Nephrology Journal Club

1. Nephrology Journal Club • Staci Smith DO

2. 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

3. Traditional CV Risk Factors • Age • Sex • Blood pressure • Dyslipidemia • Diabetes • Smoking

4. 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

5. Risk Factors That Enhance CV Mortality • Endothelial dysfunction • ESRD pts not able to make nitric oxide, vasodilator

6. Risk Factors for CV Disease

7. 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

8. Dual Blockage of the Renin-Angiotensin System for Cardiorenal Protection: An Update • Major focus on HTN control is RAS cascade

9. 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

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

11. 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

12. 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

13. Dual Blockade in Clinical Terms • ONTARGET • Primary renal outcomes increased • Doubled creatnine • Acute Dialysis • Death • Proteinuria improved • Decreased micro to macroalbuminuria

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

22. 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

23. 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.

24. ACEI and ARB Combination Safe in CKD ? • 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

25. Journal of American Society of Nephrology • Association of Incident Gout and Mortality in Dialysis Patients • J Am Soc Nephrol 19: 2204-2210, 2008.

26. 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

27. 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

28. 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

29. Association of Incident Gout and Mortality in Dialysis Patients • Lower risk for gout • DM • tobacco abuse • PVD

30. Association of Incident Gout and Mortality in Dialysis Patients • Posttransplantation • Calcineurin inhibitors • Neoral (cyclosporine) – uric acid retention • Prograf (tacrolimus) • Azathioprine

31. 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

32. Association of Incident Gout and Mortality in Dialysis Patients • Increasing Gout Incidence • Advanced age • AA population • Independently associated with mortality and higher CV mortality

33. 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

34. 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.

35. Association of Incident Gout and Mortality in Dialysis Patients • Limitations • Retrospective study • Bias potential • Gout diagnosis over vs underestimated