URIC ACID AND CKD SONIKA PURI

Transcription

1 URIC ACID AND CKD SONIKA PURI

2 Uric acid transport and disease ;JCI,2010

3 URIC ACID REABSORTION PROXIMAL TUBULAR CELLS -URAT 1-urate/anion antitransporter -Inhibitors include by uricosuric agents losartan, benzbromarone -OAT 10/4- activated by intracellular dicarboxylates -not affected by antiuricosuric agents -GLUT 9: linked to gene locus SLCA29 -; SNP in this locus are a/w gout, however no association noted with HTN, or CVD Uric acid transport and disease ;JCI,2010

4 URIC ACID EXCRETION -MRP4 and ABCG 2 ATP dependant urate extrusion -OAT1/3 dicarboxylate/ua antitransporters

5 UA PROINFLAMMATORY/ ANTI INFLAMMATORY A: peroxinitrite can block tetrahydrobiopterin (HB4) which is a cofactor necessary for action of NOS. B:Uric acid prevents copper induced oxidation of LDL which may prevent against athersclerosis. C: Proinflammatory actions of UA- in vascular sm cells, adipocytes.

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7 URIC ACID AND HTN Historically in 1800s Frederick Mohamed made an observation that many hypertensives came from gouty families. 1960s-1970s observations were made that hyperuricemia was present in 5%-6% of general population ; however elevated uric acid levels were seen in 40%-60% of hypertensive patients. Debate : Hyperuricemia seen in hypertension is merely an association vs.causality Hypertensive phenotype a/w other variables such as diuretics use, obesity, renal dysfunction which can independantly affect serum UA levels. Johnson et al, Hypertension 2005

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9 Elevated bp induces hypertension in rats, Mazzali et al, HYPERTENSION 2001

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11 Sachez-Lozada et al; KI 2005

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13 -125 patients age 6-18yrs referred for evaluation of HTN -40 normotensive controls who were referred for proteinuria, enuresis or hematuria

14 Feig ; Hypertension, 2003

15 Feig et al, NEJM 2008

16 Ua and CKD Conflicting data regarding role of hyperuricemia in progression of ckd. Evidence that hyperuricemia affects progression of IgA nephropathy

17 Weiner et al, JASN 2008 ARIC study ,792 participants; age 45-65yrs Mean follow up of 4-5yrs Baseline S.cr measured for 99%pts Outcome: Incident kidney disease- egfr decrease <15ml/min/1.73 m2/ final egfr <60ml/min CHS study participants, age >65yrs Additional 687 AA patients between ; excluded d/t limited fup. Baseline s.cr measured in 97% patients Follow up for 5 years

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21 -MDRD study : ;randomized- 840 individuals with ckd (s.cr in women, in men effect of strict bp control and effect of dietary protein restriction -All cause mortality, cv mortality and kidney failure (dialysis or transplant) Fup till Dec Madero et al, AJKD 2010

22 -Model 1- adjusted for age -Model 2-age + cvd risk factors -Model 3 Model 2 + egfr+ proteinuria -Model 4 Allopurinol use

23 UA and Type 1 DM -Single centre study of 263 patients with type 1 DM ( ), median fup on 18years -data collected 3 yrs after onset of dm normotensive (except 3- ace/diuretic); w/ normoalbuminuria -normal uric acid micromol/l in mean, micromol/l in women -72 patients developed microalbuminuria 23 progressed to macroalbuminuria (12%)

24 Serum uric acid as a predictor of development of Diabetic nephropathy in Type 1 DM -normoalbuminuria vs microalbuminuria :no difference found in mean +/- standard deviation in uric acid levels -based on single measurement of uric acid levels Hovind et al, Diabetes 2009

25 UA AND CVD Taiwanese study- 484,568 men and women, >20yrs age, followed since or more clinic visits Questionnaire regarding medical history, lifestyle and demographics along with appropriate lab work. Mean follow up of 8.5yrs. OVERT CVD RISK FACTORS -- 1 or more of the following --DM/HTN/ obesity bmi>25, hypertg PRE-CVD RF --prehtn (sbp ), predm or borderline high tg ( mg/dl)

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29 Goicoechea et al, CJASN eligible patients w/ egfr <60cc/min-Randomization allopurinol : 57 ( 51)patients Control group: 56 (47) patients

30 Renal function measured at baseline, 6,12 and 24 months Mean time to followup /- 7.8 months OUTCOMES 1) HOSPITALIZATIONS 2)CV EVENTS 3) ESRD requiring HD 4) MORTALITY

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32 -Allopurinol slowed the progression of renal disease (defined as decrease higher than 0.2ml/min /1.73m2) after adjustment for other factors HR 0.53 ( ) P patients in control group/ 12 in treatment group were hospitalized

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34 -30 ADOLESCENTS AGE 11-17YRS, new diagnosed essential htn, no prior treatment -randomized,double blinded,placebo controlled. -use ambul/office bp monitoring - cross over study 15 each received 200mg bid x 4 weeks, washout period of 2 weeks, cut off uric acid >6.0 Effect of allopurinol in bp of adolescents Feig et al,jama 2008

35 2 randomized, double blinded,placebo-controlled crossover studies performed for one month on pts with NYHA 2/3 comparing placebo, allopurinol 300mg daily and 600mg daily; 2 nd study placebo vs probenecid 1000mg Endothelial function as measured by venous forearm blood flow plethysmography- sodium nitroprusside, acetycholine and acetylcholine with vitamin c (25mg/ml) 30 patients were given medication/placebox 4 weeks, fasting samples Similar uric acid reduction was achieved with probenecid and

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