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Katherine R Tuttle

Publications and source records attributed to Katherine R Tuttle.

At least 19 recordsLinked to original sources
PubMed2026

Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis.

BACKGROUND: The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials. METHODS: Participants with CKD (FLOW) or atherosclerotic cardiovascular disease (SELECT and SOUL) were randomly assigned semaglutide (once-weekly subcutaneous 1&#xb7;0 mg [FLOW], once-weekly subcutaneous 2&#xb7;4 mg [SELECT], or once-daily oral 14 mg [SOUL]) or matching placebo, added to standard of care. The primary outcome in this pooled analysis was time to first occurrence of a kidney composite, defined as onset of persistent 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure (persistent eGFR <15 mL/min per 1&#xb7;73 m2, or initiation of kidney replacement therapy), kidney-related death, or cardiovascular-related death. Safety was also assessed. FINDINGS: The pooled participants from the trials (N=30&#x2008;787) had a mean follow-up of 39&#xb7;5-47&#xb7;5 months. Among participants assigned to semaglutide, 973 first events of the primary kidney composite occurred compared with 1134 first events for placebo (hazard ratio [HR] 0&#xb7;84 [95% CI 0&#xb7;77-0&#xb7;91]). First events of a narrower secondary kidney composite (excluding cardiovascular-related death from the primary outcome) were also reduced with semaglutide versus placebo (347 and 416, respectively; 0&#xb7;80 [0&#xb7;69-0&#xb7;92]). Safety outcomes were overall similar between groups, and in line with other GLP-1 receptor agonist trials. Serious adverse events were numberically lower with semaglutide than with placebo. INTERPRETATION: Data pooled from three large phase 3 trials suggest that semaglutide reduces the risk of major kidney outcomes in a broad population with cardio-kidney-metabolic disease while having a favourable risk-benefit profile. In people with cardio-kidney-metabolic disease, with and without diabetes, semaglutide (oral or injected) prevents kidney-related and cardiovascular complications and induces adverse events in line with GLP-1 receptor agonist studies, regardless of baseline characteristics within the cardio-kidney-metabolic spectrum. This was a participant-level analysis conducted in a large database of three randomised controlled trials of similar design and examining the same treatment, but there were some differences in participants' baseline characteristics, and in the dose and route of administration of treatment. This pooled analysis adds evidence for the benefit of GLP-1 receptor agonists in general, and semaglutide in particular, in a broad population of people with cardio-kidney-metabolic disease, suggesting that the benefit of semaglutide might not be explained only by its glycaemic effects, weight-management effects, or both. FUNDING: Novo Nordisk.

Humans↗
PubMed2006

The new KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and CKD.

BACKGROUND/AIMS: The National Kidney Foundation (NKF) recently published new guidelines and clinical practice recommendations for the diagnosis and management of patients with diabetes and chronic kidney disease (CKD). METHODS: Guidelines were developed using an evidence-based approach. When sufficient evidence was lacking, recommendations were developed that reflect expert opinion. RESULTS: Guidelines describe the process for screening and diagnosis of kidney disease in the setting of diabetes and the management of hyperglycemia, hypertension, dyslipidemia, and nutrition. Recommendations describe the management of albuminuria in the normotensive diabetic patient and the potential value of albuminuria as a marker of treatment efficacy; the impact of diabetes and CKD in special populations; the importance of behavioral self-management; and the value of intensive multifaceted intervention in these high risk patients. CONCLUSIONS: The new guidelines and recommendations update and extend the scope of the NKF's Kidney Disease Outcomes Quality Initiative (KDOQI(TM)).

Diabetes Complications↗
PubMed2006

Implications of chronic kidney disease for dietary treatment in cardiovascular disease.

Chronic kidney disease (CKD) often accompanies cardiovascular disease (CVD). Trends foretelling a greater burden of CKD and CVD are largely a result of increasing frequencies of obesity, hypertension, and diabetes. Nutritional therapy occupies a critical role in reducing risk factors and preventing progressive damage to the kidneys and heart. Nutritional assessment and treatment should take into account both health concerns. This review examines several diet components and eating styles for efficacy in the treatment of these conditions. A variety of dietary regimens claim to provide health benefits, but rigorous scientific validation of long-term efficacy is frequently lacking. An urgent need exists for eating styles that reduce risk of chronic diseases and that are acceptable and achievable in free-living populations. We describe our ongoing study, a randomized controlled trial comparing the American Heart Association Step II diet and a Mediterranean diet, in survivors of a first myocardial infarction. The primary end point is a composite of mortality and major CVD events. Because many in this population have CKD, indicators of kidney damage and function are prespecified secondary end points. Results of this trial should provide insight into optimal dietary interventions for persons with both CVD and CKD.

Cardiovascular Diseases↗
PubMed2005

A causal role for uric acid in fructose-induced metabolic syndrome.

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

Animals↗
PubMed2005

Uric acid, microalbuminuria and cardiovascular events in high-risk patients.

BACKGROUND: Elevated levels of serum uric acid and albuminuria are associated with cardiovascular disease, but the relationships have not consistently been demonstrated to be independent of hypertension, other risk factors, or each other. The purpose of this study was to evaluate people at high risk for cardiovascular disease for the influence of uric acid and microalbuminuria on cardiovascular events. METHODS: Consecutive consenting patients undergoing elective angiography (n = 316) had coronary artery disease, risk factors, renal function and diuretic use assessed at baseline. Cardiovascular mortality and major clinical events (myocardial infarction, stroke, amputation, and kidney failure) were ascertained over 5 years. RESULTS: Cardiovascular events occurred in 10% of the patients. Significant correlates (p < 0.05) of cardiovascular events with baseline measures included uric acid > or =5.2 mg/dl, total cholesterol > or =200 mg/dl, severe angiographic coronary artery disease, loop diuretic therapy, and diagnosis of hypertension. A stepwise Cox modeling procedure identified uric acid (p = 0.040), the interaction of hypertension and uric acid (p = 0.029), the interaction of total cholesterol and severe coronary artery disease (p = 0.001) and loop diuretic therapy (p = 0.009) as significant independent predictors of events. Although microalbuminuria was not retained in the final multivariate model, it was associated with poorer cardiovascular disease outcomes. The mean event-free survival for albumin-to-creatinine >30 mg/g was 51 months and for albumin-to-creatinine <30 mg/g the mean was 57 months (p = 0.021). CONCLUSIONS: Uric acid > or =5.2 mg/dl independently imparted a 3.5-fold increased risk (OR 3.5, 95% CI 1.0-11.9) for cardiovascular death and major clinical events over a 5-year period. Uric acid may be a contributing factor to the progression of atherosclerosis and its complications.

Albuminuria↗
PubMed2005

Clinical evidence for the influence of uric acid on hypertension, cardiovascular disease, and kidney disease: a statistical modeling perspective.

This article critically evaluates the clinical evidence regarding the influence of uric acid on hypertension, cardiovascular disease, and kidney disease. Data on these relationships are largely observational and exceedingly complex. The complexity is owing to indirect and direct relations, and bidirectional influences, simultaneously operating on multiple outcomes. Limitations of previous analyses include inadequate statistical methods using only bivariate correlations or poorly specified multiple regression models. As a result, great controversy developed as to whether uric acid is an independent predictor of important outcomes. An example of such analytic limitations is including hypertension as an independent variable, together with uric acid, in a multivariate model for predicting cardiovascular disease. Hypertension may predict significant variance in cardiovascular disease, but the contribution of uric acid may not be recognized if uric acid exerts its influence indirectly through hypertension. Path analysis, which can model direct and indirect influences on outcomes simultaneously, would address this substantive question. Studies of uric acid in relation to hypertension, cardiovascular disease, and kidney disease using a path-analytic approach would help specify such conditions as well as optimize design of clinical trials to determine if decreasing uric acid levels improves outcomes.

Cardiovascular Diseases↗
PubMed2005

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.

Fructose↗
PubMed2005

The next generation of diabetic nephropathy therapies: an update.

Although treatments for diabetic kidney disease are available, many patients still have progressive disease. More effective therapies are urgently needed. Novel agents currently under evaluation in clinical trials are described in this review. Sulodexide, a mixture of three glycosaminoglycans, appears to prevent diabetic nephropathy in experimental models by ameliorating abnormalities in the glomerular basement membrane and mesangial matrix. Pyridoxamine is an inhibitor of advanced glycation end-product (AGE) formation derived from vitamin B(6). Alagebrium is an AGE cross-link breaker. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking, among others. By inhibiting AGE formation or breaking AGE cross-links, experimental models have demonstrated kidney protection. Ruboxistaurin is an inhibitor of protein kinase C beta (PKC-beta), a mediator of signal transduction that leads to cell growth, fibrosis, and tissue injury. In diabetes, PKC-beta is up-regulated and activated in the kidney. Ruboxistaurin prevents diabetic kidney disease in animal models. These agents have appeared promising (by reduction of albuminuria and preservation of kidney function) in phase II studies. To determine whether clinical outcomes (mortality, renal, and cardiovascular events) are improved beyond the current standard of care, phase III trials are planned.

Animals↗
PubMed2005

Amino acids injure mesangial cells by advanced glycation end products, oxidative stress, and protein kinase C.

BACKGROUND: In diabetes, high intake of dietary protein exacerbates responses associated with kidney damage. Increased levels of amino acids could injure cells by providing free amino groups for glycation reactions leading to advanced glycation end products (AGEs). METHODS: Rat mesangial cells were cultured with increased amino acids designed to resemble protein feeding, high glucose (30.5 mmol/L), and, the combination, amino acids/high glucose. AGEs, reactive oxygen species (ROS), protein kinase C (PKC) activity and production, and mitogen-activated protein (MAP) kinase-extracellular signal regulated kinase (ERK) 1,2 activity were measured. Inhibitors were used to determine roles of these processes in fibrosis and/or AGE formation. RESULTS: AGE immunostaining increased when cells were cultured in amino acids and was comparable to that observed with high glucose. In amino acids/high glucose, AGE immunostaining appeared even greater. Amino acids, high glucose, and amino acids/high glucose induced ROS production. Aminoguanidine and vitamin E prevented AGE accumulation and induction of protein and mRNA for fibrosis markers [transforming growth factor-beta1 (TGF-beta1), fibronectin, and collagen IV]. PKC and ERK 1,2 activity increased with amino acids, high glucose, and amino acids/high glucose. PKC-beta inhibition prevented ERK 1,2 activation and fibrosis induction. ERK 1,2 inhibition also blocked the fibrosis response. CONCLUSION: A profibrotic injury response occurred in mesangial cells exposed to amino acids, with or without high glucose, by formation of AGE, oxidative stress, and activation of the PKC-beta and MAP kinase-ERK 1,2 signal pathway. These observations provide new insight into cellular mechanisms of kidney damage produced by excess dietary protein, particularly in diabetes.

Amino Acids↗
PubMed2005

The effect of ruboxistaurin on nephropathy in type 2 diabetes.

OBJECTIVE: Ruboxistaurin selectively inhibits protein kinase C-beta and ameliorates kidney disease in animal models of diabetes. The purpose of this study was to evaluate the effects of ruboxistaurin on diabetic nephropathy in humans. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, multicenter, pilot study was performed to evaluate the effects of 32 mg/day ruboxistaurin for 1 year in persons (n = 123) with type 2 diabetes and persistent albuminuria (albumin-to-creatinine ratio [ACR] 200-2,000 mg/g), despite therapy with renin-angiotensin system inhibitors. The primary end point was a change in the ACR. Estimated glomerular filtration rate (eGFR) (four-component equation from the Modification of Diet in Renal Disease study) was also calculated. RESULTS: At baseline, urinary ACR was 764 +/- 427 mg/g (means +/- SD), and eGFR was 70 +/- 24 ml/min per 1.73 m2. Systolic and diastolic blood pressures were 135 +/- 14 and 75 +/- 9 mmHg, respectively. HbA(1c) was 8.0 +/- 1.2%. After 1 year, urinary ACR decreased significantly (-24 +/- 9%) in participants treated with ruboxistaurin (P = 0.020) and nonsignificantly (-9 +/- 11%) in the placebo group (P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (-2.5 +/- 1.9 ml/min per 1.73 m2) (P = 0.185), whereas the placebo group lost significant eGFR over 1 year (-4.8 +/- 1.8 ml/min per 1.73 m2) (P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences. CONCLUSIONS: In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year. Ruboxistaurin may add benefit to established therapies for diabetic nephropathy.

Black or African American↗
PubMed2004

Atherosclerotic renal artery stenosis: current status and future directions.

PURPOSE OF REVIEW: Atherosclerotic renal artery stenosis is a common, progressive problem that increases in prevalence with age. It can have important clinical consequences such as hypertension, pulmonary edema, and renal failure. In addition, it is associated with increased cardiovascular mortality. The purpose of this review is to describe the current status of knowledge and future directions for this evolving field. RECENT FINDINGS: In patients who are suspected of having the disease, duplex Doppler ultrasound and magnetic resonance angiography remain the most promising noninvasive screening tests. Percutaneous revascularization continues to advance, and technical success is possible in the vast majority of patients. Revascularization for hypertension is of modest clinical benefit. Limited information is available on the effect of revascularization on preservation of renal function or cardiovascular events and mortality. SUMMARY: Further studies are still needed focusing on the identification of which patients will derive benefit from percutaneous revascularization and whether intervention provides an advantage over medical therapy, particularly with respect to preservation of renal function and reduction in cardiovascular morbidity and mortality.

Algorithms↗
PubMed2004

Cardiovascular implications of albuminuria.

Microalbuminuria is a major independent risk factor for cardiovascular disease (CVD) events in persons with diabetes or hypertension, the general population, and persons with known CVD. Although microalbuminuria is a stronger risk factor in men, women with increased albuminuria levels are also at a higher risk of CVD. Microalbuminuria is an indicator of generalized endothelial injury, a hallmark of systemic atherosclerosis. Treatments that decrease albuminuria, particularly agents that inhibit the renin-angiotensin system, reduce CVD risk in various populations, including those with and without diabetes or hypertension. Whether albuminuria should be a treatment target for CVD is not yet proven. Nevertheless, the measurement of albuminuria is clinically useful to identify high-risk individuals who should receive intensive risk factor management based on current treatment guidelines.

Albuminuria↗
PubMed2003

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.

Animals↗