URIC ACID AND CKD

URIC ACID AND CKD
SONIKA PURI
Uric acid transport and disease ;JCI,2010
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
URIC ACID EXCRETION
-MRP4 and ABCG 2 –ATP
dependant urate extrusion
-OAT1/3 –dicarboxylate/UA
antitransporters
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.
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
Elevated bp induces hypertension in rats , Mazzali et al, HYPERTENSION 2001
Sachez-Lozada et al;
KI 2005
-125 patients age 6-18yrs referred for evaluation of HTN
-40 normotensive controls who were referred for proteinuria,
enuresis or hematuria
Feig ; Hypertension, 2003
Feig et al, NEJM 2008
Ua and CKD
Conflicting data regarding role of hyperuricemia in
progression of ckd .
Evidence that hyperuricemia affects progression of
IgA nephropathy
Weiner et al, JASN 2008
ARIC study – 1987-1989
CHS study -1989-1990
15,792 participants; age
45-65yrs
5201 participants, age
>65yrs
Mean follow up of 45yrs
Additional 687 AA
patients between 19921993; excluded d/t
limited fup.
Baseline S.cr measured
for 99%pts
Outcome: Incident
kidney disease- egfr
decrease
<15ml/min/1.73 m2/ final
egfr <60ml/min
Baseline s.cr measured
in 97% patients
Follow up for 5 years
-MDRD study : 1989-1994;randomized- 840 individuals with ckd (s.cr 1.2-7 in
women, 1.4-7 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 2000.
Madero et al, AJKD 2010
-Model 1adjusted for
age
-Model 2-age
+ cvd risk
factors
-Model 3
Model 2 +
egfr+
proteinuria
-Model 4
Allopurinol
use
UA and Type 1 DM
-Single centre study of 263 patients with type 1 DM (1979-1984), median fup on
18years
-data collected 3 yrs after onset of dm—normotensive (except 3- ace/diuretic); w/
normoalbuminuria
-normal uric acid 200-450 micromol/l in mean, 130-350 micromol/l in women
-72 patients developed microalbuminuria 23 progressed to macroalbuminuria
(12%)
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
UA AND CVD
Taiwanese study- 484,568
men and women , >20yrs age,
followed since 1994
2 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 120-139), preDM or
borderline high tg (150199mg/dl)
Goicoechea et al,
CJASN 2010
112 eligible patients w/ egfr
<60cc/min-Randomization
allopurinol : 57 ( 51)patients
 Control group: 56 (47) patients
Renal function measured at baseline, 6,12 and 24 months
Mean time to followup 23.4 +/- 7.8 months
OUTCOMES
1)
HOSPITALIZATIONS 2)CV EVENTS 3) ESRD requiring HD
4) MORTALITY
-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 (0.28-0.99) P
0.048
22 patients in control group/ 12 in treatment group were hospitalized
-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
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; 2nd 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