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….