Tracking Biomarker Responses to Exercise in Hypertension.

PURPOSE OF REVIEW: Strong evidence is evolving that physical exercise prevents hypertension and reduces blood pressure in patients with pre- and manifest HTN. Yet, identifying and confirming the effectiveness of exercise are challenging. Herein, we discuss conventional and novel biomarkers such as extracellular vesicles (EVs) which may track responses to HTN before and after exercise. RECENT FINDINGS: Evolving data shows that improved aerobic fitness and vascular function as well as lowered oxidative stress, inflammation, and gluco-lipid toxicity are leading biomarkers considered to promote HTN, but they explain only about a half of the pathophysiology. Novel biomarkers such as EVs or microRNA are providing additional input to understand the complex mechanisms involved in exercise therapy for HTN patients. Conventional and novel biomarkers are needed to fully understand the integrative "cross-talk" between tissues to regulate vasculature physiology for blood pressure control. These biomarker studies will lead to more specific disease markers and the development of even more personalized therapy in this field. However, more systematic approaches and randomized controlled trials in larger cohorts are needed to assess exercise effectiveness across the day and with different exercise types.

Intakes of long-chain omega-3 polyunsaturated fatty acids and non-fried fish in relation to incidence of chronic kidney disease in young adults: a 25-year follow-up.

PURPOSE: The prevalence of chronic kidney disease (CKD) is increasing rapidly in many countries and has become a major public health concern. Although intakes of long-chain omega-3 polyunsaturated fatty acids (LCω3PUFA) and its food source-fish-may have renal protective effects, little is known about the longitudinal association between these dietary factors and CKD incidence. METHODS: A total of 4133 healthy individuals of black and white race aged 18-30 at baseline (1985-1986) from the Coronary Artery Risk Development in Young Adults study were enrolled and followed up over 25 years. LCω3PUFA and fish intake were assessed by an interview-based dietary history questionnaire at baseline, year 7 (1992-1993) and 20 (2005-2006). RESULTS: Four hundred and eighty-nine incident cases of CKD were identified. After adjustment for potential confounders, LCω3PUFA intake was inversely associated with CKD incidence [HR = 0.73 (95% CI 0.60-0.89), P = 0.002, with one standard division (0.19 g/day) increment in LCω3PUFA]. This inverse association was persisted among females [0.64 (95% CI 0.48, 0.84; P = 0.002], but not males (Pinteraction = 0.070). A marginal significant inverse association was also found between non-fried fish consumption and CKD incidence (HR = 0.86, 95% CI 0.73, 1.01; P = 0.073). CONCLUSIONS: Dietary LCω3PUFA intake was inversely associated with incidence of CKD among American young adults over 25 years of follow-up. The suggestive evidence of the inverse association between non-fried fish consumption with CKD incidence needs further confirmation.

A Randomized Crossover Trial of Dietary Sodium Restriction in Stage 3-4 CKD.

BACKGROUND AND OBJECTIVES: Patients with chronic kidney disease (CKD) are often volume expanded and hypertensive. Few controlled studies have assessed the effects of a sodium-restricted diet (SRD) in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a randomized crossover trial to evaluate the effect of SRD (target <2 g sodium per day) versus usual diet on hydration status (by bioelectrical impedance spectroscopy) and blood pressure (BP) between May of 2009 and May of 2013. A total of 58 adults with stage 3-4 CKD were enrolled from two academic sites: University of Michigan (n=37) and University of North Carolina at Chapel Hill (n=21); 60% were men, 43% were diabetic, 93% were hypertensive, and mean age was 61 years. Participants followed SRD or usual diet for 4 weeks, followed by a 2-week washout period and a 4-week crossover phase. During the SRD, dieticians provided counseling every 2 weeks, using motivational interviewing techniques. RESULTS: Whole-body extracellular volume and calf intracellular volume decreased by 1.02 L (95% confidence interval [95% CI], -1.48 to -0.56; P<0.001) and -0.06 L (95% CI, -0.12 to -0.01; P=0.02), respectively, implying decreased fluid content on the SRD compared with usual diet. Significant reductions in urinary sodium (-57.3 mEq/24 h; 95% CI, -81.8 to -32.9), weight (-2.3 kg; 95% CI, -3.2 to -1.5), and 24-hour systolic BP (-10.8 mmHg; 95% CI, -17.0 to -4.6) were also observed (all P<0.01). Albumin-to-creatinine ratio did not change significantly and mean serum creatinine increased slightly (0.1 mg/dl; 95% CI, -0.01 to 0.2; P=0.06). No period or carryover effects were observed. Results were similar when analyzed from phase 1 only before crossover, although P values were modestly larger because of the loss of power. CONCLUSIONS: In this randomized crossover trial, implementation of SRD in patients with CKD stage 3-4 resulted in clinically and statistically significant improvement in BP and hydration status. This simple dietary intervention merits a larger trial in CKD to evaluate effects on major clinical outcomes.

Variable clinical presentation of an MUC1 mutation causing medullary cystic kidney disease type 1.

BACKGROUND AND OBJECTIVES: The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation). RESULTS: Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to >80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract. CONCLUSION: MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

Sodium phosphate does not increase risk for acute kidney injury after routine colonoscopy, compared with polyethylene glycol.

BACKGROUND & AIMS: Oral sodium phosphate (OSP) is a common bowel purgative administered before colonoscopy; the Food and Drug Administration has warned against its use because of concerns about acute kidney injury (AKI) from the absorbed phosphate and dystrophic calcification. However, it is not clear if OSP is associated with AKI in the general population or in high-risk subgroups undergoing colonoscopy. We estimated the risk of AKI among patients undergoing a screening colonoscopy using OSP vs polyethylene glycol (PEG) for bowel cleansing in a large, US-based claims database. METHODS: We used an insurance database to identify a cohort of patients ages 50 to 75 years who underwent screening colonoscopies as outpatients from January 2000 through November 2008 (before the Food and Drug Administration warning), receiving OSP (n = 121,266) or PEG (n = 429,430) within 30 days beforehand, without prior use of either drug. We collected data from patients for 6 months afterward to identify those who developed AKI or renal failure, or received dialysis. Adjusted and propensity score-matched hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. We investigated the effects in subgroups with higher AKI risk (patients with chronic kidney disease, kidney stones, hypertension, or diabetes, or using antihypertensive or nonsteroidal anti-inflammatory drugs). RESULTS: AKI occurred in 0.2% of OSP users and in 0.3% of PEG users (adjusted HR, 0.86; 95% CI, 0.75-0.99). OSP users matched well with PEG users, producing similar estimates (HR, 0.85; 95% CI, 0.72-1.01). We did not observe a consistent increase in the risk of AKI or other outcomes in any subgroups analyzed. CONCLUSIONS: In a large database analysis, we did not associate administration of OSP before colonoscopy with increased risk of postprocedure AKI, even in high-risk clinical subgroups.

Risk of high dietary calcium for arterial calcification in older adults.

Concern has recently arisen about the potential adverse effects of excessive calcium intakes, i.e., calcium loading from supplements, on arterial calcification and risks of cardiovascular diseases (CVD) in older adults. Published reports that high calcium intakes in free-living adults have relatively little or no beneficial impact on bone mineral density (BMD) and fracture rates suggest that current recommendations of calcium for adults may be set too high. Because even healthy kidneys have limited capability of eliminating excessive calcium in the diet, the likelihood of soft-tissue calcification may increase in older adults who take calcium supplements, particularly in those with age or disease-related reduction in renal function. The maintenance of BMD and bone health continues to be an important goal of adequate dietary calcium consumption, but eliminating potential risks of CVDs from excessive calcium intakes needs to be factored into policy recommendations for calcium by adults.

Association of race and body mass index with ESRD and mortality in CKD stages 3-4: results from the Kidney Early Evaluation Program (KEEP).

BACKGROUND: A recent cross-sectional analysis of Kidney Early Evaluation Program (KEEP) participants suggested that obesity is a heterogeneous disease state in African Americans and whites with chronic kidney disease (CKD). STUDY DESIGN: In longitudinal analyses spanning 8 years of follow-up, we examined whether race and body mass index (BMI) influence end-stage renal disease (ESRD) and mortality rates in participants with CKD stages 3-4. SETTING & PARTICIPANTS: KEEP participants were included in this analysis if they met the following criteria: (1) estimated glomerular filtration rate (eGFR) of 15-59 mL/min/1.73 m(2), (2) white or African American race, and (3) no previous dialysis or transplantation. OUTCOMES & MEASUREMENTS: Survival analyses were performed for the outcomes of ESRD, death, and combined outcome of ESRD or death. RESULTS: Of 14,631 participants with CKD stages 3-4, 28% were African American and 72% were white. African American participants had higher rates of obesity and hypertension, with a higher baseline mean eGFR, higher prevalence of albuminuria, and greater degree of anemia compared with whites. In multivariable models, African American race increased the risk of ESRD (HR, 1.66; 95% CI, 1.26-2.07), but not death (HR, 0.89; 95% CI, 0.76-1.03). In these models, male sex, hypertension, diabetes, lower baseline eGFR, and albuminuria were predictive of higher rates of ESRD; age, male sex, diabetes, lower baseline eGFR, and albuminuria were predictive of overall mortality. There was no significant interaction between race and BMI in the adjusted model for outcomes of ESRD (P = 0.7) or death (P = 0.3). LIMITATIONS: Baseline values used in the analysis are from a cross-sectional data set. Dyslipidemia and secondary hyperparathyroidism were not accounted for in the analysis. CONCLUSIONS: African American race was associated with a higher incidence of ESRD, but not mortality. Although obesity may be a heterogeneous disease state in African Americans and whites with CKD, there does not appear to be a significant interaction between race and BMI in progression to ESRD or death.

Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.

Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade.

Mineralocorticoid receptor blockade in chronic kidney disease.

Mineralocorticoid receptor blockers (MRBs) have proven highly successful in the treatment of congestive heart failure and resistant hypertension. In contrast, their use in chronic kidney disease (CKD) has lagged due to the concern of hyperkalemia and, possibly, because of the incorrect assumption that traditional therapy with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers consistently reduce aldosterone activity in all patients. Low-dose MRB therapy may offer additional antihypertensive and unique anti-inflammatory benefits in select CKD populations.

Mineralocorticoid receptor blockade in chronic kidney disease.

Aldosterone antagonists have been highly successful in treating congestive heart failure and resistant hypertension. Until recently, therapies targeting the mineralocorticoid receptor in chronic kidney disease (CKD) have received little attention, largely because of the risk of hyperkalemia and the incorrect assumption that traditional therapy with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both consistently reduces activity of the renin-angiotensin system in all patients. Control of extracellular volume and low-dose mineralocorticoid receptor blocker therapy may offer additional antihypertensive and anti-inflammatory benefits in select CKD populations.

High-output heart failure secondary to arteriovenous fistula.

In the hemodialysis patient population, a surgically created arteriovenous fistula is the preferred vascular access option. Development of high-output heart failure may be an underappreciated complication in patients who have undergone this procedure. When a large proportion of arterial blood is shunted from the left-sided circulation to the right-sided circulation via the fistula, the increase in preload can lead to increased cardiac output. Over time, the demands of an increased workload may lead to cardiac hypertrophy and eventual heart failure. Patients may present with the usual signs of high-output heart failure including tachycardia, elevated pulse pressure, hyperkinetic precordium, and jugular venous distension. Typically, the AV fistula is quite large and is likely located in the upper arm, more proximal to the heart. Routine access flow monitoring should demonstrate blood flows (Qa) >2000 ML/min. Echocardiogram may reveal either a low or high left ventricular ejection fraction, and right-heart catheterization demonstrates an elevated cardiac output with a low to normal systemic vascular resistance. When addressing the problem of high-output heart failure, the nephrologist is faced with the dilemma of preventing progression of heart failure at the expense of loss of vascular access. Nevertheless, treatment should be directed at correcting the underlying problem by surgical banding or ligation of the fistula.

Racial differences in kidney function among individuals with obesity and metabolic syndrome: results from the Kidney Early Evaluation Program (KEEP).

BACKGROUND: Obesity and metabolic syndrome may differ by race. For participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP), we examined whether African American and white participants with obesity and metabolic syndrome differ regarding albuminuria, estimated glomerular filtration rate (eGFR), anemia, and bone/mineral metabolism derangements in chronic kidney disease (CKD). METHODS: 3 study cohorts were assembled: (1) eligible African American and white KEEP participants with body mass index > or = 30 kg/m(2), (2) a subgroup meeting criteria for metabolic syndrome, and (3) a subgroup with eGFR < 60 mL/min/1.73 m(2) and laboratory measurements for hemoglobin, parathyroid hormone, calcium, and phosphorus. Patient characteristics and kidney function assessments were compared and tested using chi(2) (categorical variables) and t test (continuous variables). Univariate and multivariate logistic regression analyses were performed to evaluate associations of race with kidney disease measures. RESULTS: Of 37,107 obese participants, 48% were African American and 52% were white. Whites were more likely to have metabolic syndrome components (hypertension, 87.1% vs 84.8%; dyslipidemia, 81.6% vs 66.7%; diabetes, 42.7% vs 34.9%) and more profoundly decreased eGFR than African Americans (CKD stages 3-5 prevalence, 23.6% vs 13.0%; P < 0.001). African Americans were more likely to have abnormal urinary albumin excretion (microalbuminuria, 12.5% vs 10.2%; OR, 1.60 [95% CI, 1.45-1.76]; macroalbuminuria, 1.3% vs 1.2%; OR, 1.61 [95% CI, 1.23-2.12]) and CKD stages 1-2 (10.3% vs 7.1%; OR, 1.54 [95% CI, 1.38-1.72]). For participants with CKD stages 3-5, anemia prevalence was 32.4% in African Americans and 14.1% in whites; corresponding values for secondary hyperparathyroidism were 66.2% and 46.6%, respectively. CONCLUSIONS: Obesity and metabolic syndrome may be heterogeneous disease states in African Americans and whites, possibly explaining differences in long-term kidney and cardiovascular outcomes.

Disordered aldosterone-volume relationship in end-stage kidney disease.

INTRODUCTION: Sodium loading, and subsequent volume expansion, suppresses aldosterone levels in individuals with normal renal function. We hypothesised that loss of renal function impairs this volume-aldosterone relationship. MATERIALS AND METHODS: With multifrequency bioimpedance spectroscopy, we measured total body water (TBW), extracellular volume (ECV), and intracellular volume in five haemodialysis patients at varied states of hydration and in five healthy volunteers during low-, normal-, and high-salt diets. Serum aldosterone, potassium, and C-reactive protein were measured simultaneously. Scatterplots and general estimating equations were used to examine the relationship among these variables. RESULTS: In healthy volunteers with salt loading, and in haemodialysis subjects with increased inter-dialytic weight gain, expansion of ECV led to reciprocal declines in serum aldosterone concentrations. The relationship was more profound in healthy volunteers (p<0.001) than in haemodialysis subjects (p=0.1). Notably, haemodialysis subjects posted consistently higher levels of ECV (median 49.6% TBW, IQR 43.9-51.8% compared to 41.1%, 39.9-42.8% in volunteers) and serum aldosterone (median 26.7 ng/dl, IQR 19.8-29.6 compared to 12.4 ng/dl, 8.8-16.0 in volunteers). Serum potassium did not appear to influence aldosterone concentration (p=0.9). CONCLUSIONS: The shift of the volume-aldosterone curve in haemodialysis subjects suggests that end-stage kidney disease is a state of high volume and inappropriately high aldosterone. These data have important clinical implications, as dialysis patients may benefit from both volume reduction and mineralocorticoid receptor blockade.

Sugar-sweetened beverage consumption and the progression of chronic kidney disease in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Recent studies have examined sugar-sweetened soda consumption in relation to early markers of kidney disease, but to date there have been no investigations of whether sugar-sweetened beverage consumption affects preexistent chronic kidney disease (CKD). OBJECTIVE: This prospective cohort study of 447 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with preexistent CKD examined the association between sugar-sweetened beverage consumption (<1 drink/wk, 1-6 drinks/wk, and > or =1 drink/d) and progression of CKD. DESIGN: beta-Coefficients for continuous outcomes of changes in estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) were calculated by using linear regression. Odds ratios for binary outcomes of accelerated decline in eGFR, defined as >2 mL x min(-1) x 1.73 m(-2) per year, and clinically significant progression of albuminuria (defined as attainment of UACR > or =30 mg/g for participants without microalbuminuria at visit 1 or a > or =25% increase in UACR for participants with baseline microalbuminuria) were evaluated by using logistic regression. RESULTS: The mean (+/-SD) baseline eGFR was 52 +/- 6 mL x min(-1) x 1.73 m(-2) per year, and median baseline UACR was 6.3 mg/g (interquartile range: 3.5-17.6). Univariate and multivariate analyses showed no association between sugar-sweetened beverage consumption and rate of eGFR decline or changes in urinary albumin to creatinine ratio. The multivariate odds ratios comparing participants who drank > or =1 sugary beverage daily with those who drank < or =1 beverage weekly were 0.62 (95% CI: 0.27, 1.41) for accelerated eGFR decline and 1.51 (95% CI: 0.49, 4.62) for clinically significant progression of albuminuria. CONCLUSION: A higher consumption of sugar-sweetened beverages was not associated with disease progression, on the basis of either eGFR or the urinary albumin to creatinine ratio, in MESA participants with preexistent CKD.

Interaction of aldosterone and extracellular volume in the pathogenesis of obesity-associated kidney disease: a narrative review.

Obesity and obesity-associated kidney injuries have played an important role in the rising prevalence of chronic kidney disease (CKD). The link between obesity and kidney disease begins with obesity's well-known associations with diabetes and hypertension, the two leading etiologies of CKD. However, a growing body of evidence suggests that elevated aldosterone levels and expanded extracellular volume are key components of obesity-induced renal disease via aldosterone's non-epithelial effects on the kidney. Highlighting these blood pressure- and diabetes-independent mechanisms of kidney injury in obesity allows an exploration of whether mineralocorticoid receptor blockade, coupled with weight loss and salt restriction, is an optimal treatment for overweight CKD patients.

Extracellular volume and aldosterone interaction in chronic kidney disease.

Since the advent of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, little attention has been given to the potential proinflammatory effects of aldosterone in high-volume states on the kidney and cardiovascular system. In order to be correctly interpreted, aldosterone levels require a volume cofactor which can now be determined by measurement of extracellular fluid volume by means of bioimpedance. Chronic kidney disease patients frequently have expanded extracellular volume (ECV) in the presence of elevated aldosterone levels. This combination may lead to cardiovascular and renal inflammation and fibrosis that can be mitigated by more precise control of ECV and/or blockade of the mineralocorticoid receptor.

Periodontal disease adversely affects the survival of patients with end-stage renal disease.

Periodontal disease is associated with cardiovascular disease and is thought to accelerate systemic atherosclerosis. Here we examined the relationship between periodontitis and cardiovascular disease mortality in outpatients on hemodialysis using a retrospective analysis of 168 adult patients in New York City and North Carolina. During 18 months of follow-up, cardiovascular disease and all-cause mortality were determined from a centralized dialysis registry. One hundred patients had mild or no periodontal disease but the remaining 68 had moderate-to-severe disease defined as 2 or more teeth with at least 6 mm of inter-proximal attachment loss. At baseline, the proportion of males was significantly lower in the moderate-to-severe group. Compared with mild or no periodontal disease, moderate-to-severe disease was significantly associated with death from cardiovascular causes. Adjustment for age, gender, center and dialysis vintage, smoking status, and history of diabetes mellitus or hypertension did not diminish the strength of this association. Our findings suggest a need for larger studies to confirm this connection, along with intervention trials to determine if treating periodontitis reduces cardiovascular disease mortality in dialysis patients.