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. Dual Blockage of the Renin-Angiotensin System for Cardiorenal Protection: An Update Advantages of ACEI  Preserved Ang II-related inhibition on renin release  Less AT 2 receptor stimulation  Protective effect ARB Advantages  AT 1 blockade  Vasodilation- AT 2 receptor  No aldosterone escape

10. 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 AT 2

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. 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 ?

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 3 rd year 15.4% by 5 th 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