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Uric Acid Metabolism and Tubular Sodium Handling: Title and subTitle BreakResults From a Population-Based Study FREE

Francesco P. Cappuccio, MD; Pasquale Strazzullo, MD; Eduardo Farinaro, MD; Maurizio Trevisan, MD
[+] Author Affiliations

Presented in part at the Fifth European Meeting on Hypertension, Milan, Italy, June 10, 1991, and at the 11th Congress of the European Association of Internal Medicine, Lisbon, Portugal, November 7, 1991.

Reprint requests to Blood Pressure Unit, Department of Medicine, St George's Hospital Medical School, Cranmer Terrace, London, England SW17 ORE (Dr Cappuccio).


JAMA. 1993;270(3):354-359. doi:10.1001/jama.1993.03510030078038
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Objective.  —To define the relationship, if any, between uric acid metabolism (serum and urinary levels) and proximal tubular sodium handling in a sample of general male population.

Design.  —Cross-sectional survey of a sample of the male working population conducted as part of a nationwide survey of the prevalence of cardiovascular risk factors.

Setting.  —The Olivetti factory in Pozzuoli, a suburb of Naples, Italy.

Participants.  —Five hundred sixty-eight untreated male workers aged 21 to 68 years (90.8% of those eligible).

Measurements.  —Anthropometry, blood pressure, blood tests, a detailed questionnaire, and urinary measurements on a fasting timed collection after a 300-mg lithium carbonate capsule was taken the night before the investigation.

Results.  —Serum uric acid level was inversely and significantly associated with the fractional excretion of lithium (r=-.22, P<.001), ie, the higher the serum uric acid level, the greater the amount of sodium reabsorbed at nephron sites proximal to the distal tubule. The association was graded and independent of possible confounders such as age, body mass, smoking, wine consumption, blood pressure, fractional excretion of sodium, and serum creatinine (R2=.34, P<.001).

Conclusions.  —High serum uric acid levels are independently associated with increased proximal tubular sodium reabsorption in men. This relationship suggests an altered tubular sodium handling and uric acid metabolism consistent with hyperinsulinemia, insulin resistance being the possible pathophysiological link.(JAMA. 1993;270:354-359)

REFERENCES

Breckenridge A.  Hypertension and hyperuricaemia. Lancet . 1966;;1:15-18.
Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH.  Hyperuricemia in primary and renal hypertension. N Engl J Med . 1966;;275: 457-464.
Gertler MM, Garn SM, Levine SA.  Serum uric acid in relation to age and physique in health and coronary heart disease. Ann Intern Med . 1951;;34: 1421-1431.
Tuomilehto J, Zimmet P, Wolfe E, et al.  Plasma uric acid level and its association with diabetes mellitus and some biological parameters in a biracial population of Fiji. Am J Epidemiol . 1985;;127: 321-336.
Modan M, Halkin H, Karasik A, Lusky A.  Elevated serum uric acid: a facet of hyperinsulinemia. Diabetologia . 1987;;30:713-718.
Strazzullo P, Cappuccio FP, Trevisan M, et al.  Red blood cell sodium-lithium countertransport, blood pressure and uric acid metabolism in untreated healthy men. Am J Hypertens . 1989;;2:634-636.
Facchini F, Chen Y-DI, Hollenbeck CB, Reaven GM.  Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA . 1991;;266:3008-3011.
Steele TH.  Control of uric acid excretion. N Engl J Med . 1971;;284:1193-1196.
Thomsen K.  Lithium clearance: a new method for determining proximal and distal tubular reabsorption of sodium and water. Nephron . 1984;;37: 217-223.
Strazzullo P, Iacoviello L, Iacone R, Giorgione N.  The use of fractional lithium clearance in clinical and epidemiological investigation: a methodological assessment. Clin Sci . 1988;;74:651-657.
Cappuccio FP, Strazzullo P, Mancini M.  Kidney stones and hypertension: population based study of an independent clinical association. BMJ . 1990;;300: 1234-1236.
Cappuccio FP, Strazzullo P, Giorgione N, et al.  Renal tubular sodium handling and plasma atrial natriuretic peptide, renin activity and aldosterone in untreated men under normal living conditions. Eur J Clin Invest . 1991;;21:40-46.
Shirley DG, Singer DRJ, Sagnella GA, et al.  Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man. Clin Sci . 1991;;81:59-63.
Dollery CT, Duncan H, Schumer B.  Hyperuricaemia related to treatment of hypertension. BMJ . 1960;;2:832-835.
Atherton JC, Green R, Hughes S, et al.  Lithium clearance in man: effects of dietary salt intake, acute changes in extracellular fluid volume, amiloride and frusemide. Clin Sci . 1987;;72:201-208.
Shirley DG, Yee-Yee H.  The influence of posture on renal tubular function in man. Am J Med Sci . 1990;;299:326-330.
Brand FN, McGee DL, Kannel WB, Stokes J III, Castelli WP.  Hyperuricemia as a risk factor of coronary heart disease: the Framingham Study. Am J Epidemiol . 1985;;121:11-18.
Zavaroni I, Bonora E, Pagliara M, et al.  Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med . 1989;;320:702-706.
Selby JV, Friedman GD, Quesenberry CP Jr.  Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol and other serum chemistries. Am J Epidemiol . 1990;;131:1017-1027.
Modan M, Halkin H, Almog S, Luski A, Eshkol A, Shefi M.  Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest . 1985;;75:809-817.
Ferrannini E, Buzzigoli G, Bonadonna R, et al.  Insulin resistance in essential hypertension. N Engl J Med . 1987;;317:350-357.
DeFronzo R.  The effect of insulin on renal sodium metabolism: a review with clinical implications. Diabetologia . 1981;;21:165-171.
Mahnensmith RL, Aronson PS.  The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res . 1985;;57:773-788.
Trevisan M, Laurenzi M.  Correlates of sodium-lithium countertransport: findings from the Gubbio Epidemiological Study. Circulation . 1991;;84:2011-2019.
Doria A, Fioretto P, Avogaro A, et al.  Insulin resistance is associated with high sodium-lithium countertransport in essential hypertension. Am J Physiol . 1991;;261:E684-E691.
Weder A.  Red cell lithium-sodium countertransport and renal lithium clearance in hypertension. N Engl J Med . 1986;;314:198-201.
Strazzullo P, Cappuccio FP, Trevisan M, et al.  Erythrocyte sodium/lithium countertransport and renal lithium clearance in a random sample of untreated middle-aged men. Clin Sci . 1989;;77:337-342.
Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG.  Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med . 1980;;93:817-821.

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Breckenridge A.  Hypertension and hyperuricaemia. Lancet . 1966;;1:15-18.
Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH.  Hyperuricemia in primary and renal hypertension. N Engl J Med . 1966;;275: 457-464.
Gertler MM, Garn SM, Levine SA.  Serum uric acid in relation to age and physique in health and coronary heart disease. Ann Intern Med . 1951;;34: 1421-1431.
Tuomilehto J, Zimmet P, Wolfe E, et al.  Plasma uric acid level and its association with diabetes mellitus and some biological parameters in a biracial population of Fiji. Am J Epidemiol . 1985;;127: 321-336.
Modan M, Halkin H, Karasik A, Lusky A.  Elevated serum uric acid: a facet of hyperinsulinemia. Diabetologia . 1987;;30:713-718.
Strazzullo P, Cappuccio FP, Trevisan M, et al.  Red blood cell sodium-lithium countertransport, blood pressure and uric acid metabolism in untreated healthy men. Am J Hypertens . 1989;;2:634-636.
Facchini F, Chen Y-DI, Hollenbeck CB, Reaven GM.  Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA . 1991;;266:3008-3011.
Steele TH.  Control of uric acid excretion. N Engl J Med . 1971;;284:1193-1196.
Thomsen K.  Lithium clearance: a new method for determining proximal and distal tubular reabsorption of sodium and water. Nephron . 1984;;37: 217-223.
Strazzullo P, Iacoviello L, Iacone R, Giorgione N.  The use of fractional lithium clearance in clinical and epidemiological investigation: a methodological assessment. Clin Sci . 1988;;74:651-657.
Cappuccio FP, Strazzullo P, Mancini M.  Kidney stones and hypertension: population based study of an independent clinical association. BMJ . 1990;;300: 1234-1236.
Cappuccio FP, Strazzullo P, Giorgione N, et al.  Renal tubular sodium handling and plasma atrial natriuretic peptide, renin activity and aldosterone in untreated men under normal living conditions. Eur J Clin Invest . 1991;;21:40-46.
Shirley DG, Singer DRJ, Sagnella GA, et al.  Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man. Clin Sci . 1991;;81:59-63.
Dollery CT, Duncan H, Schumer B.  Hyperuricaemia related to treatment of hypertension. BMJ . 1960;;2:832-835.
Atherton JC, Green R, Hughes S, et al.  Lithium clearance in man: effects of dietary salt intake, acute changes in extracellular fluid volume, amiloride and frusemide. Clin Sci . 1987;;72:201-208.
Shirley DG, Yee-Yee H.  The influence of posture on renal tubular function in man. Am J Med Sci . 1990;;299:326-330.
Brand FN, McGee DL, Kannel WB, Stokes J III, Castelli WP.  Hyperuricemia as a risk factor of coronary heart disease: the Framingham Study. Am J Epidemiol . 1985;;121:11-18.
Zavaroni I, Bonora E, Pagliara M, et al.  Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med . 1989;;320:702-706.
Selby JV, Friedman GD, Quesenberry CP Jr.  Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol and other serum chemistries. Am J Epidemiol . 1990;;131:1017-1027.
Modan M, Halkin H, Almog S, Luski A, Eshkol A, Shefi M.  Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest . 1985;;75:809-817.
Ferrannini E, Buzzigoli G, Bonadonna R, et al.  Insulin resistance in essential hypertension. N Engl J Med . 1987;;317:350-357.
DeFronzo R.  The effect of insulin on renal sodium metabolism: a review with clinical implications. Diabetologia . 1981;;21:165-171.
Mahnensmith RL, Aronson PS.  The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res . 1985;;57:773-788.
Trevisan M, Laurenzi M.  Correlates of sodium-lithium countertransport: findings from the Gubbio Epidemiological Study. Circulation . 1991;;84:2011-2019.
Doria A, Fioretto P, Avogaro A, et al.  Insulin resistance is associated with high sodium-lithium countertransport in essential hypertension. Am J Physiol . 1991;;261:E684-E691.
Weder A.  Red cell lithium-sodium countertransport and renal lithium clearance in hypertension. N Engl J Med . 1986;;314:198-201.
Strazzullo P, Cappuccio FP, Trevisan M, et al.  Erythrocyte sodium/lithium countertransport and renal lithium clearance in a random sample of untreated middle-aged men. Clin Sci . 1989;;77:337-342.
Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG.  Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med . 1980;;93:817-821.
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