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ABSTRACT: Over the last few decades, much of the world has experienced an epidemic of obesity. In the year 2008, 1.4 billion people worldwide were overweight, and 500 million were obese. Even more alarming is a fact that in the year 2010, 40 million children under the age of 5 years were overweight or obese. In the same time period, the incidence of CKD has also increased worldwide. Obesity has been recognized as a driving force of another global epidemic-diabetes, the leading cause of ESRD. Recent studies are confirming that in addition to risk associated with diabetes per se, increased body mass index is independently linked to increased risk for various kidney disorders, prominently CKD, but also renal cell carcinoma and nephrolithiasis. The purpose of this article is to review current knowledge regarding adverse effects of obesity on the kidney.
Advances in chronic kidney disease 03/2013; 20(2):121-127. · 2.42 Impact Factor
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ABSTRACT: Background
Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo.Methods
Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold >control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 µg/mL); (vi) BSA (300 µg/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples.ResultsIn podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase-polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls.Conclusions
High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.
Nephrology Dialysis Transplantation 01/2013; · 3.40 Impact Factor
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ABSTRACT: Background/Aims: The link between CKD and CAC has been mostly established by studies of patients who have abnormally high phosphorus levels and advanced CKD or end-stage renal disease. The aim of this study was to examine if there are distinct trajectory classes of serum phosphorus (controlling for eGFR) that are associated CAC in a relatively healthy, community sample. Methods: Phosphorus and eGFR were classified as a combined biomarker variable with 4 trajectory classes by growth mixture modeling. This classification variable was subsequently used to predict CAC as both a binary (i.e., onset) and continuous (i.e., accumulation) outcome using a two-part growth model. Results: Membership in one class of phosphorus trajectory versus the next lowest level was associated with a 97.9 Agatston unit increase in CAC (p <.001). The magnitude of this finding is similar in size as some primary risk factors for cardiovascular disease, including a 55.3 Agatston unit (p <.001) increase associated with age, and a - 75.1 Agatston unit (p <.001) decrease associated with female gender. Conclusions: Classification of phosphorus trajectories provides further definition for prediction of CAC within the conventional 'normal' range. Classifying trajectories may help determine clinically-relevant thresholds for interventions aimed at phosphorus reduction.
Kidney and Blood Pressure Research 07/2012; 36(1):26-35. · 1.46 Impact Factor
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ABSTRACT: The objective was to determine if patients hospitalized with a primary medical diagnosis and any co-occurring serious mental illness (SMI) were more likely than patients without any co-occurring SMI diagnosis to experience a subsequent medical hospitalization.
This was a longitudinal cohort study of 925,705 adult persons (aged 18+ years). Patients hospitalized in Washington State from 2004 to 2008 were followed through 2009 (for an average of 43 months).
Compared to patients hospitalized for medical conditions without co-occurring SMI, patients with co-occurring dysthymia, bipolar and major depressive disorders were at an elevated risk for long-term subsequent hospitalization. Patients in the combined co-occurring mood disorders cohort were more likely (hazard ratio=1.13; 99% confidence interval=1.10-1.16; P<.001) than patients in the reference cohort to experience a subsequent medical hospitalization. A significant interaction between substance and mood disorders that increased risk for subsequent hospitalization was also observed.
Hospitalized patients with co-occurring mood disorders are at high risk for repeat hospitalization for a medical reason. This high-risk population, including those with substance abuse, should be a focus of research efforts to identify and address ambulatory-care-sensitive conditions amenable to strategies that decrease complications and illness leading to subsequent hospitalizations.
General hospital psychiatry 06/2012; 34(5):500-5. · 2.67 Impact Factor
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ABSTRACT: Rates of hospitalization are known to be high in patients with kidney disease. However, ongoing risks of subsequent hospitalization and mortality are uncertain. The primary objective was to evaluate patients with kidney disease for long-term risks of subsequent hospitalization, including admissions resulting in death.
Patients hospitalized in Washington State between April of 2006 and December of 2008 who survived to discharge (n=676,343) were classified by International Classification of Disease codes into CKD (n=27,870), dialysis (n=6131), kidney transplant (n=1100), and reference (n=641,242) cohorts. Cox proportional hazard models controlling for age, sex, payer, comorbidity, previous hospitalization, primary diagnosis category, and length of stay were conducted for time to event analyses.
Compared with the reference cohort, risks for subsequent hospitalization were increased in the CKD (hazard ratio=1.20, 99% confidence interval=1.18-1.23, P<0.001), dialysis (hazard ratio=1.76, 99% confidence interval=1.69-1.83, P<0.001), and kidney transplant (hazard ratio=1.85, 99% confidence interval=1.68-2.03, P<0.001) cohorts, with a mean follow-up time of 29 months. Similarly, risks for fatal hospitalization were increased for patients in the CKD (hazard ratio=1.41, 99% confidence interval=1.34-1.49, P<0.001), dialysis (hazard ratio=3.04, 99% confidence interval=2.78-3.31, P<0.001), and kidney transplant (hazard ratio=2.25, 99% confidence interval=1.67-3.03, P<0.001) cohorts. Risks for hospitalization and fatal hospitalization increased in a graded manner by CKD stage.
Risks of subsequent hospitalization, including admission resulting in death, among patients with kidney disease were substantially increased in a large statewide population. Patients with kidney disease should be a focus of efforts to reduce hospitalizations and mortality.
Clinical Journal of the American Society of Nephrology 03/2012; 7(3):409-16. · 5.23 Impact Factor
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ABSTRACT: Dietary protein has been variably reported to either lower or raise blood pressure. The purpose of this study was to determine whether intakes of specific amino acids differentially associate with blood pressure.
Observational cohort study by secondary analysis of clinical trial data.
Study of low-fat versus Mediterranean-style diets in patients with prevalent cardiovascular disease.
Dietary amino acids.
Systolic and diastolic blood pressure.
Dietary nutrients and cardiovascular risk factors were assessed at baseline, 3 and 6 months, and then every 6 months for 2 years.
Baseline blood pressure was 119 ± 16 (SD)/72 ± 10 (SD) mm Hg (n = 92) and dietary protein intake was 80 ± 31 g/d. Independent amino acid variables (quartiles of intake) were analyzed by generalized estimating equation models with prespecified covariates for time-varying systolic and diastolic blood pressure. The odds of each 1-SD higher systolic or diastolic blood pressure (ie, 16 and 10 mm Hg, respectively) were increased per quartile of intake for methionine (ORs of 1.29 [95% CI, 1.14-1.46] and 1.21 [95% CI, 1.05-1.39], respectively) and alanine (ORs of 1.17 [95% CI, 1.05-1.30] and 1.22 [95% CI, 1.07-1.38], respectively). Quartiles of intake for threonine (ORs of 0.84 [95% CI, 0.74-0.96] and 0.87 [95% CI, 0.75-1.01], respectively) and histidine (ORs of 0.92 [95% CI, 0.86-1.00] and 0.89 [95% CI, 0.82-0.97], respectively) had inverse associations with the same degree of difference in blood pressure.
Modest sample-size biases toward the chance of false-negative results; potential for residual confounding; colinearity between amino acids may obscure relevant relationships to blood pressure; associational findings do not establish causality.
Intakes of methionine and alanine were associated positively with higher blood pressure, whereas intakes of threonine and histidine had inverse associations. These amino acids merit further study for advancing dietary approaches to blood pressure reduction.
American Journal of Kidney Diseases 02/2012; 59(6):803-9. · 5.43 Impact Factor
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Katherine R Tuttle
Kidney International 11/2011; 80(10):1008-9. · 6.61 Impact Factor
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ABSTRACT: Diabetes mellitus leads to the development of a host of micro- and macrovascular complications, which collectively lead to substantial morbidity and mortality. Among the microvascular complications of diabetes, diabetic kidney disease is the most common. Macrovascular complications from diabetes lead to a 2- to 4-fold increase in the incidence of cardiovascular disease and up to twice the mortality from cardiovascular causes as compared with nondiabetic individuals. This article discusses the various drug classes used to treat diabetes mellitus, and reviews the current clinical evidence linking glycemic control using these drug classes on diabetic kidney and cardiovascular disease.
Cardiology clinics 08/2010; 28(3):497-516. · 1.25 Impact Factor
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Katherine R Tuttle
Clinical Journal of the American Society of Nephrology 04/2010; 5(5):750-2. · 5.23 Impact Factor
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ABSTRACT: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), and one of the most prevalent microvascular complications of both type 1 and type 2 diabetes. Additionally, risk of death is increased at all stages of DKD. As early as the microalbuminuric stage, the death rate approaches 20% per year. Therefore, management strategies should address reducing risk of mortality as well as progression to ESRD. DKD is associated with multiple co-morbidities including hypertension, dyslipidemia, cardiovascular disease, anemia, and bone and mineral metabolism disorders (BMD). Anemia and BMD often occur earlier in the course of DKD than with other forms of chronic kidney disease. Pharmacological and dietary management of hyperglycemia, hypertension, dyslipidemia, anemia, and BMD pose specific challenges in DKD. However, with heightened awareness of risks and a multifactorial management approach, the impact of DKD on micro- and macrovascular complications and death can be reduced.
Seminars in Dialysis 03/2010; 23(2):140-7. · 2.27 Impact Factor
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ABSTRACT: Coronary artery calcification (CAC) is common in advanced chronic kidney disease (CKD), yet its onset and time course are uncertain. The study objective was to assess longitudinal relationships among CAC, kidney function, and traditional and putative cardiovascular disease (CVD) risk factors.
This is a prospective cohort analysis from the Spokane Heart Study, a long-term observational study of community-dwelling adults who were assessed every 2 yr for CAC (electron-beam computed tomography), CVD risk factors, and laboratory testing. Estimated GFR (eGFR) was determined by the reexpressed Modification of Diet in Renal Disease equation.
CAC was present in 28% (245 of 883) at baseline. After 6 yr, new-onset CAC developed in 33% (122 of 371); severity increased from a median CAC score of 38 to 152 in those with baseline CAC. Neither eGFR (101 +/- 34 versus 104 +/- 31 ml/min per 1.73 m(2), respectively) nor serum phosphorus (3.25 +/- 0.49 versus 3.29 +/- 0.48 mg/dl, respectively) differed by CAC presence or absence at baseline; however, multivariate models (generalized estimating equations for incidence and prevalence) revealed that independent predictors of CAC over time were greater baseline CAC scores, higher serum phosphorus levels, lower eGFR levels, and traditional CVD risk factors. Each 1-mg/dl increase in phosphorus imparted odds ratios for CAC of 1.61 (incidence) and 1.54 (prevalence), risks comparable to traditional CVD risk factors.
CAC becomes more frequent and severe over time. Higher levels of serum phosphorus and reduced kidney function independently predicted CAC.
Clinical Journal of the American Society of Nephrology 12/2009; 4(12):1968-73. · 5.23 Impact Factor
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ABSTRACT: Albuminuria has been recognized as a risk marker for both chronic kidney disease and cardiovascular disease in large observational cohorts. In addition, post hoc analyses of many large randomized trials have found a positive relationship between albu-minuria and adverse renal and cardiovascular outcomes, leading some to suggest that albuminuria may be a potential therapeutic target for antihypertensive treatment. However, direct clinical evidence linking albuminuria reduction to reduction in adverse renal and cardiovascular events is scarce. This paper reviews the evidence in the current literature to address whether albuminuria can be used as a credible predictor of risk for chronic kidney disease and cardiovascular disease and also reviews the clinical trial evidence to appraise the prospect of using albuminuria as a therapeutic target to prevent adverse renal and cardiovascular events.
Current Hypertension Reports 11/2009; 11(5):354-62. · 2.50 Impact Factor
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ABSTRACT: High-protein, low-carbohydrate diets are advocated by many, predominantly commercial, weight loss programs. Most of these diets have been promoted within popular culture and until recently have been subjected to little scientific scrutiny. Substantial concern has been raised about the potential for adverse effects. Meat is commonly consumed as a major source of dietary protein. However, meat derived from animal muscle also typically contains large amounts of saturated fat and cholesterol. Consequently, low-density lipoprotein cholesterol (LDL-C) levels may increase, or do not decrease, presumably because augmented consumption of fats counterbalances the benefits of weight loss. In addition to the nonbeneficial effects on lipid levels, greater meat intake has been associated with a host of health concerns, such as all-cause mortality, coronary heart disease, cancers of the digestive tract, acceleration of chronic kidney disease, kidney stones, and osteoporosis, to name just a few.1- 2 Conversely, plant-based proteins may have health benefits when dietary intake is boosted within reasonable bounds. For example, augmenting the intake of predominantly vegetable protein lowers blood pressure and LDL-C levels in people with prehypertension or stage 1 hypertension.3 Plant protein sources also appear less likely than meat to induce the aforementioned health problems.
Archives of internal medicine 07/2009; 169(11):1027. · 11.46 Impact Factor
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Katherine R Tuttle
American Journal of Kidney Diseases 02/2009; 53(1):12-5. · 5.43 Impact Factor
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Katherine R Tuttle
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ABSTRACT: Amid the rapidly rising number of people with diabetes worldwide, the prevalence of diabetic kidney disease (DKD) is expected to increase considerably despite available treatments. Consequently, novel therapeutic agents are urgently needed. Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta isoform of protein kinase C (PKC). In experimental models of DKD, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved kidney function, and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. These beneficial effects of ruboxistaurin, both alone and combined with renin-angiotensin system inhibition, have been observed in a variety of experimental models of DKD. A phase 2 study of PKC-beta inhibition in persons with type 2 diabetes and DKD already treated with angiotensin converting enzyme inhibition and/or angiotensin receptor blockade has been conducted. Addition of ruboxistaurin for 1 year reduced urinary albumin, prevented an increase in urinary transforming growth factor-beta, and stabilized estimated glomerular filtration rate. Based on secondary analyses of clinical trials in patients with diabetic retinopathy or neuropathy, ruboxistaurin appears safe and may also prevent onset of DKD. PKC-beta inhibition holds promise as a new strategy to improve kidney disease outcomes in diabetes. Large-scale clinical trials will be required to confirm safety and to validate prospective benefits of ruboxistaurin on relevant clinical endpoints in DKD.
Diabetes research and clinical practice 12/2008; 82 Suppl 1:S70-4. · 2.16 Impact Factor
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Katherine R Tuttle
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ABSTRACT: The current standard-of-care is inadequate to stem the rising tide of kidney failure, cardiovascular disease, and death attributable to diabetic kidney disease (DKD). Improved treatment approaches for DKD are, therefore, urgently needed. In this Practice Point commentary, I discuss a randomized, placebo-controlled clinical trial performed by Parving et al., which evaluated the effects of a renin inhibitor, aliskiren, on albuminuria in patients with type 2 diabetes mellitus and macroalbuminuria. The investigators administered aliskiren combined with losartan, an angiotensin-receptor blocker that represents current standard-of-care treatment for DKD. The primary outcome measure of the study-a 20% reduction in the mean urinary albumin-to-creatinine ratio in aliskiren-treated participants as compared with the placebo group-was achieved after 6 months' treatment. Although aliskiren holds promise, large, long-term studies are necessary to confirm its safety and to demonstrate its beneficial effect on clinical end points before renin inhibition is embraced as the next step forward in the treatment of DKD.
Nature Clinical Practice Endocrinology & Metabolism 11/2008; 5(1):20-1. · 7.55 Impact Factor
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ABSTRACT: High levels of glucose and/or amino acids increase advanced glycation end products (AGE) and activate protein kinase C (PKC), a key signal for injury in mesangial cells. The aim was to determine whether oxidative stress mediates bidirectional interactions between AGE and PKC ('cross-activation') in this model.
Rat mesangial cells were examined after 48 h of exposure to: high glucose (30.5 mM), increased amino acids designed to resemble a protein meal, the combination of both conditions, and control. Cells were treated with antioxidants (vitamin E, alpha-lipoic acid, N-acetylcysteine, apocynin, doses based on suppression of reactive oxygen species), PKC inhibitors (calphostin C orPLY379196, 100 nM), or AGE inhibitors (aminoguanidine or pyridoxamine 0.5 mM).
Carboxymethyllysine, an AGE marker, increased twofold in mesangial cells exposed to the experimental conditions. Antioxidants and PKC inhibition prevented carboxymethyllysine increases. Likewise, antioxidants and AGE inhibition prevented PKC activation. Inhibition of carboxymethyllysine increases and PKC activation by apocynin indicates a primary role for NADPH oxidase in producing oxidative stress. Induction of transforming growth factor-beta(1) and fibronectin was inhibited by antioxidants and inhibitors of PKC and AGE.
Oxidative stress mediated cross-activation between PKC and AGE in this mesangial cell model of diabetes and high protein diet.PKC may amplify cellular injury by promoting AGE accumulation.
American Journal of Nephrology 10/2008; 29(3):171-80. · 2.54 Impact Factor
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ABSTRACT: The aim of this article is to review the pertinent physiology and pathophysiology of the renin-angiotensin-aldosterone system (RAAS), summarize the proven beneficial cardiovascular and renal effects of RAAS blockade, examine clinical situations in which RAAS blockade may induce reductions in glomerular filtration rate, and explore why increases in serum creatinine in the setting of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy do not necessarily signify the presence of clinically relevant kidney failure.
RAAS inhibition appears to reduce the likelihood of atrial fibrillation. RAAS inhibition leads to improved insulin sensitivity and glycemic control, but does not appear to prevent diabetes. The beneficial effects of ACEi/ARB therapy extend to those with significant renal disease. Combination ACEi/ARB is safe, and reduces proteinuria more than either agent alone in patients with macroalbuminuric nephropathy. Acute deteriorations in renal function that result from RAAS inhibition are usually reversible.
RAAS blockade exerts potent hemodynamic, antihypertensive, and antiinflammatory effects, and slows progression of kidney disease beyond that due to lowering of blood pressure. The benefit extends to those with advanced disease. In spite of established benefit, ACEi and ARB therapy remains underutilized, in part due to concerns about acute deteriorations in renal function that result from interruption of the RAAS.
Current Opinion in Nephrology and Hypertension 10/2008; 17(5):443-9. · 4.33 Impact Factor
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ABSTRACT: Whether a Mediterranean-style diet reduces cardiovascular events and mortality more than a low-fat diet is uncertain. The objectives of this study were to actively compare low-fat and Mediterranean-style diets after first myocardial infarction (MI) in a randomized, controlled clinical trial and to compare dietary intervention per se with usual care in a case-control analysis. First MI survivors were randomized to a low-fat (n = 50) or Mediterranean-style (n = 51) diet. The 2 diets were low in saturated fat (< or =7% kcal) and cholesterol (< or =200 mg/day); the Mediterranean-style diet was distinguished by greater omega-3 fat intake (>0.75% kcal). Participants received individual dietary counseling sessions, 2 within the first month and again at 3, 6, 12, 18, and 24 months, along with 6 group sessions. Combined dietary intervention groups (cases, n = 101) were compared with a usual-care group (controls, n = 101) matched for age, gender, MI type and treatment, and status of diabetes mellitus and hypertension. Primary-outcome-free survival (a composite of all-cause and cardiac deaths, MI, hospital admissions for heart failure, unstable angina pectoris, or stroke) did not differ between low-fat (42 of 50) and Mediterranean-style (43 of 51) diet groups over a median follow-up period of 46 months (range 18 to 72; log-rank p = 0.81). Patients receiving dietary intervention had better primary-outcome-free survival (85 of 101) than usual-care controls (61 of 101) (log-rank p <0.001), with unadjusted and adjusted odds ratios of 0.33 (95% confidence interval 0.18 to 0.60, p <0.001) and 0.28 (95% confidence interval 0.13 to 0.63, p = 0.002), respectively. In conclusion, active intervention with either a low-fat or a Mediterranean-style diet similarly and significantly benefits overall and cardiovascular-event-free survival after MI.
The American Journal of Cardiology 06/2008; 101(11):1523-30. · 3.37 Impact Factor
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ABSTRACT: Clinical practice guidelines from many professional societies endorse renin-angiotensin system (RAS) antagonists as first-line antihypertensive agents in diabetes and chronic kidney disease, largely based on putative renoprotective properties that may be blood pressure (BP) independent. To evaluate the relevance of these recommendations to early stage, nonproteinuric nephropathy, studies of primary and secondary prevention of kidney disease were reviewed. Primary prevention studies were reviewed only for diabetic populations. Secondary prevention studies included hypertensive and normotensive, and diabetic and nondiabetic patients with microalbuminuria or low glomerular filtration rate. Overall, use of RAS antagonists as first-line agents does not appear to be as important as control of BP. To achieve protective levels of BP, multiple antihypertensive agents are usually required. Long-term studies with clinically relevant outcomes (death and loss of kidney function) are needed to clarify whether specific agents provide benefits beyond that of BP control in early stage, nonproteinuric nephropathy.
Current Hypertension Reports 12/2007; 9(5):393-402. · 2.50 Impact Factor
