RENAL AND CARDIOVASCULAR INTERACTION

1
RENAL AND CARDIOVASCULAR INTERACTION
2
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)

3
(No Transcript)
4
Cardiorenal Risk
Cardiac Disease
Renal Disease
Acute Renal Failure and Death in the Cardiac
Patient
Myocardial Infarction, Heart Failure,
Arrhythmias, and Cardiac Death in the Renal
Patient
5
CARDIOVASCULAR DISEASE

• Renal hypoperfusion
• Prerenal azotemia
• Atheroembolism
• Septic embolism
• Immunologic phenomena
• Side effect of drugs

6
CHRONIC KIDNEY DISEASE

• Accelerates atherosclerosis
• Hypertension
• Heart failure
• Pericardial effusion
• Myocardial disease
• Valvular disease
• Cardiac arrhythmias
• Sudden death
• Dialysis related problems

7
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 )

8
(No Transcript)
9
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

10
Predictors of All-Cause Mortality to 7 Years
BARI Trial Registry
RR 95 CI P
CKD (baseline Cr gt 1.5 mg/dl) 2.31 1.63-3.28 lt0.001
Sex, female vs. male 0.91 0.75-1.10 0.32
Race, black vs. non-black 1.40 1.04-1.89 0.028
Age, y 1.05 1.04-1.06 lt0.001
Diabetes mellitus
Oral hypoglycemics 1.63 1.29-2.06 lt0.001
Insulin 1.80 1.26-2.58 lt0.001
PTCS vs. CABG 1.04 0.87-1.25 0.67
Interaction between PTCA and insulin-treated diabetics 1.73 1.11-2.69 0.02
Smoking history
Prior tobacco use 1.30 1.06-1.59 0.01
Tobacco use at baseline 1.82 1.42-2.33 lt0.001
Szczech L. et al., Circulation 2002 1052253-8.
11
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

12
Anemia and CKD

• Relative deficiency of EPO causes
• impaired vascular repair, progression of
  atherosclerosis

13
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

14
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

15
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.

16
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.

17
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.

18
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.

19
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.

20
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 .

21
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.

22
Antihypertensive Agents in CKD
Type of Kidney Disease Blood Pressure Target (mm Hg) Preferred Agents for CKD, With (or Without) Hypertension Other Agents to Reduce CVD Risk and Reach Blood Pressure Target Other Agents to Reduce CVD Risk and Reach Blood Pressure Target
Diabetic kidney disease lt130/80 B ACE inhibitor or ARB A(A) Diuretic preferred, then BB or CCB A A
Nondiabetic kidney disease with spot urine total protein-to-creatinine ratio ?200 mg/g lt130/80 A ACE inhibitor or ARB A(C) Diuretic preferred, then BB or CCB A A
Nondiabetic kidney disease with spot urine total protein-to-creatinine ratio lt200 mg/g lt130/80 B None preferred Diuretic preferred, then ACE inhibitor, ARB, BB, or CCB A A
Kidney disease in the transplant recipient lt130/80 B None preferred CCB, diuretic, BB, ACE inhibitor, ARB B B
23
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

24
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.

25
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 .

26
(No Transcript)
27
CONTRAST-INDUCED NEPHROPATHY
28
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

29
Contrast-Induced Nephropathy

• Definition
• New onset or exacerbation of renal dysfunction
  after contrast administration in the absence of
  other causes
• increase by gt 25
• or
• absolute ? of gt 0.5 mg/dL

from baseline serum creatinine
Occurs 24 to 48 hrs postcontrast exposure, with
creatinine peaking 5 to 7 days later and
normalizing within 7 to 10 days in most cases
30
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.

31
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).
• lt 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.

32
Prognostic Implications- Increased In-Hospital
mortality.

• Retrospective, 16,248 inpatients
• Cases with CIN(n183) matched with controls
• (n 174). Adjusted co-morbidity
• CIN gt 25 increase in baseline creatinine.

OR 5.5
Levy EM, et al JAMA 1996275(19)1489-94
33
PATHOPHYSIOLOGY
34
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 atheroemboli-induced
  intrarenal vasoconstriction.

35
(No Transcript)
36
Pathophysiology of CIN

• The most important predictor of CIN is underlying
  renal dysfunction.

37
(No Transcript)
38
Risk Stratification
Patient related
Procedural related

• Pre-existing renal impairment
• Age
• Diabetes
• Heart failure
• Acute MI
• Cardiogenic shock
• Nephrotoxins
• Hypoalbuminemia
• Anemia
• Volume depletion

• Procedural hypotension
• Intra-aortic balloon pump
• Cholesterol embolization
• Contrast volume and type

39
Risk Stratification- Risk score
Diabetes - any Tx
Age over 70
SVG treated
Multiple vessels treated
Female
IABP use
Acute coronary syndrome
CrCl lt 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
40
(No Transcript)
41
CIN PREVENTION
42
PREVENTION OF CONTRAST-INDUCED NEPHROPATHY

• CIN must be discussed in detail during the
  informed consent process of high-risk patients
  before use of intravascular iodinated contrast.

43
Basic concepts in CIN prevention

• (1) hydration and volume expansion
• (2) choice and quantity of contrast material
• (3) pre-, intra-, and postprocedural end-organ
  protection with pharmacotherapy
• (4) postprocedural monitoring and expectant care.

44
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
45
HYDRATION
46
Hydration
47
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.

48
Prevention of CIN with Sodium Bicarbonate
Patients With Baseline Serum Creatinine 1 to 8
mg/dl who Underwent Contrast Exposure (Iopamidol
in All) N137
Primary endpoint increase in serum creatinine
25 within 2 days post-exposure
Merten GJ et al. JAMA, 20042912328-2334
49
Prevention of CIN with Sodium Bicarbonate
Baseline Characteristics
Characteristics Sodium Chloride N59 Sodium Bicarbonate N60 P value
Age () 69.2 66.7 NS
Male () 45 44 NS
Diabetes () 27 30 NS
Baseline SCr (mg/dL) 1.71 1.89 0.09
Baseline eGFR (mL/min per 1.73m2) 45 41 NS
Merten GJ et al. JAMA, 20042912328-2334
50
Prevention of CIN with Sodium Bicarbonate Results
Endpoints Sodium Chloride N59 Sodium Bicarbonate N60 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
Merten GJ et al. JAMA, 20042912328-2334
51
Iodinated contrast agents
52
Name Osmolality Ionicity Viscosity
Diatrizoate (renografin) High 1940 Ionic 14
Ioxaglate Low 600 Ionic 15
Iohexol (omnipaque) Low 844 Nonionic 10-20
Iodixinol (Visipaque) Iso-osmolar 290 Nonionic 26
53
Iodinated contrast agents

• lowest rates of CIN with nonionic, iso-osmolar
  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

54
LOCM vs HOCM Normal Renal Function
p NS
55
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.

56
Prevention- Contrast LOCM vs. HOCM

• Meta-analysis
• 39 trials, n 5146
• CIN gt 0.5 mg/dl
• Overall 7 CIN

Barrett and Carlisle J Am Soc Nephrol 92.
57
Prevention- Contrast IOCM vs. LOCM
P0.003

• Meta-analysis
• 16 trials, n 2727
• SCr .50 mg/dl

P0.001
CIN
Plt0.001
McCullough et al, JACC 2006
58
(No Transcript)
59
PHARMACOTHERAPY
60
N-ACETYLCYSTEINE (NAC)
61
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

62
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

63
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

64
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

65
Postprocedural monitoring

• 2-Outpatients, particularly with eGFR lt 60
  ml/min/1.73 m2
• overnight stay or discharge to home with 48-hour
  follow-up and Cr measurement is advised.

66
Postprocedural monitoring

• 3-Those with eGFR lt 30 ml/min/1.73 m2
• - The possibility of dialysis
• - Preprocedural nephrology consultation

67
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.

68
(No Transcript)
69
PREVENTION
70
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.

71
INNOVA SPIN TECHNOLOGY
72
INNOVA SPIN TECHNOLOGY(GE Medical Systems)
73
ROTATIONAL ANGIOGRAPHY
74
(No Transcript)
75
(No Transcript)
76
(No Transcript)
77
(No Transcript)
78
(No Transcript)
79
Specific DA-1 Agonism Fenoldopam

• A New Renal and Systemic Vasodilator

80
Varying Effects of Parenteral Vasodilators on
Regional Blood Flow in the Kidney
Dopamine Cortex Medulla
Contrast Media Cortex Medulla
Mannitol Cortex Medulla
Endothelin Cortex Medulla
Fenoldopam Cortex Medulla
81
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
82
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
83
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 Recommendation
s 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 either1)
structural or functional abnormalities of the
kidney, or 2) GFR lt60 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 lt130/60 mm
Hg, and antihypertensive agents specific for
type of CKD
84
Evaluation and Management of HTN and Use of
Antihypertensive Agents in CKD
Evaluation of the patient with CKD
Diabetic kidney disease? OR Nondiabetic kidney
disease with urine total protein-to-creatinine
ratio ?200 mg/g?
Periodicallyre-evaluate
Yes
Is BP lt130/60 mm Hg?
Can an ACEI or ARB be introducedor ?
Yes
No
Yes
No
Yes
No
Introduce or increaseACEI or ARB
Introduce or increasediuretic or other agent
Introduce or increaseACEI or ARB
Introduce or increasediuretic or other agent
Monitor response, manage side effects
Monitor response, manage side effects
National Kidney Foundation. Am J Kidney Dis.
200443(suppl 1)S1-S290.
85
(No Transcript)
86
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

87
Recommendations on Antihypertensive Agents in CKD
(contd)

• Blood pressure goal of lt130/80 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 lt130 mm Hg is
  usually associated with reduction in DBP to lt80
  mm Hg

National Kidney Foundation. Am J Kidney Dis.
200443(suppl 1)S1-S290.
88
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

89
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

90
ACUTE CORONARY SYNDROMES

• Excess thrombin generation and decreased platelet
  aggregation
• Increased rates of coronary thrombosis and
  increased bleeding

91
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.

92
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

93
CKD and HF

• Pressure overload (related to HTN)
• Volume overload
• Cardiomyopathy