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Department of MedicineDepartment of Medicine
Division of NephrologyDivision of NephrologyJournal ClubJournal Club
Sridhar Reddy Allam, MD, MPHSridhar Reddy Allam, MD, MPH
Nephrology FellowNephrology FellowMount Sinai School of MedicineMount Sinai School of Medicine
July 14, 2010July 14, 2010
Clin J Am Soc Nephrol. June, 2010Clin J Am Soc Nephrol. June, 2010
BACKGROUNDBACKGROUND
Uric acid….Uric acid….
@
Mount Sinai and Uric AcidMount Sinai and Uric Acid
Dr. Alexander Gutman and Dr. Tsai-Fan Yu helped establish a Dr. Alexander Gutman and Dr. Tsai-Fan Yu helped establish a connection between elevated levels of uric acid and goutconnection between elevated levels of uric acid and gout
In the 1950s, they established one of the first gout clinics in the In the 1950s, they established one of the first gout clinics in the United States at Mount SinaiUnited States at Mount Sinai
They conducted trials on Probenecid, Colchicine and Allopurinol. They conducted trials on Probenecid, Colchicine and Allopurinol. These agents still remain in use as primary treatment modalities for These agents still remain in use as primary treatment modalities for goutgout
They also elucidated renal mechanisms of uric acid regulationThey also elucidated renal mechanisms of uric acid regulation
In 2001, Drs. Ruth Abramson and Mike Lipkowitz identified galectin In 2001, Drs. Ruth Abramson and Mike Lipkowitz identified galectin 9 as hUAT, the first identified human urate transporter9 as hUAT, the first identified human urate transporter
Dr. Alexander Gutman and Dr.Tsai-Fan Yu
Adverse outcomes with Adverse outcomes with HyperuricemiaHyperuricemia
D. Feig, D. Kang and R. Johnson 2008:359;1811-21
Adverse effects of Hyperuricemia
Hyperuricemia and renal outcomesHyperuricemia and renal outcomes
AuthorsAuthors MethodsMethods OutcomeOutcome ReferenceReference
Iseki et alIseki et al Population cohort of Population cohort of 48177 individuals48177 individuals
HR for ESRD is 2.0 in men, HR for ESRD is 2.0 in men, 5.7 in women5.7 in women
AJKD 2004AJKD 2004
Lee et alLee et al 1952 subjects with 1952 subjects with pre-hypertension pre-hypertension
Strong association with Strong association with microalbuminuriamicroalbuminuria
Hypertension Hypertension 20062006
Madero et Madero et alal
840 patients from 840 patients from MDRD studyMDRD study
HR for all cause mortality 1.6, HR for all cause mortality 1.6, CV mortality 1.5, ESRD 1.2CV mortality 1.5, ESRD 1.2
AJKD 2009AJKD 2009
Chonchon Chonchon et alet al
5808 patients in 5808 patients in Cardiovascular Cardiovascular Health Study cohortHealth Study cohort
Association with higher Association with higher prevalence and progression prevalence and progression of CKDof CKD
AJKD 2007AJKD 2007
Akalin &Akalin &WinstonWinston
307 renal transplant 307 renal transplant recipients at MSSM recipients at MSSM from 2001-2004from 2001-2004
Strong association with new Strong association with new CV events and development CV events and development of CANof CAN
Transplantation Transplantation 20082008
J-shaped mortality relationship J-shaped mortality relationship for uric acid in patients with CKD5for uric acid in patients with CKD5
Suliman et al, AJKD 2006: 48;761-771
Problems with association studiesProblems with association studies
Just an association, no causal relation can be Just an association, no causal relation can be ascertainedascertained
Chicken and the egg: is it hyperuricemia the cause or the Chicken and the egg: is it hyperuricemia the cause or the consequence of impaired renal function, use of diuretics consequence of impaired renal function, use of diuretics in HTN, oxidative stress or elevated renal vascular in HTN, oxidative stress or elevated renal vascular resistanceresistance
Hyperuricemia is not considered a risk factor by Joint Hyperuricemia is not considered a risk factor by Joint National Committee or most expert organizationsNational Committee or most expert organizations
Evidence that hyperuricemia is Evidence that hyperuricemia is indeed a risk factor comes fromindeed a risk factor comes from
Longitudinal follow up studiesLongitudinal follow up studies
Animal experimentsAnimal experiments
Effect of treatment of hyperuricemia on outcomesEffect of treatment of hyperuricemia on outcomes
D. Feig, D. Kang and R. Johnson 2008:359;1811-21
Risk of hypertension with Hyperuricemia
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
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
D. Feig, D. Kang and R. Johnson 2008:359;1811-21
Proposed mechanism of uric acid mediated adverse effects
Effect of treatment of Hyperuricemia Effect of treatment of Hyperuricemia
AuthorsAuthors MethodsMethods OutcomeOutcome ReferenceReference
Siu et alSiu et al RCT of 54 patients with RCT of 54 patients with CKD: 12 months of CKD: 12 months of AllopurinolAllopurinol
Stable renal function in Stable renal function in 84% in AP group vs. 84% in AP group vs. 54% in control group54% in control group
AJKD 2006AJKD 2006
Kanbay Kanbay et alet al
48 patients with GFR > 60 48 patients with GFR > 60 given 3 months of given 3 months of AllopurinolAllopurinol
Improvement in BP and Improvement in BP and GFRGFR
Int Urol Int Urol Nephrol 2007Nephrol 2007
Talaat Talaat et alet al
Allopurinol withdrawn in 50 Allopurinol withdrawn in 50 patients with CKD stages patients with CKD stages 3 and 43 and 4
Worsening of GFR and Worsening of GFR and HTN in patients not on HTN in patients not on RAAS blockersRAAS blockers
Am J Nephorl Am J Nephorl 20072007
Fieg et Fieg et alal
RCT of Allopurinol in 30 RCT of Allopurinol in 30 adolescents with newly adolescents with newly diagnosed HTNdiagnosed HTN
Reduction of BPReduction of BP JAMA 2008JAMA 2008
Feig, D. I. et al. JAMA 2008;300:924-932
Blood Pressure Response of Adolescents to Allopurinol and Placebo
Serum creatinine trend over 12 months in patients Serum creatinine trend over 12 months in patients treated with Allopurinol vs. control (n=25)treated with Allopurinol vs. control (n=25)
Siu et al, AJKD 2006: 47(1); 51-59
Clin J Am Soc Nephrol. June, 2010Clin J Am Soc Nephrol. June, 2010
HypothesisHypothesis
Allopurinol attenuates progression of Allopurinol attenuates progression of CKD and lowers cardiovascular riskCKD and lowers cardiovascular risk
MATERIALS & METHODSMATERIALS & METHODS
MethodsMethods
Prospective, randomized trialProspective, randomized trial
Inclusion criteriaInclusion criteria
1.1. CKD with eGFR < 60CKD with eGFR < 60
2.2. Stable clinical condition within 3 months before Stable clinical condition within 3 months before screeningscreening
3.3. Stable renal function in the 3 months before Stable renal function in the 3 months before screeningscreening
Exclusion criteriaExclusion criteria
History of Allopurinol intoleranceHistory of Allopurinol intolerance
Those already on AllopurinolThose already on Allopurinol
Active infections or inflammatory diseasesActive infections or inflammatory diseases
Chronic liver diseaseChronic liver disease
Those on immunosuppressive therapyThose on immunosuppressive therapy
MethodsMethodsPatients were randomly assigned to a control group or Patients were randomly assigned to a control group or treatment grouptreatment group
Treatment group patients were prescribed Allopurinol Treatment group patients were prescribed Allopurinol 100 mg/d100 mg/d
Dosage of antihypertensive drug, lipid-lowering agents, Dosage of antihypertensive drug, lipid-lowering agents, and antiplatelet drugs were continued and adjusted and antiplatelet drugs were continued and adjusted according to the individual patient’s clinical conditionaccording to the individual patient’s clinical condition
Clinical, biochemical, and inflammatory parameters were Clinical, biochemical, and inflammatory parameters were measured at baseline and every 6 months aftermeasured at baseline and every 6 months after
Mean follow up 24 monthsMean follow up 24 months
End PointsEnd Points
Renal disease progression as estimated by Renal disease progression as estimated by eGFR using MDRD equationeGFR using MDRD equation
Cardiovascular events (MI, CHF)Cardiovascular events (MI, CHF)
Hospitalizations of any causeHospitalizations of any cause
MortalityMortality
Statistical analysisStatistical analysis
Results expressed as mean +/- SD, mean +/- SEM or Results expressed as mean +/- SD, mean +/- SEM or median with interquartile rangemedian with interquartile range
Categorical variables compared by Chi-square test and Categorical variables compared by Chi-square test and continuous variables by t-test or ANOVA testcontinuous variables by t-test or ANOVA test
Kaplan-meier survival analysis and Cox regression Kaplan-meier survival analysis and Cox regression models were used to evaluate the risk between two models were used to evaluate the risk between two groupsgroups
SPSS was used for statistical analysisSPSS was used for statistical analysis
RESULTSRESULTS
No effect of Allopurinol on No effect of Allopurinol on Blood Pressure controlBlood Pressure control
Allopurinol attenuated GFR declineAllopurinol attenuated GFR decline
GFR change in Allopurinol group vs. control groupGFR 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
Allopurinol decreased the levels Allopurinol decreased the levels of inflammatory markersof inflammatory markers
Allopurinol group had less Allopurinol group had less cardiovascular eventscardiovascular events
Allopurinol treatment lowered the risk of cardiovascular events by 71%Allopurinol treatment lowered the risk of cardiovascular events by 71%
Cox regression analysis confirmed independent benefit of Allopurinol treatment on cardiovascular risk
Adverse eventsAdverse events
In the treatment group, Allopurinol was withdrawn in two In the treatment group, Allopurinol was withdrawn in two patients for gastrointestinal symptomspatients for gastrointestinal symptoms
No abnormalities in liver function tests, hematological No abnormalities in liver function tests, hematological alterations or serious adverse events were noted in the alterations or serious adverse events were noted in the treatment grouptreatment group
Strengths of the studyStrengths of the study
Prospective randomized trialProspective randomized trial
Sample size of 113 and follow up of 2 years: Sample size of 113 and follow up of 2 years: better than the studies that investigated similar better than the studies that investigated similar hypothesishypothesis
No prior data about Allopurinol effect in No prior data about Allopurinol effect in decreasing cardiovascular risk in general decreasing cardiovascular risk in general population or in CKD: This study is the first to population or in CKD: This study is the first to provide these dataprovide these data
LimitationsLimitations
Open label study and there was no placebo Open label study and there was no placebo ?? Observer bias - researchers tend to observe what they expect?? Observer bias - researchers tend to observe what they expect?? Rosenthal effect - study participants tend to behave in the way ?? Rosenthal effect - study participants tend to behave in the way
researchers expectresearchers expect
Single center studySingle center study
Sample size is not robust, study is likely underpoweredSample size is not robust, study is likely underpowered
There were 2 deaths in control group: although study was There were 2 deaths in control group: although study was randomized, are the two groups different?randomized, are the two groups different?
No hard renal end points like doubling of serum creatinine or No hard renal end points like doubling of serum creatinine or requirement for dialysisrequirement for dialysis
No info on race: if we assume all patients are Spaniards, ?? No info on race: if we assume all patients are Spaniards, ?? applicability to other racesapplicability to other races
CaveatsCaveats
Risk of hyperuricemia questioned by few studiesRisk of hyperuricemia questioned by few studies
Although Allopurinol is inexpensive, it is not a benign drug and may Although Allopurinol is inexpensive, it is not a benign drug and may cause fatal adverse effects likecause fatal adverse effects like
- Dermatologic: Stevens-Johnson syndrome, Toxic epidermal Dermatologic: Stevens-Johnson syndrome, Toxic epidermal necrolysisnecrolysis
- Hematological: Agranulocytosis, Aplastic anemia, Hematological: Agranulocytosis, Aplastic anemia, ThrombocytopeniaThrombocytopenia
- Hepatic: Granulomatous hepatitis, Hepatic necrosisHepatic: Granulomatous hepatitis, Hepatic necrosis
- Immunologic: Immune hypersensitivity reaction Immunologic: Immune hypersensitivity reaction
Would want to wait for better studies with similar results before Would want to wait for better studies with similar results before embracing Allopurinol for attenuating CKD progressionembracing Allopurinol for attenuating CKD progression
Thank You….Thank You….
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