Àcid úric i progressió de la malaltia renal

José Luño Hospital General Universitario

Gregorio Marañon

Homeostasis del ácido úrico

Efecto de dietas ricas en fructosa

Adaptado de R. Johnson et al. JASN 2010, 21:2036-2039

 Arterial Hypertension  Metabolic Syndrome  Obstructive sleep apnea Syndrome  Vascular Disease (coronary and carotid)  Cerebrovascular disease and vascular dementia  Preeclampsia  Inflammatory biomarkers (hs- CRP, PAI-1, ..)  Endothelial Dysfunction  Oxydative Stress  Renal Disease Progression

Uric Acid and Cardiovascular Risk Daniel I. Feig, Duk-Hee Kang, and Richard J. Johnson, M.D. NEJM 2008

Proposed Mechanism for Uric Acid Mediated Hypertension

Feig et al, NEJM 2008,358:1811-1821

Ugtwo "Wtke"Cekf "Rtgf kevu"J { r gtvgpukqpStudy Population RelativeRisk

IsraeliHeartStudy(Khan,1972) 10,000males 2‐ foldriskat5YRS

KaiserPermanente(Selby,1990) 2,062subjects 2‐foldriskat6YRS

UnivofUtah(Hunt,1991) 1482adults 2‐foldriskat7YRS

OlivettiHeartStudy(Jossa,1994) 619males 2‐foldriskat12YRS

CARDIAstudy(Dyer,1999) 5115adults 2‐foldriskat10YRS

OsakaHealthSurvey(Taniguchi,2001) 6,356males 2‐foldriskat10YRS

Hawaii‐LosAngeles‐HiroshimaStudy(Imazu,2001) 140males 3.5‐foldriskat15YR

OsakaFactoryStudy(Masuo,2003) 433males 1.0mg/dlUApredicts_27mmHgat5YR

OsakaHealthSurvey(Nakanishi,2003) 2310males 1.6‐ foldriskat6YRS

Okinawa(Nagahama,2004) 4489adults 1.7‐foldriskat13YRSBogalusaHeart(Alper,2005) 679children Increasedriskat11yearsFramingham(Sündstrom,2005) 3329adults 1.6‐foldat4yesrsNormativeAgingStudy(Perlstein,2006) 2062males 1.5‐foldat21YRS

MRFIT(Krishnan,2007) 3073men 1.8‐foldat6YRS

ARIC(Mellen,2006) 9,104adults 1.5‐foldat9YRS

NurseHealthStudy(Forman,2009) 1500women 1.89foldat5years

HealthProfessionalFollowup(Forman,2007) 750men 1.08‐foldat8YRS*(Notsignificant)

The overall risk for incident hypertension increased 13% per 1 mg/dl increase in serum uric acid level

Uric Acid Level and Elevated Blood Pressure in US Adolescents (NHANES, 1999–2006)

Lauren F. Loeffler. Hypertension. 2012; 59:811-817.

Serum Uric Acid in Adolescents with Hypertension

•  125 consecutive referrals involved with

hypertension •  After hypertension work-up the diagnosis

were; •  Primary hypertension: 50% (n=63) •  Secondary hypertension: 32% (n=40) • White-coat hypertension: 18% (n=22)

Feig and Johnson. Hypertension (2003) Feig and Johnson, Hypertension 42:247-252, 2003

1

9

8

7

6

5

4

3

2 Seru

m U

ric A

cid

(mg/

dl)

Primary Hypertension

N=63 Mean = 6.7mg/dl

Secondary Hypertension

N=39 Mean = 4.3 mg/dl

White Coat Hypertension

N=22 Mean = 3.5 mg/dl

Controls

N=41 Mean = 3.6mg/dl

Serum Uric Acid in Adolescents with Hypertension

Feig and Johnson, Hypertension 42:247-252, 2003

6.7

4.3 3.5 3.6

Age 15.1±2.1 yrs % Male 60% Weight 97±23 kg BMI 33±6.5 kg/m2

Race White 46% Hispanic 23% African American 31%

Uric Acid 6.9±1.2mg/dL Feig et al, JAMA 2008 Aug 27;300(8):924-32

Effect of allopurinol vs placebo in newly diagnosed hypertension in adolescents.

A Randomized, double-blind, placebo-controlled, crossover trial

Lowering Uric Acid Reduces SBP in Adolescents with Hypertension

In Subjects whose Uric acid was reduced to < 5 mg/dl, 86% (19/22) became normotensive versus 3% (1/30) controls

Risk of cardiovascular events for hyperuricemia

Gagliardi AC et al, Atherosclerosis 2009; 202:11-17

Letho et al

Hoieggen et al(LIFE)

Hozawa et al (ARIC)

Bos et al (Rotterdam)

1.93 (1.30-2.86)

0.91 (0.83-0.99)

1.22 (1.11-1.35)

1.17 (1.06-1.28) 1.00 (0.99-1.01) 1.49 (1.00-2.23) (stroke,no diuréticos)

1.68 (1.24-2.23) 1.11 (1.08-1.115)

RR (IC 95%)

Krishan et al

Fang et al (NHANES I) Alderman et al Culleton et al

3 1 0.1 Risk Ratio

Strasak et al (Austriaco) 1.51 (1.03-2.22)

Copyright ©2000 American Heart Association

Verdecchia, P. et al. Hypertension 2000;36:1072-1078

With multivariate Cox regression, age- and cholesterol-adjusted 4-year risk of CV disease was standardized to different levels of

significant explanatory variables in either gender

Is High Serum UA a Risk Marker or a Target for Treatment? Independent Effect in a Large Cohort With Low CV Risk 484,568 adults (mean age: 41 years) participating in a medical screening program in Taiwan since 1994 were followed up for a median of 8.5 years

Chi Pang Wen, AJKD, 56, 2, 273-288, 2010

Uric Acid and Renal Disease

Efectos de hiperuricemia sobre el riñón Modelos experimentales

 Vasoconstricción cortical  Arteriolopatía aferente  Hipertensión glomerular  Infiltración macrófagos y linfocitos T  Fibrosis intersticial

Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats

L.G.Sanchez Lozada. Kidney International (2005) 67, 237–247

Sanchez-Lozada et al, Kidney Int 2005, 67:237-247

Hiperuricemia y arteriolopatía aferente Ácido oxónico Alopurinol

5/6 nefrectomizadas

Copyright ©2002 American Society of Nephrology Kang, D.-H. et al. J Am Soc Nephrol 2002;13:2888-2897

Changes in serum uric acid and BP in the remnant kidney (RK), remnant kidney + oxonic acid (RK+OA; ), remnant kidney + oxonic acid + allopurinol (RK+OA+AP);

and remnant kidney + oxonic acid + benziodarone (RK+OA+BZ; rats

Copyright ©2002 American Society of Nephrology

Kang, D.-H. et al. J Am Soc Nephrol 2002;13:2888-2897

Changes in proteinuria in the RK, RK+OA; RK+OA+AP), and RK+OA+BZ rats

Copyright ©2002 American Society of Nephrology

Kang, D.-H. et al. J Am Soc Nephrol 2002;13:2888-2897

Correlation of serum uric acid with renin expression in renal cortex

Copyright ©2002 American Society of Nephrology Kang, D.-H. et al. J Am Soc Nephrol 2002;13:2888-2897

Comparison of renal scarring

An association between uric acid levels and renal arteriolopathy in CKD: a biopsy-based study

OR IC (95%) P Hyalinosis grade 3.13 1.23-7.94 0.02 Thickening wall grade 2.66 1.11-6.38 0.03

Hyperuricemia (UA > 7 mg/dl)

167 CKD patients

Kohagura K et al, Hypertens Res 2012, sep 6 (on line)

Adjusted for age, sex, hypertension , diabetes mellitus, eGFR

Association of Uric Acid with Change in Kidney Function in 900 Healthy Normotensive Individuals

Bellomo G. AJKD, Vol 56, 2 : 264-272, 2010

Richard J. Johnson. NDT Advance Access published March 29, 2013

Uric Acid and Risk of CKD

Feig et al, Curr Opin Nephrol Hypertens 18: 526-530,2009

Serum uric acid is a GFR-independent long-term predictor of acute and CKD: the Jerusalem Lipid Research Clinic cohort study 2449 participants with normal renal function (1470 men, 979 women aged 35–78 years ; FU:25 years)

Iddo Z. Ben-Dov. Nephrol Dial Transplant 26: 2558–2566 (2011)

Uric Acid levels and fall of GFR in type 1 diabetic patients

Rosolowsky et al, cJASN 2008, 3:706-713

Type 1 DM 364 NA 311 MA

Serum Uric Acid as a Predictor for Development of Nephropathy in Type 1 Diabetes

Hovind et al, Diabetes 2009, 1668-1671

277 patients

LA HIPERURICEMIA PREDICE LA PROGRESIÓN DE ERC EN PACIENTES CON DISMINUCIÓN DE LA MASA RENAL FUNCIONANTE. MONORRENOS N=337; Edad 59±17 años; Seguimiento : 60 ( 36-98 meses)

Adjusted HRs for all-cause mortality per 1 mg/dl greater uric acid level in all subjects stratified by presence or absence of DM, CVD, HTN, and gout n=(3303 stages 3–5 CKD patients . FU: 2.8 years)

Wan-Chun Liu. Clin J Am Soc Nephrol 7: 541–548, 2012

Uric Acid Levels and All-Cause and CV Mortality in 4637 hemodialysis patients (DOPPS Study)

Walead Latif. Clin J Am Soc Nephrol 6: 2470–2477, 2011

Uric Acid Levels during the first six months post RT and renal graft survival

212 patients Living Renal Transplants

FU:68±27 months

Haririan et al, Transplantation 2010, 89 (5) 573

Uric Acid levels and Cardiovascular Risk after Renal Transplantation

0

5

10

15

20

hiperuricemia normouricemia

CV Events

Bandukwala et al, Am J Cardiol 2009, 103: 867-871

405 patients

36

P=0,007

Niveles de ácido úrico en pacientes con ERC

Hombres (n=228) Mujeres (n=172)

Goicoechea M, Garcia de Vinuesa S, Arroyo D, Luño J. Nefrología 2012, supl , 3:12-15

45 % de los hombres tienen hiperuricemia y un 11% de ellos están tratados con alopurinol

51 % de las mujeres tienen hiperuricemia y un 9% de ellas están tratados con alopurinol

A pesar del tratamiento con alopurinol,

un gran porcentaje de pacientes con ERC

presentan hiperuricemia.

ADENURIC® (Febuxostat): una nueva opción terapéutica

para la hiperuricemia en el tratamiento de la gota

Clinical interventional studies

Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis

H. Wang. J . Ren Nutr 2012 Nov 3.

Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis

H. Wang. J . Ren Nutr 2012 Nov 3

H. Wang. J . Ren Nutr 2012 Nov 3

Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis

Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis

H. Wang. J . Ren Nutr 2012 Nov 3.

A Randomized Study of Allopurinol on Endothelial Function and eGFR in Asymptomatic Hyperuricemic Subjects with Normal Renal Function

Kanbay M. Clin J Am Soc Nephrol 6: 1887–1894, August 2011

Reduction in SUA on Renal Outcomes During Losartan Treatment . Post Hoc Analysis of RENAAL Study

Risk reduction per 0.5 mg/dL SUA decrement: 6% (95%CI:13-10)

Month 6 change uric acid (mg/dL)

Yan Miao. Hypertension. July 2011;58:2-7

M.Goicoechea, S. García de Vinuesa, U. Verdalles, C. Ruiz-Caro, J. Ampuero, A.Rincón, MA. Dominguez1, D.

Arroyo, J. Luño.

Effect of allopurinol in chronic kidney disease (CKD) progression and cardiovascular risk.

Clin J Am Soc Nephrol 5: 1388-1393, 2010

Allopurinol and progression of CKD and CV risk

•  Inclusion criteria: eGFR < 60 ml/min., stable clinical condition & renal function, baseline serum uric acid 7.6 mg/dl

• Randomised to – Allopurinol 100 mg/d (N= 57) or – Placebo (N= 56)

Effect of Allopurinol in UA levels, albuminuria and inflammatory parameters

Control Group

Uric Acid mg/dl (p=0.016

HsCRP mg/L (p=0.018)

Fibrinogen mg/dl

Albuminuria mg/day

Baseline 7.3±1.6 3.4 (5.2) 384±104 32(383)

6 months 7.0±1.6 3.0 (7.6) 373±112 43(417)

12 months 7.4±2.0 3.2 (10.8) 402±98 51(296)

24 months 7.5±1.7

Allopurinol Group

Uric Acid mg/dl

HsCRP mg/L

Fibrinogen mg/dl

Albuminuria mg/day

Baseline 7.8± 2.1 4.4 (4.5) 381±78 36(388)

6 months 6.2±1.5* 3.0 (4.0)* 367±58 15(103)

12 months 6.0±1.8* 3.0 (2.5)* 369±49 16(166)

24 months 6.0±1.2*

-4

-3

-2

-1

0

1

2

control group

allopurinol group

Effect of allopurinol on GFR changes (ml/min) at two years of FU

p=0.018

3.39±1.2

1.3±1.3

Cox Regression model : independent variable on renal disease progression

Adjusted for : age, gender, diabetes, uric acid levels, hs-CRP, RAS blockers use, CKD ethiology and albuminuria Progression : Decrease in GFR higher than 0,2 ml/min/1,73 m2/month

HR IC (95%) P Allopurinol treatment 0.53 0.28-0.99 0.048

Log rank=4.255 p=0.039

Effect of Allopurinol on CV events

22 CV events (15 patients on control group and 7 on the allopurinol group : 8 Heart failure; 7 CHD; 5 CVD; 1 PAD;1 Arrythmia.

Cox Regression Analysis . Risk of new Cardiovascular events

HR IC (95%) P Diabetes 4.38 1.59-12.09 0.004 Previous coronary heart disease

4.49 1.56-12.86 0.005

CRP (mg/L) 2.83 1.09-7.32 0.031

Allopurinol treatment 0.29 0.09-0.86 0.026

Adjusted for age, GFR changes and uric acid levels

ADVERSE EVENTS ALLOPURINOL WAS WITHDRAWN IN TWO PATIENTS FOR

GASTROINTESTINAL SYMPTOMS. NO ABNORMALITIES IN LIVER FUNCTION TEST WERE ATTRIBUTED TO ALLOPURINOL TREATMENT. NO HEMATOLOGIC ALTERATIONS OR SERIOUS ADVERSE EVENTS IN RELATION TO ALLOPURINOL TREATMENT APPEARED IN THE FOLLOW-UP STUDY. SIX PATIENTS IN THE CONTROL GROUP AND THREE IN THE ALLOPURINOL GROUP WERE LOST DURING THE STUDY PERIOD .

CONCLUSIONS

 We conclude that allopurinol treatment decreases inflammation and slows down the progression of renal disease in patients with moderate CKD.

  In addition, allopurinol reduces cardiovascular and hospitalization risk.

 These results have to be confirmed in larger prospective trials and are the basis for a hypothesis that still needs to be tested.

An initial reduction in serum UA during ARB treatment is associated with CV protection: a post-hoc analysis of the RENAAL trial Risk reduction per 0.5 mg/dL SUA decrement: 5.3% (95%CI:10.9-9.9)

Paul A. Smink, Journal of Hypertension 2012, 30:1022–1028

Effect of allopurinol on CV incidence among hypertensive nephropathy patients

H. Terawaki. Clinical Experimental Nephrology. On line November 2012

One hundred and seventy-eight patients diagnosed with hypertensive nephropathy and presenting with impaired kidney function (estimated glomerular filtration rate 45 mL/min/

1.73 m2) were recruited from nephrology clinics. Oral allopurinol was prescribed in 67 of these patients. The effects of allopurinol use on the development of cardiovascular disease (i.e.

ischemic heart disease, congestive heart failure, and stroke) and all-cause death was analyzed using the Cox proportional hazard model. During the follow-up of 18.4 months (mean), 28

primary events occurred. Basal use of allopurinol was a significant beneficial factor (hazard ratio = 0.342, p = 0.0434, standard error = 0.53058) after adjusting for confounding factors.

The use of allopurinol in hypertensive subjects with impaired kidney function appears to be beneficial in preventing cardiovascular morbidity and all-cause mortality,

indicating that this xanthine oxidase inhibitor protects the vascular system.

Is necessary to treat all patients with CKD And asymptomatic Hyperuricemia ?

Challenges of conducting a trial of uric-acid-lowering therapy in CKD Sunil V. Badve, Fiona Brown, Carmel M. Hawley, David W. Johnson, John Kanellis, Gopala K. Rangan and Vlado Perkovic. Nat. Rev. Nephrol. advance online publication 15 February 2011

An adequately powered randomized controlled trial is required to determine whether uric-acid-lowering therapy slows the progression of CKD. International collaboration is required to plan and conduct a large-scale multicenter trial in order to better inform clinical practice and public health policy about the optimal management of asymptomatic hyperuricemia in patients with CKD

HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency

Jae-Woo Jung. Nephrol Dial Transplant (2011) 26: 3567–3572

Allopurinol association of severe coutaneous adverse reactions

Jae-Woo Jung. Nephrol Dial Transplant (2011) 26: 3567–3572

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Rapid screening for the detection of HLA-B57 and HLA-B58 in prevention of drug hypersensitivity

L. Kostenko Tissue Antigens: 78: 1; 11–20, July 2011

HLA-B57 and HLA-B58 are major histocompatibility class (MHC)-I allotypes that are potentially predictive of important clinical immune phenotypes. HLA-B*5701 is strongly associated with hypersensitivity to the HIV drug abacavir, liver toxicity from the antibiotic flucloxacillin and is a marker for slow progression of HIV AIDS. HLA-B*5801 is associated with hypersensitivity to allopurinol used to treat hyperuricaemia and recurrent gout. Here we describe a monoclonal antibody (mAb) specific for HLA-B57 and HLA-B58 that provides an inexpensive and sensitive screen for these MHC-I allotypes. The usefulness of HLA-B57 screening for prediction of abacavir hypersensitivity was shown in three independent laboratories, including confirmation of the mAb sensitivity and specificity in a cohort of patients enrolled in the PREDICT-1 trial. Our data show that patients who test negative by mAb screening comprise 90%–95% of all individuals in most human populations and require no further human leukocyte antigen (HLA) typing. Patients who test positive by mAb screening should proceed to high-resolution typing to ascertain the presence of HLA-B*5701 or HLA-B*5801. Hence, mAb screening provides a low-cost alternative to high-resolution typing of all patients and lends itself to point-of-care diagnostics and rapid ascertainment of low-risk patients who can begin immediate therapy with abacavir, flucloxacillin or allopurinol.

Hyperuricemia and Risk of Renal Failure

Tomita et al, J Epidemiol 2000, 10:403-409

49,413 male railroad workers Average follow up: 5.4 years

Serum uric acid and chronic kidney disease: the Severance cohort study

Yejin Mok. Nephrol Dial Transplant (2012) 27: 1831–1835

Uric Acid and Mortality in stages 3-4 CKD Patients

Madero et al, AJKD 2009, 53:796-803

  20 of the 30 participants achieved normal BP during

the allopurinol phase, whereas only 1 of 30 achieved

normal BP during the placebo phase

  Of the 10 participants who remained hypertensive

while taking allopurinol, 7 had a uric acid level of 5.0

mg/dl or higher at the end of the allopurinol phase

Lowering Uric Acid Reduces SBP in Adolescents with Hypertension

Use of Allopurinol in Slowing the Progression of Renal Disease Siu YP. American Journal of Kidney Diseases. 47:1, 51-59 , 2006

54 CKD patients with mean uric acid 9.75 mg/dl were randomized to treatment with allopurinol 100–300 mg/day o usual care during 12 moths. Treated patients had a tendency to slower progression. There was no statistically significant difference in serum Cr as a continuous variable, but the study was not powered to detect this endpoint

GFR at baseline and after 12 weeks in the control (21) and allopurinol* (48) treated groups * (300 mg during 3 weeks)

Kanbay M. Int Urol Nephrol (2007) 39:1227–1233