Nephrology Journal Club

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Nephrology Journal Club

• Staci Smith DO

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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

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Traditional CV Risk Factors

• Age
• Sex
• Blood pressure
• Dyslipidemia
• Diabetes
• Smoking

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Risk Factors That Enhance CV Mortality

• Disordered Mineral Metabolism
• calcium and phosphorous (CaP) gt55
• significant increase in mortality
• Pro-inflammatory state
• links hsCRP to mortality
• Anemia
• Hb concentration as independent risk factor for
  LVH
• Dyslipidemia

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Risk Factors That Enhance CV Mortality

• Endothelial dysfunction
• ESRD pts not able to make nitric oxide,
  vasodilator

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Risk Factors for CV Disease
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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

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Dual Blockage of the Renin-Angiotensin System for
Cardiorenal Protection An Update

• Major focus on HTN control is RAS cascade

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Dual Blockage of the Renin-Angiotensin System for
Cardiorenal Protection An Update

• Advantages of ACEI
• Preserved Ang II-related inhibition on renin
  release
• Less AT2 receptor stimulation
• Protective effect

• ARB Advantages
• AT1 blockade
• Vasodilation- AT2 receptor
• No aldosterone escape

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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

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Why do dual blockade?

• Ang II escape phenomenon
• 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

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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

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Dual Blockade in Clinical Terms

• ONTARGET
• Primary renal outcomes increased
• Doubled creatnine
• Acute Dialysis
• Death
• Proteinuria improved
• Decreased micro to macroalbuminuria

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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

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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

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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

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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

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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
• telmisartan 80 mg daily
• ramipril 10 mg daily
• combination telmisartan and ramipril

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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

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ACEI and ARB Combination Safe in CKD ?

• Primary Outcome
• Death from CV diseases
• MI
• CVA
• Heart failure hospitalization
• Secondary Outcomes
• included nephropathy
• Follow up was for 56 months

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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

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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.

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ACEI and ARB Combination Safe in CKD ?

• Important Points
• 5.6 hyperkalemia ( K gt5.5) 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

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Journal of American Society of Nephrology

• Association of Incident Gout and Mortality in
  Dialysis Patients
• J Am Soc Nephrol 19 2204-2210, 2008.

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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

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Association of Incident Gout and Mortality in
Dialysis Patients

• Risk factors for gout in general population
• Hyperuricemia
• Genetics
• Obesity
• Alcohol intake
• Purine intake
• Metabolic syndrome
• Age
• Male gender
• HTN
• Diuretics
• CKD

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Association of Incident Gout and Mortality in
Dialysis Patients

• Independent risk factors for gout
• African American race
• Older age
• BMI
• Female gender
• HTN
• Ischemic heart disease
• CHF
• Alcohol use

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Association of Incident Gout and Mortality in
Dialysis Patients

• Lower risk for gout
• DM
• tobacco abuse
• PVD

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Association of Incident Gout and Mortality in
Dialysis Patients

• Posttransplantation
• Calcineurin inhibitors
• Neoral (cyclosporine) uric acid retention
• Prograf (tacrolimus)
• Azathioprine

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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

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Association of Incident Gout and Mortality in
Dialysis Patients

• Increasing Gout Incidence
• Advanced age
• AA population
• Independently associated with mortality and
  higher CV mortality

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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

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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.

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Association of Incident Gout and Mortality in
Dialysis Patients

• Limitations
• Retrospective study
• Bias potential
• Gout diagnosis over vs underestimated