Fructose, Uric Acid and Hypertension in Children and Adolescents

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1 Fructose, Uric Acid and Hypertension in Children and Adolescents Daniel I. Feig, MD, PhD, MS Director, Division of Nephrology Department of Pediatrics University of Alabama, Birmingham

2 Topics for Discussion The Obesity Epidemic The Sugar Primer Fructose Biochemical Considerations Animal models Human studies Uric Acid/Hypertension Hypothesis What can we do?

3 The Obesity Epidemic 2017 Estimates 2.7 billion overweight 720 million obese

4 Sugar and Obesity Men Women Sugar Tax WW 2 WW 1 HFCS Mean Annual Individual Sugar Intake kg kg kg kg kg Johnson, et al. Am J Clin Nutrit. 2007; 86:

5 What is Fructose? Table sugar (Sucrose) is a disaccharide of glucose and fructose. Naturally occurring fructose is found in honey, fruits and vegetables. High fructose corn syrup most commonly contains 55% fructose and 45% glucose. Adolescents consume 72.8 grams per day.

6 Fructose Metabolism Increases Uric Acid Triglycerides

7 Health Risks of SSBs Health Professionals F/U: top quartile of SSB intake had 20% increased risk of coronary disease De Koning et al. Circulation 2012; 123:1735 Meta-analysis of data from 94 countries: each % point increase of caloric intake from sugar associated with 5% increase in T2DM risk Siegel et al. Diabetes Res Clin Pract 2012; 96:76 Quebec Adiposity and Lifestyle In Youth: 100mL/d increase in SSB associated with insulin resistance and weight increase Wang et al. Pediatr Obesity 2012; 8:284

8 Proposed Mechanisms IMPAIRED SATIETY: animal models suggest fructose consumption suppresses leptin release disruption hypothalamic control of hunger and energy metabolism Melanson et al. Am J Clin Nutr. 2008; 88:1738S HIBERNATION METABOLISM: animal and human studies suggest >25% caloric intake from fructose results in decreased energy expenditure and fatty acid oxidation Stanhope et al. J Clin Invest. 2009; 119:1322 HYPERURICEMIA: dysregulated fructose metabolism results in purine release and uric acid production. Uric acid acts as a vascular toxin causing hypertension and organ damage Feig et al. New Engl J Med. 2008; 359:1811

9 It s the Quantity not the Source Gm sugar per 6oz serving

10 Soft Drinks and Hyperuricemia 1-2 servings per day increases sua by 1mg/dL Wong, et al. Arthritis and Rheumatism. 2008; 59 (1):

11 Effect of Fructose (200 g/d) for 2 weeks on Metabolic syndrome in Men: Menorca Study Baseline After 2wks Metabolic Syndrome (%) 19% 28% P Value Triglycerides 136 ± ±20 <0.001 HDL Cholesterol 46.5 ± ±0.7 <0.001 Insulin resistance (HOMA) 1.7 ± ±0.2 <0.005 Weight (kg) 84.3 ± ± BMI (kg/m2) 29.0 ± ± hr Systolic BP (mm Hg) 126±2 133±2 < hr Diastolic BP (mm Hg) 75 ± 2 81±3 <0.001 Uric acid (mg/dl) 5.2 ± ±0.8 <0.001 Perez-Pozo et al. Int J Obes. 2010; 34:454-61

12 Fructose withdrawal may be helpful 28 patients with CKD II-III, low sweetener diet for 6wks then resume normal diet for 6 more weeks. Brymora et al. NDT, 2011

13 Fructose Summary Acute Fructose Loading Causes Weight gain Increased serum uric acid Onset of metabolic syndrome Increase in BP Increase TG Fructose reduction may reverse symptoms

14 Age-Adjusted CV Mortality Rates by Serum Uric Acid Quartile NHANES Fang, J. et al. JAMA 2000;283:

15 Rat Model of Hyperuricemia Uricase inhibitor Oxonic acid (OA) Normal Rat Uric Acid ( mg/dl) Hyperuricemic Rat Uric Acid ( mg/dl)

16 Hyperuricemia Induces Hypertension Watanabe S et al., Hypertension 2002; 40:

17 Vascular model of Uric Acid Mediated Hypertension Phase 1: Reversible Vasoconstriction Uric Acid Increased renin Decreased NO Remains uric acid dependent Sodium resistant Phase 2: Arteriolar Wall Thickening Uric Acid Vascular smooth muscle proliferation mediated by PDGF and MCP-1 Becomes uric acid independent Sodium sensitive

18 Uric acid and Vascular Compliance Framingham Cohort Mehta et al. Am J Hypertens. 2015; 28:877

19 Hyperuricemia in Patients

20 Serum Uric Acid in Children with Hypertension Feig and Johnson. Hypertension. 2003; 42;

21 Allopurinol for the Treatment of Hypertension in Adolescents Feig, et al. JAMA. 2008; 300:

22 Effect of Allopurinol on Blood Pressure Feig et al., JAMA 2008; 300(8):924-32

23 Screen and Randomize PHOA Trial: Prevention of Hypertension in Obese Adolescents 60 Adolescents BMI >30kg/m2 Pre-hypertension Uric acid >5mg/dL No current meds Never Rx d for HTN 20 Adolescents, 2 mo Placebo 20 Adolescents, 2 mo Probenecid 1 mo f/u 1 mo f/u 20 Adolescents, 2 mo Allopurinol 1 mo f/u Soletsky and Feig. Hypertension. 2012; 60:

24 Uric Acid Reduction in Prehypertensive Adolescents: Allopurinol vs. Probenecid End Point Placebo Allopurinol Probenecid Serum Uric Acid (mg/dl) Change from baseline (0.0005) (0.0026) 24hr Systolic BP (mmhg) Change from baseline (0.0008) (0.0002) 24hr Diastolic BP (mmhg) Change from baseline (0.0009) (0.0006) Weight (kg) Change from baseline (0.039) (0.03) Soletsky and Feig. Hypertension. 2012; 60:

25 Urate Lowering Therapy With ACEi in Children Assadi et al. J Nephrol 2014; 27:51 52 hypertensive adolescents Mean uric acid 6.6mg/dL Randomized to enalapril vs +allopurinol 8wks therapy ABPM is endpoint

26 Counter Evidence BP Urate Lowering Therapy Forman et al. CJASN 2017; 12: patients, mean age 41 Mean sua 6.1mg/dL Mean BP: Casual 119/77, Control 119/77 ABPM 127/74, Control 121/58 No change in BP with UrLT Differences Older population Completely normotensive 79/150 had BP data (53%) Less Hyperuricemic Most smokers

27 Febuxostat in Adults with CKD Gunawardhana et al. JAHA 2017; 6:e adults Mean age 53 Mixed renal function Normal: 37% CKD 1-2: 52% CKD 3-4: 11% Hypertensive 100% No Meds: 28% 1 Med: 62% 2 Meds: 9% No change in BP in whole population In Patients with Normal Renal Function, mean decrease of SBP of 6.6mmHg

28 Influence of UrA on CKD Progression in Young Patients CKID Cohort Rodenbach et al., AJKD 2015;66:984

29 Summary of Human Data Uric acid correlates with the development of essential hypertension in children Uric acid lowering therapy, regardless of mechanism lowers blood pressure in hypertensive and prehypertensive adolescents Hypertensive effect appear more pronounced in young Age, lack of hypertension, severity of CKD attenuate the BP response to uric acid reduction Hyperuricemia associated with impaired vascular compliance, consistent with mechanistic studies Hyperuricemia is associated with progressive decline in GFR

30 Conclusions Sweetener consumption parallels the obesity, metabolic syndrome and CV disease epidemic Fructose mediates some of its effects through uric acid which causes vasoconstriction and vasculopathy Uric acid mediates hypertension in young patients Markedly attenuated response in older patients First line therapy should be dietary fructose reduction Management of hyperuricemia holds promise as additive therapy and in prevention but needs more study

31 The End