Uric acid, Hypertension and Kidney Disease

Richard J Johnson, MD, University of Colorado

Dr Johnson has a laybook (Fat Switch, mercola.com) and patents and patent applications related to this work. He also has shares with XORT therapeutics.

Uric Acid

Uricase

Man and

Apes

Most

mammals

Mutation

Allantoin

A Mutation in Uric acid Metabolism occurred in

Humans

Gout, the Disease of Kings and King of Diseases

•Obesity 60-80%•Hypertension 50-60%•Metabolic Syndrome 70-80%•Chronic Kidney Disease 50-100%•Cardiovascular Disease in 90%

Gout, a High Uric acid Condition, is Associated

with the Metabolic Syndrome

Study Population F/U Independent Year Author Israeli Heart Study 10,000 males 5 YRS Not done 1972 KahnKaiser Permanente 2,062 subjects 6 YRS Yes 1990 SelbyUniv of Utah 1482 adults 7 YRS Yes 1991 HuntOlivetti Heart Study 619 males 12 YRS Yes 1994 JossaCARDIA study 5,115 adults 10 YRS Yes 1999 DyerOsaka Health Survey 6,356 males 10 YRS Yes 2001 TaniguchiHawaii-Los Angeles-Hiroshima 140 males 15 YRS Yes 2001 ImazuOsaka Factory Study 433 males 5 YRS Yes 2003 MasuoOsaka Health Survey 2310 males 6 YRS Yes 2003 NaganishiOkinawa 4,489 adults 13YRS Yes 2004 NagahamaBogalusa Heart 679 children 11 YRS Yes 2005 AlperFramingham 3,329 adults 4 YRS Yes 2005 SundstromNormative Aging Study 2062 males 21 YRS Yes 2006 PerlsteinARIC 9,104 adults 9 YRS Yes 2006 MellenBeaver Dam 2,520 adults 10 YRS Yes 2006 ShankarMRFIT 3,073 men 6 YRS Yes 2007 KrishnanHealth Professional Followup 750 men 18 YRS No 2007 FormanNurse Health Study 1,500 women 5 YRS Yes 2009 FormanChina 7,220 adults 4 YRS Yes 2009 Zhang

18 of 19 studies found Uric Acid to Independently Predict the Development of Hypertension

Elevated Serum Uric acid Predicts

Hypertension

Normal Rat

Uric Acid (0.5-1.4 mg/dl)

Hyperuricemic Rat

Uric Acid (2.0-3.0 mg/dl)

Uricase inhibitor

Oxonic acid (OA)

A Model of Chronic Hyperuricemia

Sy

sto

lic

BP

(m

m H

g)

Time (weeks))

**

****

**

* LSD = 0.125% NaCl, ** p<0.05

Mazzali M et al Hypertension 2001; 38:1101-1106

An Elevated Uric acid Increases Blood Pressure

in the Rat

Hypertension 2003; 41: 1287-93 Kidney Int 2005; 267: 1739-42 Am J Physiol 2002;282: F991-7, J Hypertens 2010; 28: 1234-42

Oxidants

Nitric Oxide

Uric Acid Control Inflammation (MCP-1)

Angiotensin II

Cellular Effects of Uric acid

1

9

8

7

6

5

4

3

2

Seru

m U

ric

Aci

d (

mg/d

l)

PrimaryHypertension

N=64Mean = 6.7mg/dl

SecondaryHypertension

N=39Mean = 4.3 mg/dl

White CoatHypertension

N=22Mean = 3.5 mg/dl

Controls

N=41Mean = 3.6mg/dl

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

Serum Uric acid in Adolescents with

Hypertension

Systolic BP

(mm Hg)

Serum Uric Acid (mg/dl)

Sy

sto

lic

Blo

od

Pre

ss

ure

(m

m/H

g)

60

80

100

120

140

160

180

1 2 3 4 5 6 7 8 9 10

Uric Acid (mg/dl)

R= 0.80

Feig and Johnson

Hypertension 2003;

42:247-252

Serum Uric acid Correlates with Blood Pressure

in Adolescents

In Subjects whose Uric acid was reduced to < 5 mg/dl, 86%

(19/22) became normotensive versus 3% (1/30) controls

Feig et al, JAMA 2008 Aug 27;300(8):924-32

•Double-blind placebo controlled•Cross-over•30 Hypertensive Adolescents•Baseline Uric Acid 6.9 mg/dl•Allopurinol or placebo

Lowering Uric acid Improves Blood Pressure in

Adolescents

Randomized trial of 60 obese prehypertensiveadolescents, treated for 2 months to determine effect on blood pressure

Randomized Trial in Obese Prehypertensive

Adolescents

Soletsky and Feig. Hypertension 2012; 60: 1148-1156.

Soletsky and Feig. Hypertension 2012; 60: 1148-1156.

Randomized Trial in Obese Prehypertensive

Adolescents

Higgins et al, Heart 2014

Randomized Trial in Elderly Subjects following a

Transient Ischemic Attack (TIA)

6.6

00

1

2

3

4

5

6

7

1 2

Ch

an

g i

n C

en

tra

l B

P

(mm

Hg

)

Allopurinol Placebo

Study (year) Population F/U Type Indep? Author, YearJapan 6,403 adults 2 YRS CKD Yes Iseki, 2001Japan 48,177 adults 10 YRS ESRD Women Iseki, 2004Thailand 3,499 adults 12YRS CKD Yes Domrongkitchaiporn, 2005USA 5,808 adults 5 YRS CKD No Chonchol, 2007Austria 21,457 adults 7YRS CKD Yes Obermayr, 2008USA 13,338 adults 8.5YRS CKD Yes Weiner, 2008Austria 17,375 adults 7 YRS CKD Yes Obermayr, 2008USA 177,500 adults 25 YRS ESRD Yes Hsu, 2009USA 355 type 1 diabetes* 6 YRS CKD Yes Ficociello, 2010Italy 900 adults 5 YRS CKD Yes Bellomo, 2010Japan 7,078 adults 5YRS CKD Yes Sonoda, 2011Taiwan 94,422 adults 3.5 YRS CKD Men Wang, 2011Israel 2449 adults 26 YRS ESRD Yes Ben-Dov, 2011Korea 14,939 adults 10.2YRS CKD Yes Mok, 2012Italy 1,449 type 2 diabetics 5YRS CKD Yes Zoppini, 2012

Uric Acid Predicts Chronic Kidney Disease

14 of 15 studies found Uric Acid to Independently Predict the Development of CKD or ESRD

Study (year) Population F/U Type Indep? Author, YearDenmark 263 type 1 18 YRS Albuminuria Yes Hovind, 2009USA 324 type 1 6 YRS Micro/Albuminuria Yes Jalal, 2011

Uric Acid Predicts Diabetic Nephropathy

Elevated Uric Acid Predicts Progression in IgA

Nephropathy

15614413212010896847260483624120

m o n th s a fte r re n a l b io p s y

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Cum

Sur

viva

l

hype rurice mia

normourice mia

P <0.001353 patients

Followup > 5yrs

Shi et al Kidney Blood Pressure 2012

0

1

2

3

4

Uric a

cid

mg/d

L

* *

Pgc m

mH

g40

45

50

55

60

Uric Acid Glomerular Pgc

Sánchez-Lozada LG, et al. Am J Physiol Renal 2002; 283:F1105

Control UA UA+Allop

Hyperuricemia Causes Glomerular Hypertension in Rats

* *

Control UA UA+Allop

Role of Uric acid in Renal Progression

Remnant Kidney Model

Groups:

•Sham

•Remnant Kidney (RK)

•RK + Hyperuricemia (RK-OA) (induced by the uricase inhibitor, oxonic acid)

•RK –OA and Allopurinol (RK-OA-AP)

Kang et al, JASN 2002; 13:2888-97

Role of Uric acid in Renal Progression

Kang et al, JASN 2002; 13:2888-97

Systolic BP

Proteinuria Glomerulosclerosis

Serum Creatinine (mg/dl)

Siu YP et al, Am J Kid Dis, 2006

51 patients, 1 yr,

asymptomatic, uric

acid >7.5 mg/dl

and creat >1.5

mg/dl

Lowering Uric acid Slows Renal Progression in Hyperuricemic Individuals

% with 40% increase in creatinine

A 16 pound weight gain occurred in 74 subjects with a

baseline UA of 5.5 mg/dl

A 4 pound weight gain occurred in the 359 subjects with a

mean uric acid of 4.0 mg/dl

433 normal weight (BMI <25), young (age <50 yrs),

normotensive Japanese men followed for 5 yrs

Masuo et al , Hypertension 2003; 42:474-80

Elevated Serum Uric acid Predicts Obesity

Study Population F/U Indep? RR (C.I.) Author, YearIsrael 10,000 men 5 YRS Yes 1.35 ` Medalie 1975 and Herman 1976USA 5,209 adults 26 YRS Men 2.3 (men), 2.1 (women) Brand, 1985Nauru 266 adults 6 YRS Women Not given Balkau, 1985Sweden 766 men 13.5 YRS Yes 5.8 (2.2 - 16.0) Ohlson, 1988 Britain 7,735 men 12.8 YRS Yes 1.5 (0.9-2.5) Perry, 1995Kinmen 654 high risk 3 YRS Yes 1.7 (1.2-2.6) Chou, 1998Mauritius 2,605 adults 5 YRS Yes 1.37 (1.20-1.57) Boyko, 2000Japan 6,356 men 9 YRS No 1.24 (0.9-1.7) Taniguchi, 2001Germany 6,166 adults 3-14YRS Women 1.6 (1.34-1.91) Meisinger, 2002 USA 9,020 adults 11 YRS Yes 1.3 (1.2-1.4) Carnethon, 2003 Japan 2,310 men 6 YRS Yes 1.78 (1.11-2.85) Nakanishi, 2003China 641 adults 7 YRS Women 1.44 (1.13-2.25) Lin, 2004USA 60 adults with MI 6 MOS Yes 5.47 (1.6-17.7) Nakagawa, 2005Finland 522 adults 4.1 YRS Yes 1.87 (1.07-3.26) Niskanen, 2006Netherlands 4,536 adults 10 YRS Yes 1.68 (1.22-1.30) Dehgan, 2008Mauritius 4,259 adults 5 YRS Men 1.37 (1.11-1.68) Nan, 2008China 2,609 adults 9 YRS Yes 1.4 (1.02-1.92) Chien, 2008USA 9,689 adults 5.7 YRS Yes 1.6 (1.3-1.9) Sui, 2008USA 566 adults 13 YRS Yes 1.75 (1.1-2.9) Kramer, 2009USA 9,175 adults 26-28 YRS Yes 1.71 (1.24-2.36) Bhole, 2010Korea 4,779 men 3 YRS Yes 1.41 (1.08-1.84) Ryu, 2011Japan 12,643 adults 5 YRS Women Yamada, 2011China 924 adults 3.5 YRS Yes 2.45 (men),and 1.39 (women) Wang, 2011Italy 758 hypertensive adults 3 YRS Yes 2.78 (1.35-5.70) Viazzi, 2011

23 of 24 studies found Uric Acid to Independently Predict the Development of Diabetes or Insulin Resistance

Johnson et al Diabetes 2013

Elevated Serum Uric acid Predicts Diabetes

Ishimoto T, PNAS 2012; 109:4320-5

*

Control Mouse

Fructose-fed Mouse

Role of Fructose in Obesity and Diabetes

Fructose Depletes ATP

Fructose

Fructose-1-P

Glycogen

Triglycerides

Glucose

ATP

AMP Uric acid

AMPDFructokinase

Fructose Increases Serum Uric acid

Serum Uric acid

0

0.5

1

1.5

2

Control Fr Fr + AP

mg/d

l

P<0.05 P<0.01

Nakagawa et al, Am J Physiol 2006; 290:F625-631

100

110

120

130

140

150

160

0 4 8 Weeks

Systo

lic B

P (

mm

Hg)

Control

Fr

Fr + AP #

*

Allopurinol

Blood Pressure

#

Fructose-Induced Hypertension is Uric acid

Dependent

Fasting insulin

0

500

1000

1500

2000

2500

Control Fructose Fruc + AP

pg/m

l

P<0.01 P<0.05

Nakagawa et al, Am J Physiol 2006; 290:F625-631

0

100

200

300

Control Fructose Fruc + AP

mg/d

l

#

Triglyceride

Allopurinol Improves Fructose Induced

Metabolic Syndrome

Uric AcidControl

Lanaspa MA and Kang DH, J Biol Chem 2012; 287:40732-44

Uric acid stimulates Fat Accumulation in Liver

Cells

The Rise of Sugar

Sugar intake per

year

1700 4 lbs

1800 18 lbs

1900 90 lbs

2000 155 lbs

Johnson et al Am J Clin Nutr 86:899-906, 2007

0

1

2

3

4

5

6

7

1920 1950 1960 1970 1980

3.5

5 5.5

6 6.5

Uric acid (mg/dl)

Obesity and Serum Uric acid are Rising in

Parallel in the USA

• Serum Uric acid may have a role in Hypertension, especially adolescents

• Pilot Studies suggest Uric acid may have a role in Chronic Kidney Disease

• Intriguing studies suggest uric acid may also have a contributory role of obesity and diabetes

Conclusions

And to all of my collaborators, past and present

Special Thanks

Taka Nakagawa

Duk-Hee Kang

Marilda Mazzali

Dan Feig

Gaby Sanchez-Lozada