Katherine R. Tuttle

Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

BACKGROUND Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain. METHODS We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy). RESULTS Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95% CI, -4.4 to -0.2; P=0.03). CONCLUSIONS Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.).

Kidney Disease and Increased Mortality Risk in Type 2 Diabetes

Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio ≥30 mg/g and/or estimated GFR ≤60 ml/min per 1.73 m(2), was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval [95% CI], 7.0%-8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%-15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%-7.7%), adjusted for demographics, and 3.4% (95% CI, -0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%-37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%-29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%-29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes.

Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome.

The increasing incidence of obesity and the metabolic syndrome over the past two decades has coincided with a marked increase in total fructose intake. Fructose—unlike other sugars—causes serum uric acid levels to rise rapidly. We recently reported that uric acid reduces levels of endothelial nitric oxide (NO), a key mediator of insulin action. NO increases blood flow to skeletal muscle and enhances glucose uptake. Animals deficient in endothelial NO develop insulin resistance and other features of the metabolic syndrome. As such, we propose that the epidemic of the metabolic syndrome is due in part to fructose-induced hyperuricemia that reduces endothelial NO levels and induces insulin resistance. Consistent with this hypothesis is the observation that changes in mean uric acid levels correlate with the increasing prevalence of metabolic syndrome in the US and developing countries. In addition, we observed that a serum uric acid level above 5.5 mg/dl independently predicted the development of hyperinsulinemia at both 6 and 12 months in nondiabetic patients with first-time myocardial infarction. Fructose-induced hyperuricemia results in endothelial dysfunction and insulin resistance, and might be a novel causal mechanism of the metabolic syndrome. Studies in humans should be performed to address whether lowering uric acid levels will help to prevent this condition.

Diabetic Kidney Disease: A Report From an ADA Consensus Conference

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly

Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.

25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Linking metabolism and immunology: diabetic nephropathy is an inflammatory disease.

Changes in proteinuria have been suggested as a surrogate outcome for kidney disease progression to facilitate the conduct of clinical trials. This report summarizes a workshop sponsored by the National Kidney Foundation and US Food and Drug Administration (FDA) with the following goals: (1) to evaluate the strengths and limitations of criteria for assessment of proteinuria as a potential surrogate end point for clinical trials in chronic kidney disease (CKD), (2) to explore the strengths and limitations of available data for proteinuria as a potential surrogate end point, and (3) to delineate what more needs to be done to evaluate proteinuria as a potential surrogate end point. We review the importance of proteinuria in CKD, including the conceptual model for CKD, measurement of proteinuria and albuminuria, and epidemiological characteristics of albuminuria in the United States. We discuss surrogate end points in clinical trials of drug therapy, including criteria for drug approval, the definition of a surrogate end point, and criteria for evaluation of surrogacy based on biological plausibility, epidemiological characteristics, and clinical trials. Next, the report summarizes data for proteinuria as a potential surrogate outcome in 3 broad clinical areas: early diabetic kidney disease, nephrotic syndrome, and diseases with mild to moderate proteinuria. We conclude with a synthesis of data and recommendations for further research. At the present time, there appears to be sufficient evidence to recommend changes in proteinuria as a surrogate for kidney disease progression in only selected circumstances. Further research is needed to define additional contexts in which changes in proteinuria can be expected to predict treatment effect. We recommend collaboration among many groups, including academia, industry, the FDA, and the National Institutes of Health, to share data from past and future studies.

Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus

Diabetic nephropathy is one of the most important concerns in nephrology, as well as in medicine at large. Rapidly increasing rates of diabetes throughout the developed world represent an emerging epidemic with profound consequences. This epidemic is likely to drive previously unforeseen rates of vascular target organ complications. As survival from acute cardiovascular complications continues to improve, management of chronic complications such as kidney disease assume ever-larger roles. Diabetes is the leading cause of end-stage renal disease in the United States, accounting for approximately 45% of incident cases and 55% of prevalent cases in the present decade (1,2). End-stage renal disease in diabetes, particularly type 2, has been described as a medical catastrophe of worldwide dimensions (3). So what can be done to reduce the burden of diabetic nephropathy? Available therapies shown to prevent or slow progression should be broadly applied. These therapies include strict glycemic control and treatment of hypertension with inhibitors of the reninangiotensin system (4–10). However, in recent clinical trials in which care was presumably optimized, renoprotecion was far from complete. And, in reality, controlling hyperglycemia and hypertension in usual care settings is often more challenging than in clinical trials. Hence, even more effective therapies that interrupt mechanisms of kidney damage induced by hyperglycemia and/or hypertension are urgently needed. The bench-to-bedside paradigm of translational research is that two-way street where the clinic and the laboratory meet. For clinicians and patients, this is an opportunity to obtain more effective therapies. For scientists, discovery and technology can be applied to a meaningful clinical problem. Two elegant papers in this issue of the journal illustrate the hope of translational research (11,12). The paper by Kelly and colleagues utilized a model of diabetes and hypertension produced by administration of streptozotocin to a rat transgenic for the renin gene (11). Groups of diabetic and control rats were treated, or not, with an inhibitor of protein kinase C– (PKC-), ruboxistaurin. Although glomerular pathology has been well characterized in this model, the current paper emphasizes the importance of tubulointerstitial injury (11,13). Macrophage accumulation and injury at this site correlate closely with loss of kidney function in humans and animals with a range of kidney diseases, including diabetic nephropathy (14,15). This model of diabetes and hypertension demonstrated numerous macrophages in the interstitium of untreated rats, along with widespread and intense tubular staining for osteopontin, a protein known to recruit macrophages (11). Pro-fibrotic injury markers (interstitial collagen, tubular TGF-, and a marker of its activity, phosphorylated Smad2) were also increased. Despite persistent hyperglycemia and hypertension, albuminuria was reduced, and renal function was preserved in rats treated with ruboxistaurin. Moreover, tubulointerstitial macrophage accumulation, osteopontin expression, and pro-fibrotic injury markers were returned to control levels by this treatment. These observations have important translational implications. First, ruboxistaurin has already moved into clinical trials for diabetic nephropathy, as well as for other microvascular

Sex Differences in Uric Acid and Risk Factors for Coronary Artery Disease

BACKGROUND Many patients with insulin-dependent diabetes mellitus have an increase in the glomerular filtration rate and renal enlargement early in the course of their disease. Both these changes may be risk factors for the later development of diabetic nephropathy. Their cause is not known, but they could be due to augmented renal responses to the increase in plasma amino acid concentrations that occurs when dietary protein intake is high, a factor known to increase glomerular filtration and renal blood flow in normal subjects. METHODS We measured the glomerular filtration rate and renal plasma flow after an overnight fast and during an infusion of amino acids in 12 patients with insulin-dependent diabetes mellitus and 9 normal subjects. The diabetic patients were studied when they were hyperglycemic, when they were euglycemic after an insulin infusion for 36 hours, and after intensive insulin therapy for 3 weeks. Kidney volume was measured by ultrasonography before and after the period of intensive insulin therapy. RESULTS The glomerular filtration rate and renal plasma flow were normal after fasting when the patients were hyperglycemic (mean [+/- SE] fasting plasma glucose level, 11.5 +/- 0.7 mmol per liter). After the amino acid infusion, these values increased more in the patients (glomerular filtration rate, 2.65 +/- 0.07 ml per second per 1.73 m2 of body-surface area; renal plasma flow, 13.30 +/- 0.68 ml per second per 1.73 m2; P less than 0.05 for both) than in the normal subjects (2.25 +/- 0.08 and 11.20 +/- 0.65 ml per second per 1.73 m2, respectively). The 36-hour infusion of insulin in the diabetic patients did not alter the glomerular filtration rate or renal plasma flow either before or during the amino acid infusion. After three weeks of intensive insulin therapy (fasting plasma glucose level, 5.3 +/- 0.2 mmol per liter), the glomerular filtration rate and renal plasma flow after the amino acid infusion (2.33 +/- 0.03 and 11.30 +/- 0.43 ml per second per 1.73 m2, respectively) were similar to those in the normal subjects. The kidney volumes in the normal subjects and the patients with diabetes were 219 +/- 14 and 312 +/- 14 ml per 1.73 m2, respectively (P less than 0.01); the volume decreased to 267 +/- 22 ml per 1.73 m2 (P less than 0.001) in the diabetic patients after three weeks of intensive insulin therapy, which was not significantly different from the volume in the normal subjects (P = 0.1). CONCLUSIONS Conventionally treated diabetic patients who have normal renal function while fasting have augmented renal hemodynamic responses to increased plasma amino acid concentrations. The concomitant decrease in these hemodynamic responses and in kidney size with strict glycemic control suggests that these phenomena are related and influenced by the metabolic state.

Treatment of atherosclerotic ostial renal artery stenosis with the intravascular stent.

966. 8. Soejima H, Ogawa H, Yasue H, Kaikita K, Takazoe K, Nishiyama K, Misumi K, Miyamoto S, Yoshimura M, Kugiyama K, Nakamura S, Tsuji I. Angiotensinconverting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction. J Am Coll Cardiol 1999;34:983–988. 9. Brown NJ, Agirbasli M, Vaughan DE. Comparative effect of angiotensinconverting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension 1999;34:285–290. 10. Goodfield NER, Newby DE, Ludlam CA, Flapan AD. Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999;99:2983–2985. 11. Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res 1980;47:1–9. 12. Lottermoser K, Weisser B, Hertfelder HJ, Wostmann B, Vetter H, Dusing R. Antihypertensive drug treatment and fibrinolytic function. Am J Hypertens 1998; 11:378–384. 13. Kaikita K, Ogawa H, Yasue H, Takeya M, Takahashi K, Saito T, Hayasaki K, Horiuchi K, Takizawa A, Kamikubo Y, Nakamura S. Tissue factor expression on macrophages in coronary plaques in patients with unstable angina. Arterioscler Thromb Vasc Biol 1997;17:2232–2237. 14. Marmur JD, Thiruvikraman SV, Fyfe BS, Guha A, Sharma SK, Ambrose JA, Fallon JT, Nemerson Y, Taubman MB. Identification of active tissue factor in human coronary atheroma. Circulation 1996;94:1226–1232. 15. Ardissino D, Merlini PA, Arlns R, Coppola R, Bramucci E, Mannucci PM. Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet 1997;349:769–771. 16. Nishimura H, Tsuji H, Masuda H, Kasahara T, Yoshizumi M, Sugano T, Kimura S, Kawano H, Kunieda Y, Yano S, Nakagawa K, Kitamura H, Nakahara Y, Sawada S, Nakagawa M. The effects of angiotensin metabolites on the regulation of coagulation and fibrinolysis in cultured rat aortic endothelial cells. Thromb Haemost 1999;82:1516–1521. 17. Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985;313:1557–1563. 18. Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombeck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987;2:3–9. 19. Soejima H, Ogawa H, Yasue H, Kaikita K, Nishiyama K, Misumi K, Takazoe K, Miyao Y, Yoshimura M, Kugiyama K, Nakamura S, Tsuji I, Kumeda K. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 1999; 99:2908 –2913.