Nephrology Journal Club
 Staci Smith DO
Introduction
 The Cardiorenal Syndrome
 Nontraditional CV risk factors in patients
with renal disease
 Cardiovascular disease CVD is the leading
cause of death among patients with ESRD
 Patients with ESRD have cardiovascular
mortality rates 10- to 20-fold higher than the
general population
Traditional CV Risk Factors
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Age
Sex
Blood pressure
Dyslipidemia
Diabetes
Smoking
Risk Factors That Enhance CV Mortality
 Disordered Mineral Metabolism
 calcium and phosphorous (CaP) >55
 significant increase in mortality
 Pro-inflammatory state
 links hsCRP to mortality
 Anemia
 Hb concentration as independent risk factor for
LVH
 Dyslipidemia
Risk Factors That Enhance CV Mortality
 Endothelial dysfunction
 ESRD pts not able to make nitric oxide,
vasodilator
Risk Factors for CV Disease
American Journal of Kidney Diseases
 Dual Blockage of the Renin-Angiotensin
System for Cardiorenal Protection: An
Update
 Mustafa Arici, MD et al
 February 2009 pp 332-345
Dual Blockage of the Renin-Angiotensin System for
Cardiorenal Protection: An Update
 Major focus on
HTN control is
RAS cascade
Dual Blockage of the Renin-Angiotensin System for
Cardiorenal Protection: An Update
 Advantages of ACEI  ARB Advantages
 Preserved Ang II-related
inhibition on renin release
 Less AT2 receptor stimulation
 Protective effect
 AT1 blockade
 Vasodilation- AT2 receptor
 No aldosterone escape
Dual Blockage of the Renin-Angiotensin System for
Cardiorenal Protection: An Update
 ACEI Disadvantages
 Continued And II
production via non ACE
pathways
 NO intrarenal ACE
inhibition
 ARB Disadvantages
 Elevated Ang II levels
 Elevated renin levels
 Drop in BP d/t
vasodilating effect of
AT2
Why do dual blockade?
 Ang II escape phenomenon
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Prevents total ACE inhibitor
Can occur after long term use of ACEI
Production of Ang II via non ACE path
Does not occur with ARB use
 downstream pathway
Dual Blockade in Clinical Terms
 Combination tx- only 4mm systolic bp and
3 mm diastolic drop in bp
 ONTARGET
 Ramipril 10mg daily plus Telmisartan 80mg
daily
 Decreased 2.4/1.4 bp
 Not enough evidence to use for bp
Dual Blockade in Clinical Terms
 ONTARGET
 Primary renal outcomes increased
 Doubled creatnine
 Acute Dialysis
 Death
 Proteinuria improved
 Decreased micro to macroalbuminuria
Negative Outcomes in Dual Therapy
 Valsartan Heart Failure Trial (Val-HeFT )
 Subgroup analysis
 Use with an ACEI inhibitor and Beta blocker yielded
negative results
 CHARM
 VALIANT
 All reveal that dual therapy yields
 Hyperkalemia, worsening renal failure,
hypotension
Current Evidence of Dual RAS Inhibition
 Suggests that ACEI and ARBs are equal
 ARBs are better tolerated
 No perfect doses to achieve complete
blockade
 Combination therapy leads to a greater bp
decrease
 ONTARGET and VALIANT – no benefit
Conclusions
 Until new safety data emerges
 Wise to withhold use of combination therapy in
general practice, especially for “low risk” kidney
pts, elderly, high risk pts, or advanced kidney
disease
American Journal of Kidney Diseases
 Is Angiotensin-Converting Enzyme Inhibitor and
Angiotensin Receptor Combination Therapy
Better Than Monotherapy and Safe in Patients
With CKD?
 Vol 53, No 2. February 2009: pp 192-196
ACEI and ARB Combination
Safe in CKD ?
 Close relationship in CKD progression and proteinuria
 reduction in GFR over time
 Synergistic effect of prolonged blockade of RAAS
 dual or triple combination therapy
 ONTARGET
 randomized, double blind study
 three comparison groups
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telmisartan 80 mg daily
ramipril 10 mg daily
combination telmisartan and ramipril
ACEI and ARB Combination
Safe in CKD ?
 Study Design of ONTARGET
 25,620 participants
 55 yo or older with DM, atherosclerosis, or associated
end organ damage
 2.5 mg of ramipril for 3 days
 followed by 2.5 mg of ramipril and 40 mg telmisartan for 7
days
 both 40 mg telmisartan and 5mg ramipril
 for 11-18 days
ACEI and ARB Combination
Safe in CKD ?
 Primary Outcome
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Death from CV diseases
MI
CVA
Heart failure hospitalization
 Secondary Outcomes
 included nephropathy
 Follow up was for 56 months
ACEI and ARB Combination
Safe in CKD ?
 Results
 Mean bp was lower in both the telmisartan
group than the ramipril group
 0.9/0.6 mm Hg greater reduction
 Mean bp was lower in the combination-therapy
group than the ramipril group
 a 2.4/1.4 mm Hg greater reduction
ACEI and ARB Combination
Safe in CKD ?
 Conclusion:
 Telmisartan was equivalent to ramipril in
patients with vascular disease or high-risk
diabetes.
 The combination of the two drugs was
associated with more adverse events without
an increase in benefit.
ACEI and ARB Combination
Safe in CKD ?
 Important Points
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5.6% hyperkalemia ( K >5.5) with combination tx
3.3% hyperkalemia in monotherapy
Creatinine doubled in 2.1%-combination tx
Combination therapy showed no benefit
 increased the risk of hypotension, syncope, renal
dysfunction, and hyperkalemia, with a trend toward an
increased risk of renal dysfunction requiring dialysis
 Abandon dual therapy at the first sign of trouble
Journal of American Society of Nephrology
 Association of Incident Gout and Mortality in
Dialysis Patients
 J Am Soc Nephrol 19: 2204-2210, 2008.
Association of Incident Gout and Mortality
in Dialysis Patients
 Introduction
 gout as a marker for progression of CKD
 associated with decreased patient survival
 incidence of gout in ESRD pts may be low
Association of Incident Gout and Mortality
in Dialysis Patients
 Risk factors for gout in general population
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Hyperuricemia
Genetics
Obesity
Alcohol intake
Purine intake
Metabolic syndrome
Age
Male gender
HTN
Diuretics
CKD
Association of Incident Gout and Mortality
in Dialysis Patients
 Independent risk factors for gout
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African American race
Older age
BMI
Female gender
HTN
Ischemic heart disease
CHF
Alcohol use
Association of Incident Gout and Mortality
in Dialysis Patients
 Lower risk for gout
 DM
 tobacco abuse
 PVD
Association of Incident Gout and Mortality
in Dialysis Patients
 Posttransplantation
 Calcineurin inhibitors
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Neoral (cyclosporine) – uric acid retention
Prograf (tacrolimus)
Azathioprine
Association of Incident Gout and Mortality
in Dialysis Patients
 Results
 Table 1 page 2207
 Jan 1, 1999-Dec 31, 2003
 Only 101 had gouty nephropathy as cause of ESRD
 Excluded from study
 5.4% gout incidence in first year of dialysis
 11.5% by 3rd year
 15.4% by 5th year
Association of Incident Gout and Mortality
in Dialysis Patients
 Increasing Gout Incidence
 Advanced age
 AA population
 Independently associated with mortality and
higher CV mortality
Association of Incident Gout and Mortality
in Dialysis Patients
 Discussion
 True amount of people that have renal dz and a
gout dx and start dialysis is unknown
 5% incidence of ESRD pts with gout
 After 1 yr on dialysis
 Similar to that in general population
 African Americans
 Increased incidence of HTN and BMI, leading to
gout
Association of Incident Gout and Mortality
in Dialysis Patients
 Discussion
 Unclear associations with mortality
 25% increase in ACS
 CV disease primary cause of mortality in ESRD pts
 Increased renal tubular sodium reabsorption
 HTN
 Most patients with hyperuricemia do not develop gout
but ALL patients with gout have hyperuricemia.
Association of Incident Gout and Mortality
in Dialysis Patients
 Limitations
 Retrospective study
 Bias potential
 Gout diagnosis over vs underestimated