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

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 Preserved Ang II-related

inhibition on renin release Less AT2 receptor stimulation

Protective effect

ARB Advantages 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 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

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 Death from CV diseases MI CVA Heart failure hospitalization

Secondary Outcomes included nephropathy

Follow up was for 56 months

http://content.nejm.org/content/vol358/issue15/images/large/05t3.jpeg

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.

Important Points 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

ACEI and ARB Combination Safe in CKD ?

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 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 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

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