Мочевая кислота, артериальная гипертензия и заболевания почек.2014 [ENG] Оригинал презентации : http://www.theisn.org/education/education-topics/hypertension/item/1728-uric-acid-hypertension-kidney-disease

1. 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.

2. Uric Acid
Uricase
Man and
Apes
Most
mammals
Mutation
Allantoin
A Mutation in Uric acid Metabolism occurred in
Humans

3. Gout, the Disease of Kings and King of
Diseases

4. •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

5. Study Population F/U Independent Year Author
Israeli Heart Study 10,000 males 5 YRS Not done 1972 Kahn
Kaiser Permanente 2,062 subjects 6 YRS Yes 1990 Selby
Univ of Utah 1482 adults 7 YRS Yes 1991 Hunt
Olivetti Heart Study 619 males 12 YRS Yes 1994 Jossa
CARDIA study 5,115 adults 10 YRS Yes 1999 Dyer
Osaka Health Survey 6,356 males 10 YRS Yes 2001 Taniguchi
Hawaii-Los Angeles-Hiroshima 140 males 15 YRS Yes 2001 Imazu
Osaka Factory Study 433 males 5 YRS Yes 2003 Masuo
Osaka Health Survey 2310 males 6 YRS Yes 2003 Naganishi
Okinawa 4,489 adults 13YRS Yes 2004 Nagahama
Bogalusa Heart 679 children 11 YRS Yes 2005 Alper
Framingham 3,329 adults 4 YRS Yes 2005 Sundstrom
Normative Aging Study 2062 males 21 YRS Yes 2006 Perlstein
ARIC 9,104 adults 9 YRS Yes 2006 Mellen
Beaver Dam 2,520 adults 10 YRS Yes 2006 Shankar
MRFIT 3,073 men 6 YRS Yes 2007 Krishnan
Health Professional Followup 750 men 18 YRS No 2007 Forman
Nurse Health Study 1,500 women 5 YRS Yes 2009 Forman
China 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

6. 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

7. SystolicBP(mmHg)
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

8. 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

9. 1
9
8
7
6
5
4
3
2
SerumUricAcid(mg/dl)
Primary
Hypertension
N=64
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
Feig and Johnson, Hypertension 42:247-252, 2003
Serum Uric acid in Adolescents with
Hypertension

10. Systolic
BP
(mm Hg)
Serum Uric Acid (mg/dl)
SystolicBloodPressure(mm/Hg)
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

11. 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

12. Randomized trial
of 60 obese
prehypertensive
adolescents,
treated for 2
months to
determine effect
on blood pressure
Randomized Trial in Obese Prehypertensive
Adolescents
Soletsky and Feig. Hypertension 2012; 60: 1148-1156.

13. Soletsky and Feig. Hypertension 2012; 60: 1148-1156.
Randomized Trial in Obese Prehypertensive
Adolescents

14. Higgins et al, Heart 2014
Randomized Trial in Elderly Subjects following a
Transient Ischemic Attack (TIA)
6.6
0
0
1
2
3
4
5
6
7
1 2
ChanginCentralBP
(mmHg)
Allopurinol Placebo

15. Study (year) Population F/U Type Indep? Author, Year
Japan 6,403 adults 2 YRS CKD Yes Iseki, 2001
Japan 48,177 adults 10 YRS ESRD Women Iseki, 2004
Thailand 3,499 adults 12YRS CKD Yes Domrongkitchaiporn, 2005
USA 5,808 adults 5 YRS CKD No Chonchol, 2007
Austria 21,457 adults 7YRS CKD Yes Obermayr, 2008
USA 13,338 adults 8.5YRS CKD Yes Weiner, 2008
Austria 17,375 adults 7 YRS CKD Yes Obermayr, 2008
USA 177,500 adults 25 YRS ESRD Yes Hsu, 2009
USA 355 type 1 diabetes* 6 YRS CKD Yes Ficociello, 2010
Italy 900 adults 5 YRS CKD Yes Bellomo, 2010
Japan 7,078 adults 5YRS CKD Yes Sonoda, 2011
Taiwan 94,422 adults 3.5 YRS CKD Men Wang, 2011
Israel 2449 adults 26 YRS ESRD Yes Ben-Dov, 2011
Korea 14,939 adults 10.2YRS CKD Yes Mok, 2012
Italy 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, Year
Denmark 263 type 1 18 YRS Albuminuria Yes Hovind, 2009
USA 324 type 1 6 YRS Micro/Albuminuria Yes Jalal, 2011
Uric Acid Predicts Diabetic Nephropathy

16. 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
CumSurvival
hype rurice mia
normourice mia
P <0.001
353 patients
Followup > 5yrs
Shi et al Kidney Blood Pressure 2012

17. 0
1
2
3
4
Uricacidmg/dL
* *
PgcmmHg
40
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

18. 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

19. Role of Uric acid in Renal Progression
Kang et al, JASN 2002; 13:2888-97
Systolic BP
Proteinuria Glomerulosclerosis
Serum Creatinine (mg/dl)

20. 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

21. 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

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

23. Ishimoto T, PNAS 2012; 109:4320-5
*
Control Mouse
Fructose-fed Mouse
Role of Fructose in Obesity and Diabetes

24. Fructose Depletes ATP
Fructose
Fructose-1-P
Glycogen
Triglycerides
Glucose
ATP
AMP Uric acid
AMPD
Fructokinase
Fructose Increases Serum Uric acid

25. Serum Uric acid
0
0.5
1
1.5
2
Control Fr Fr + AP
mg/dl
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
SystolicBP(mmHg)
Control
Fr
Fr + AP #
*
Allopurinol
Blood Pressure
#
Fructose-Induced Hypertension is Uric acid
Dependent

26. Fasting insulin
0
500
1000
1500
2000
2500
Control Fructose Fruc + AP
pg/ml
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/dl
#
Triglyceride
Allopurinol Improves Fructose Induced
Metabolic Syndrome

27. Uric AcidControl
Lanaspa MA and Kang DH, J Biol Chem 2012; 287:40732-44
Uric acid stimulates Fat Accumulation in Liver
Cells

28. 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

29. 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

30. • 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

31. And to all of my collaborators, past and present
Special Thanks
Taka
Nakagawa
Duk-Hee
Kang
Marilda
Mazzali
Dan
Feig
Gaby Sanchez-
Lozada