Effect of Allopurinol on CKD and CVD

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  • Morphology of preglomerular vessels in the RK and RK+OA rats. Compared with RK rats (A, x400, PAS; D, x400, PCNA+ -SMA double-staining), there was marked wall thickening with smooth muscle cell (SMC) proliferation in RK+OA rats (B, x400, PAS; E, x400, PCNA+ -SMA double-staining). Occasional arteries in RK+OA rats showed an increase in SMC number, migration of SMC into intima consistent with an obliterative arteriopathy (C, x400, PAS). Perivascular adventitial fibrosis was also prominent in RK+OA rats (F, x400, Collagen III immunostaining).
  • Reduction of uric acid levels was associated with BP control and protection of interstitial injury (experiment IV). Rats were placed on LS/OA diet (OA 2%) for 7 weeks and then matched on the basis of uric acid level and BP into 3 groups: (1) OA 2%, (2) withdrawal of OA but continuation of the LS diet (OA withdrawal), and (3) the addition of allopurinol (150 mg/L drinking water) with continuation of the OA 2% diet (allopurinol). Panel A shows the BP, and panel B shows the uric acid levels. * P <0.05 vs other groups. Control of uric acid and BP levels was associated with a reduction in the tubulointerstitial injury index, as shown by OPN (magnification, x200; C through E) and type III collagen (magnification, x100; F through H) immunostaining. Panels C and F show kidneys after OA (2%) was continued for 11 weeks, panels D and G show kidneys after OA withdrawal, and panels E and H show kidneys from OA-treated rats that received allopurinol.

Transcript

  • 1. Department of Medicine Division of Nephrology Journal Club Sridhar Reddy Allam, MD, MPH Nephrology Fellow Mount Sinai School of Medicine       July 14, 2010
  • 2. Clin J Am Soc Nephrol. June, 2010
  • 3. BACKGROUND
  • 4. Uric acid…. @
  • 5. Mount Sinai and Uric Acid
    • Dr. Alexander Gutman and Dr. Tsai-Fan Yu helped establish a connection between elevated levels of uric acid and gout
    • In the 1950s, they established one of the first gout clinics in the United States at Mount Sinai
    • They conducted trials on Probenecid, Colchicine and Allopurinol. These agents still remain in use as primary treatment modalities for gout
    • They also elucidated renal mechanisms of uric acid regulation
    • In 2001, Drs. Ruth Abramson and Mike Lipkowitz identified galectin 9 as hUAT, the first identified human urate transporter
  • 6. Dr. Alexander Gutman and Dr.Tsai-Fan Yu
  • 7.  
  • 8.  
  • 9.  
  • 10. Adverse outcomes with Hyperuricemia
  • 11. D. Feig, D. Kang and R. Johnson 2008:359;1811-21 Adverse effects of Hyperuricemia
  • 12. Hyperuricemia and renal outcomes Authors Methods Outcome Reference Iseki et al Population cohort of 48177 individuals HR for ESRD is 2.0 in men, 5.7 in women AJKD 2004 Lee et al 1952 subjects with pre-hypertension Strong association with microalbuminuria Hypertension 2006 Madero et al 840 patients from MDRD study HR for all cause mortality 1.6, CV mortality 1.5, ESRD 1.2 AJKD 2009 Chonchon et al 5808 patients in Cardiovascular Health Study cohort Association with higher prevalence and progression of CKD AJKD 2007 Akalin & Winston 307 renal transplant recipients at MSSM from 2001-2004 Strong association with new CV events and development of CAN Transplantation 2008
  • 13. J-shaped mortality relationship for uric acid in patients with CKD5 Suliman et al, AJKD 2006: 48;761-771
  • 14. Problems with association studies
    • Just an association, no causal relation can be ascertained
    • Chicken and the egg: is it hyperuricemia the cause or the consequence of impaired renal function, use of diuretics in HTN, oxidative stress or elevated renal vascular resistance
    • Hyperuricemia is not considered a risk factor by Joint National Committee or most expert organizations
  • 15. Evidence that hyperuricemia is indeed a risk factor comes from
    • Longitudinal follow up studies
    • Animal experiments
    • Effect of treatment of hyperuricemia on outcomes
  • 16. D. Feig, D. Kang and R. Johnson 2008:359;1811-21 Risk of hypertension with Hyperuricemia
  • 17. Kang, D.-H. et al. J Am Soc Nephrol 2002;13:2888-2897 Morphology of preglomerular vessels in RK and RK+OA rats RK RK+OA RK+OA PAS SMA+PCNA
  • 18. Mazzali, M. et al. Hypertension 2001;38:1101-1106 Reduction of uric acid levels was associated with BP control and protection of interstitial injury OPN Collagen
  • 19. D. Feig, D. Kang and R. Johnson 2008:359;1811-21 Proposed mechanism of uric acid mediated adverse effects
  • 20. Effect of treatment of Hyperuricemia Authors Methods Outcome Reference Siu et al RCT of 54 patients with CKD: 12 months of Allopurinol Stable renal function in 84% in AP group vs. 54% in control group AJKD 2006 Kanbay et al 48 patients with GFR > 60 given 3 months of Allopurinol Improvement in BP and GFR Int Urol Nephrol 2007 Talaat et al Allopurinol withdrawn in 50 patients with CKD stages 3 and 4 Worsening of GFR and HTN in patients not on RAAS blockers Am J Nephorl 2007 Fieg et al RCT of Allopurinol in 30 adolescents with newly diagnosed HTN Reduction of BP JAMA 2008
  • 21. Feig, D. I. et al. JAMA 2008;300:924-932 Blood Pressure Response of Adolescents to Allopurinol and Placebo
  • 22. Serum creatinine trend over 12 months in patients treated with Allopurinol vs. control (n=25) Siu et al, AJKD 2006: 47(1); 51-59
  • 23. Clin J Am Soc Nephrol. June, 2010
  • 24. Hypothesis Allopurinol attenuates progression of CKD and lowers cardiovascular risk
  • 25. MATERIALS & METHODS
  • 26. Methods
    • Prospective, randomized trial
    • Inclusion criteria
    • CKD with eGFR < 60
    • Stable clinical condition within 3 months before screening
    • Stable renal function in the 3 months before screening
  • 27. Exclusion criteria
    • History of Allopurinol intolerance
    • Those already on Allopurinol
    • Active infections or inflammatory diseases
    • Chronic liver disease
    • Those on immunosuppressive therapy
  • 28. Methods
    • Patients were randomly assigned to a control group or treatment group
    • Treatment group patients were prescribed Allopurinol 100 mg/d
    • Dosage of antihypertensive drug, lipid-lowering agents, and antiplatelet drugs were continued and adjusted according to the individual patient’s clinical condition
    • Clinical, biochemical, and inflammatory parameters were measured at baseline and every 6 months after
    • Mean follow up 24 months
  • 29. End Points
    • Renal disease progression as estimated by eGFR using MDRD equation
    • Cardiovascular events (MI, CHF)
    • Hospitalizations of any cause
    • Mortality
  • 30. Statistical analysis
    • Results expressed as mean +/- SD, mean +/- SEM or median with interquartile range
    • Categorical variables compared by Chi-square test and continuous variables by t-test or ANOVA test
    • Kaplan-meier survival analysis and Cox regression models were used to evaluate the risk between two groups
    • SPSS was used for statistical analysis
  • 31.  
  • 32. RESULTS
  • 33.  
  • 34.  
  • 35. No effect of Allopurinol on Blood Pressure control
  • 36. Allopurinol attenuated GFR decline
  • 37. GFR change in Allopurinol group vs. control group Cox regression analysis (adjusting for age, gender, diabetes, RAAS blockade, CRP, CKD etiology and albuminuria) revealed statistically significant benefit with Allopurinol
  • 38. Allopurinol decreased the levels of inflammatory markers
  • 39. Allopurinol group had less cardiovascular events
  • 40. Allopurinol treatment lowered the risk of cardiovascular events by 71% Cox regression analysis confirmed independent benefit of Allopurinol treatment on cardiovascular risk
  • 41. Adverse events
    • In the treatment group, Allopurinol was withdrawn in two patients for gastrointestinal symptoms
    • No abnormalities in liver function tests, hematological alterations or serious adverse events were noted in the treatment group
  • 42. Strengths of the study
    • Prospective randomized trial
    • Sample size of 113 and follow up of 2 years: better than the studies that investigated similar hypothesis
    • No prior data about Allopurinol effect in decreasing cardiovascular risk in general population or in CKD: This study is the first to provide these data
  • 43. Limitations
    • Open label study and there was no placebo
    • ?? Observer bias - researchers tend to observe what they expect
    • ?? Rosenthal effect - study participants tend to behave in the way researchers expect
    • Single center study
    • Sample size is not robust, study is likely underpowered
    • There were 2 deaths in control group: although study was randomized, are the two groups different?
    • No hard renal end points like doubling of serum creatinine or requirement for dialysis
    • No info on race: if we assume all patients are Spaniards, ?? applicability to other races
  • 44. Caveats
    • Risk of hyperuricemia questioned by few studies
    • Although Allopurinol is inexpensive, it is not a benign drug and may cause fatal adverse effects like
    • Dermatologic: Stevens-Johnson syndrome, Toxic epidermal necrolysis
    • Hematological: Agranulocytosis, Aplastic anemia, Thrombocytopenia
    • Hepatic: Granulomatous hepatitis, Hepatic necrosis
    • Immunologic: Immune hypersensitivity reaction
    • Would want to wait for better studies with similar results before embracing Allopurinol for attenuating CKD progression
  • 45. Thank You….