours before the
procedure at a rate of 1 to 2 ml/kg/hr
• In those at risk, at least 300 to 500 ml of IV
hydration before the contrast material is
administered
• The postprocedural hydration target is a
urine output of 150 ml/hr.
Prevention of CIN with
Sodium Bicarbonate
Patients With Baseline Serum Creatinine 1 to 8 mg/dl
who Underwent Contrast Exposure (Iopamidol in All)
N=137
Sodium Chloride
Hydration (154 mEq/L of
Sodium Chloride)
N=68
Sodium Bicarbonate
Hydration (154 mEq/L of
Sodium Bicarbonate)
N=69
Primary endpoint: increase in serum creatinine ≥25%
within 2 days post-exposure
Merten GJ et al. JAMA, 2004;291:2328-2334
Prevention of CIN with
Sodium Bicarbonate: Results
Sodium
Chloride
N=59
Sodium
Bicarbonate
N=60
P value
Incidence of CIN (%)
13.6%
1.7%
0.02
Incidence of CIN
(↑SCr 0.5 mg/dL)
11.9%
1.7%
0.03
Endpoints
Merten GJ et al. JAMA, 2004;291:2328-2334
Iodinated contrast agents
Name
Osmolality Ionicity
Diatrizoate High
(renografin 1940
)
Ioxaglate
Low
600
Iohexol
Low
(omnipaqu 844
e)
Iodixinol
Iso(Visipaque) osmolar
Viscosity
Ionic
14
Ionic
15
Nonionic
10-20
Nonionic
26
Iodinated contrast agents
• lowest rates of CIN with nonionic, isoosmolar iodixanol (visipaque)
• Iodixanol(290 mOsm/kg) is less
nephrotoxic than LOCM agents with
osmolalities ranging from 600 to 800
mOsm/kg in the volumes of contrast used
in trials.
• Iodixanol is the contrast agent of choice in
patients at high renal risk undergoing PCI
Iodinated contrast agents
• The lower the eGFR, the smaller the
amount of contrast
• Less than 30 ml for a diagnostic and less
than 100 ml for interventional procedure
• More than 10 days between the 1st and
2nd contrast exposures if CIN has
occurred with the 1st procedure.
PreventionContrast: LOCM vs. HOCM
1.2
1
Relative Risk of CIN
 Meta-analysis:
39 trials, n= 5146
 CIN > 0.5 mg/dl
 Overall: 7% CIN
0.8
0.6
0.4
0.2
0
High Osm
Low Osm
Barrett and Carlisle J Am Soc Nephrol 92.
PreventionContrast: IOCM vs. LOCM
P=0.003
16
14
16 trials, n= 2727
12
SCr≥ .50 mg/dl
10
% CIN
Meta-analysis:
P=0.001
IOCM
LOCM
8
6
4
P<0.001
2
0
All patients
CKD
CKD+DM
McCullough et al, JACC 2006
PHARMACOTHERAPY
N-ACETYLCYSTEINE (NAC)
N-ACETYLCYSTEINE (NAC)
• metabolite of the sulfur-containing amino
acid, Cysteine.
• Is produced within the human body.
• Increases Glutathione Levels (acts as a
powerful antioxidant in the body )
• Glutathione also detoxifies chemicals into
less harmful compounds.
• Protects the body from acetaminophen
toxicity
N-ACETYLCYSTEINE (NAC)
• Heavy metals like lead, mercury, and
arsenic are detoxified and removed from
the body by N-Acetyl Cysteine
• may reduce the risk of colon cancer
N-acetylcysteine
• standard dose : 600 mg IV bolus before
and 600 mg P.O BID for the 48 hours after
angioplasty
• double dose : 1200 mg IV bolus and 1200
mg P.O BID for the 48 hours after
intervention
Postprocedural monitoring
1-High-risk hospitalized:
• Hydration 12 hours before the procedure
and continued at least 6 hours afterward
• A serum Cr should be measured 24 hours
after the procedure
Postprocedural monitoring
2-Outpatients, particularly with eGFR <
60 ml/min/1.73 m2:
• overnight stay or discharge to home with
48-hour follow-up and Cr measurement is
advised.
Postprocedural monitoring
3-Those with eGFR < 30 ml/min/1.73 m2:
• - The possibility of dialysis
• - Preprocedural nephrology consultation
CIN prevention strategy
• 1-Hydration
• 2-Use of iodixanol (Visipaque)
• 3-Prophylactic NAC
is a reasonable three-pronged approach to
minimize CIN and the risk of acute renal
failure requiring dialysis in patients at risk.
PREVENTION
ROTATIONAL CORONARY
ANGIOGRAPHY
• CAD is a 3-D disease process
• Single-plane acquisition requires multiple
injections of contrast at multiple fixed angle.
• Digital flat panel technology provides larger field
of vision and keeps all anatomy on the screen.
INNOVA SPIN TECHNOLOGY
INNOVA SPIN TECHNOLOGY
(GE Medical Systems)
ROTATIONAL ANGIOGRAPHY
Specific DA-1 Agonism:
Fenoldopam
A New Renal and Systemic Vasodilator
The CONTRAST Trial
Algorithm
300 patients
at increased risk for contrast nephropathy undergoing PCI
Hydrate
Randomize
Fenoldopam
Matching placebo
1º prior to and 12 º after cath
Primary endpoint
Worsening renal insufficiency within 12-96 hours
Prevention- Medical therapies
Positive results
Neutral results
Negative results
Theophylline
N-acetylcysteine
Furosemide
Statins
Fenoldopam
Mannitol
Ascorbic acid
Calcium channel
blockers
Endothelin receptor
antagonist
Prostaglandins E1
ANP, L-Arginine
CIN Consensus Working Panel, AJC 2006
Evolution of National Kidney Foundation
Guidelines on Hypertension and
Antihypertensive Agents in CKD
NKF Task Force on CVD (1998)
Target Population: Women with Cr 1.2 mg/dL, men with Cr 1.4 mg/dL, patients
with protenuria, patients with kidney failure treated with hemodialysis,
pertiioneal dialysis, or kidney transplantation
Recommendations: Use JNC 6 Guidelines, but consider patients to
be at highest CVD risk
K/DOQI Guidelines on CKD (2002)
Target Population: At least 3 months of either:
1) structural or functional abnormalities of the kidney, or 2) GFR <60 mL/min/1.73 m2
Recommendations: Consider patients to be at highest CVD risk. Treat risk factors
K/DOQI Guidelines on Hypertension and Antihypertensive Agents (2004)
Target Population: CKD stages 1-4 (as defined by the K/DOQI Guidelines on CKD)
Recommendations: Lifestyle modifications, blood pressure target <130/60 mm Hg,
and antihypertensive agents specific for type of CKD
Evaluation and Management of HTN and
Use of Antihypertensive Agents in CKD
Evaluation of the patient with CKD
Yes
Can an
ACEI or ARB
be introduced
or ↑
Diabetic
kidney disease? OR
Nondiabetic kidney disease with
urine total protein-to-creatinine
ratio 200 mg/g?
Periodically
re-evaluate
Is BP
<130/60
mm Hg?
No
Yes
No
Introduce or increase
diuretic or other agent
Introduce or increase
ACEI or ARB
Monitor response,
manage side effects
National Kidney Foundation. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.
Yes
Recommendations on Antihypertensive
Agents in CKD
– 50% to 75% of patients with CKD have HTN
– HTN is a risk factor for development and
progression of kidney disease and
development and worsening of CVD in CKD
– Antihypertensive therapy can slow
progression of kidney disease and reduce
risk of CVD in CKD
– Antihypertensive agents can slow
progression of kidney disease, even in
patients who are not hypertensive
Recommendations on Antihypertensive
Agents in CKD (cont’d)
• Blood pressure goal of <130/80 mm Hg is
appropriate for all types of CKD
– Patients with CKD are in the “highest-risk”
group for CVD
– For most patients with CKD, 2 or more
antihypertensive agents will be necessary to
achieve the blood pressure goal
– Achievement of the target SBP of <130 mm
Hg is usually associated with reduction in
DBP to <80 mm Hg
National Kidney Foundation. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.
ACUTE CORONARY
SYNDROMES
• Renal dysfunction as the most significant
prognostic factor for long-term mortality
• Comorbidities, in particular DM and HF
• Therapeutic nihilism (underutilization of
proven therapies such as beta blockers,
thrombolysis or primary angioplasty )
• Toxicity of therapies.
• Biological and pathophysiological factors
in renal dysfunction
DIAGNOSIS OF ACUTE
CORONARY SYNDROMES
• Patients with CKD presenting to the
hospital with chest discomfort represent a
high-risk group
• 40 % cardiac event rate at 30 days.
• Higher silent ischemia rates .
• Troponin I is the preferred biomarker.
• Skeletal myopathy of CKD can elevate
creatine kinase, myoglobin, and some
troponin T assays
ACUTE CORONARY
SYNDROMES
• Excess thrombin generation and
decreased platelet aggregation
• Increased rates of coronary thrombosis
and increased bleeding
ACUTE CORONARY
SYNDROMES
•
•
•
•
•
•
LPL function ;
HDL, TG,
LDL
Elevations in homocysteine
Enhancing oxidation of LDL-C
progression of atherosclerotic lesions
High rate of plaque rupture &CVD events.
Imbalance between ET and NO, may
worsen HTN and may augment
intravascular wall stress that could further
contribute to CVD events.
TREATMENT OF ACUTE
MYOCARDIAL INFARCTION
• Good benefit to risk ratio for ASA, beta
blockers, ACEI, ARB, aldosterone receptor
antagonists, and statins.
• dose adjustment for LMWH, bivalirudin,
GP IIb/IIIa antagonists
CKD and HF
• Pressure overload (related to HTN)
• Volume overload
• Cardiomyopathy