Cerebrovascular Pulsatility Index Is Reduced in Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Cerebrovascular dysfunction, characterized by increased brain pulsatile flow, reduced cerebrovascular reactivity, and cerebral hypoperfusion precedes the onset of dementia and is linked to cognitive dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of dementia, and intracranial aneurysms are more prevalent in ADPKD patients. However, cerebrovascular function has not been previously characterized in patients with ADPKD. METHODS: Using transcranial Doppler, we compared middle cerebral artery (MCA) pulsatility index (PI, cerebrovascular stiffness) and MCA blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO2, cerebrovascular reactivity) in patients with early-stage ADPKD versus age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function) and measured carotid-femoral pulse-wave velocity (PWV, aortic stiffness). RESULTS: Fifteen participants with ADPKD (9F, 27 ± 4 yrs, eGFR: 106 ± 22 mL/min/1.73 m2) were compared to 15 healthy controls (8F, 29 ± 4 yrs, eGFR: 109 ± 14 mL/min/1.73 m2). MCA PI was unexpectedly lower in ADPKD (0.71 ± 0.07) versus controls (0.82 ± 0.09 AU; p < 0.001); however, normalized MCA blood velocity in response to hypercapnia did not differ between groups (2.0 ± 1.2 vs. 2.1 ± 0.8 %Δ/mm Hg; p = 0.85). Lower MCA PI was associated with a lower crystalized composite score (cognition), which persisted after adjustment for age, sex, eGFR, and education (ß = 0.58, p = 0.007). There was no association of MCA PI with carotid-femoral PWV (r = 0.01, p = 0.96), despite greater carotid-femoral PWV in ADPKD, suggesting MCA PI reflects vascular properties other than arterial stiffness (such as low wall shear stress) in ADPKD. DISCUSSION/CONCLUSION: MCA PI is lower in patients with ADPKD. Follow-up research on this observation is merited as low PI has been associated with intracranial aneurysm in other populations.

Nonpharmacological Management of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease is a slowly progressive, lifelong disease characterized by continuous development and enlargement of kidney cysts. Thus, nonpharmacological interventions are crucial in disease management and have the potential for a large clinical impact as standalone interventions or in conjunction with pharmacological therapies. Current potential strategies regarding nonpharmacological management of autosomal dominant polycystic kidney disease include nonpharmacological management of blood pressure, calorie restriction, weight loss or weight management, enhanced hydration, limiting caffeine, dietary sodium restriction, protein restriction or altering the type of protein intake, phosphorus restriction, and reducing net acid load. This brief review discusses the available evidence, including cell culture, animal, epidemiological, and clinical studies, regarding the utility of such strategies in the nonpharmacological management of autosomal dominant polycystic kidney disease. We assert that lifestyle modification strategies should be a critical aspect of the treatment of autosomal dominant polycystic kidney disease, while further trial and mechanistic evidence continue to become available.

Cerebrovascular pulsatility index is higher in chronic kidney disease.

Patients with chronic kidney disease (CKD) are more likely to die of cardiovascular diseases, including cerebrovascular disease, than to progress to end-stage kidney disease. Cerebrovascular dysfunction, characterized by reduced cerebrovascular reactivity, cerebral hypoperfusion, and increased pulsatile flow within the brain, precedes the onset of dementia and is linked to cognitive dysfunction. However, whether impaired cerebrovascular function is present in non-dialysis dependent CKD is largely unknown. Using transcranial Doppler, we compared middle cerebral artery (MCA) blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO2 ; a measure of cerebrovascular reactivity) and MCA pulsatility index (PI; a measure of cerebrovascular stiffness) in patients with stage 3-4 CKD vs. age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function), measured carotid-femoral pulse-wave velocity (PWV; aortic stiffness), and assessed ex vivo nitric oxide (NO) and reactive oxygen species (ROS) production from human brain endothelial cells incubated with serum obtained from study participants. MCA PI was higher in patients with CKD vs. controls; however, normalized MCA blood velocity response to hypercapnia did not differ between groups. Similar results were observed in a validation cohort of midlife and older adults divided by the median estimated glomerular filtration rate (eGFR). MCA PI was associated with greater large-elastic artery stiffness (carotid-femoral PWV), worse executive function (trails B time), lower eGFR, and higher ex vivo ROS production. These data suggest that impaired kidney function is associated with greater cerebrovascular stiffness, which may contribute to the known increased risk for cognitive impairment in patients with CKD.

Sex hormones and the risk of cardiovascular disease and mortality in male and female patients with chronic kidney disease: A systematic review and meta-analysis.

Patients with chronic kidney disease (CKD) commonly experience sex hormone disturbances, which may be associated with the risk of cardiovascular disease (CVD) and mortality. This review aimed to systematically evaluate current findings on the association of sex hormone levels with the risk of CVD events and mortality (CVD and all-cause) in the CKD population. Articles were systematically searched in CINAHL, Cochrane, and PubMed. A total of 1739 articles were independently screened by two reviewers and 17 prospective cohort studies were included. The clinical conditions of the patients were those with non-dialysis CKD [mean/median estimated glomerular filtration rate (eGFR) between 15-51 ml/min/1.73 m2 ] and those on chronic dialysis (mean/median vintage between 6-125 months). The sample size ranged from 111 to 2419 and the mean/median age of subjects ranged from 52 to 72 years. The sex hormones studied were testosterone, estradiol, prolactin, dehydroepiandrosterone sulfate, and relaxin. A random-effects model was used to generate a pooled hazard ratio (HR) to evaluate the association of total testosterone levels with the risk of CVD and all-cause mortality. Most studies examined total testosterone levels (11 out of 17 studies) and studied only male patients (12 out of 17 studies). A lower total testosterone level was associated with a higher risk of CVD mortality [HR 4.37 (95% CI 1.40-13.65)] and all-cause mortality [1.96 (1.35-2.83)] in males with CKD. To conclude, there is a strong need for additional studies examining the association of sex hormones with cardiovascular and mortality risk in female patients with CKD.

Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease.

Progression of autosomal dominant polycystic kidney disease (ADPKD) is modified by metabolic defects and obesity. Indeed, reduced food intake slows cyst growth in preclinical rodent studies. Here, we demonstrate the feasibility of daily caloric restriction (DCR) and intermittent fasting (IMF) in a cohort of overweight or obese patients with ADPKD. Clinically significant weight loss occurred with both DCR and IMF; however, weight loss was greater and adherence and tolerability were better with DCR. Further, slowed kidney growth correlated with body weight and visceral adiposity loss independent of dietary regimen. Similarly, we compared the therapeutic efficacy of DCR, IMF, and time restricted feeding (TRF) using an orthologous ADPKD mouse model. Only ADPKD animals on DCR lost significant weight and showed slowed cyst growth compared to ad libitum, IMF, or TRF feeding. Collectively, this supports therapeutic feasibility of caloric restriction in ADPKD, with potential efficacy benefits driven by weight loss.

Fasting and postprandial trimethylamine N-oxide in sedentary and endurance-trained males following a short-term high-fat diet.

Gut bacteria release trimethylamine (TMA) from dietary substrates. TMA is absorbed and is subsequently oxidized in the liver to produce trimethylamine N-oxide (TMAO). Plasma TMAO levels are positively correlated with risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). High-fat diet (HFD) consumption has been reported to increase fasting and postprandial TMAO in sedentary individuals. However, whether the increase in TMAO with consumption of an HFD is observed in endurance-trained males is unknown. Healthy, sedentary (n = 17), and endurance-trained (n = 7) males consumed a 10-day eucaloric diet comprised of 55% carbohydrate, 30% total fat, and <10% saturated fat prior to baseline testing. Blood samples were obtained in a fasted state and for a 4-hour high-fat challenge (HFC) meal at baseline and then again following 5-day HFD (30% carbohydrate, 55% total fat, and 25% saturated fat). Plasma TMAO and TMA-moiety (choline, betaine, L-carnitine) concentrations were measured using isocratic ultraperformance liquid chromatography-tandem mass spectrometry. Age (23 ±3 vs. 22 ± 2 years) and body mass index (23.0 ± 3.0 vs. 23.5 ± 2.1 kg/m2 ) were similar (both p > 0.05) in the sedentary and endurance-trained group, respectively. VO2max was significantly higher in the endurance-trained compared with sedentary males (56.7 ± 8.2 vs. 39.9 ± 6.0 ml/kg/min). Neither the HFC nor the HFD evoked a detectable change in plasma TMAO (p > 0.05) in either group. Future studies are needed to identify the effects of endurance training on TMAO production.

Use of dietary phytochemicals for inhibition of trimethylamine N-oxide formation.

Trimethylamine-N-oxide (TMAO) has been reported as a risk factor for atherosclerosis development, as well as for other cardiovascular disease (CVD) pathologies. The objective of this review is to provide a useful summary on the use of phytochemicals as TMAO-reducing agents. This review discusses the main mechanisms by which TMAO promotes CVD, including the modulation of lipid and bile acid metabolism, and the promotion of endothelial dysfunction and oxidative stress. Current knowledge on the available strategies to reduce TMAO formation are discussed, highlighting the effect and potential of phytochemicals. Overall, phytochemicals (i.e., phenolic compounds or glucosinolates) reduce TMAO formation by modulating gut microbiota composition and/or function, inhibiting host's capacity to metabolize TMA to TMAO, or a combination of both. Perspectives for design of future studies involving phytochemicals as TMAO-reducing agents are discussed. Overall, the information provided by this review outlines the current state of the art of the role of phytochemicals as TMAO reducing agents, providing valuable insight to further advance in this field of study.

Impact of short-term flavanol supplementation on fasting plasma trimethylamine N-oxide concentrations in obese adults.

The gut microbiome metabolizes choline and carnitine to release trimethylamine (TMA), which subsequently undergoes hepatic conversion to trimethylamine N-oxide (TMAO). Elevated TMAO levels are associated with cardiovascular disease and all-cause mortality risk. Dietary flavanols modulate the composition and function of the gut microbiome. Therefore, the possibility exists that these compounds could reduce intestinal TMA production and lower circulating TMAO. However, this hypothesis has never been tested in humans. A secondary analysis was performed on blood samples from a clinical study in which obese subjects at risk for insulin resistance consumed tea or cocoa flavanols in a randomized crossover design while consuming a controlled diet. These subjects generally had elevated TMAO levels (∼5 µM) compared to levels previously measured in healthy subjects (∼1 µM). None of the interventions significantly altered TMAO levels. Individual variability for choline and carnitine was relatively low. However, TMAO exhibited somewhat greater inter-individual variability. No differences in mean TMAO concentrations observed across interventions were seen based on separating subjects by glycemic status, body mass index (BMI), race, age, or gender. However, subject minimum and maximum values observed across the interventions appeared to be more strongly associated with glycemic status and age than mean values across interventions, suggesting that average TMAO values over time may be less useful than maximum or minimum values as markers of disease risk. Traditional physiological characteristics do not appear to predict TMAO responsiveness to flavanol interventions. However, African-American subjects appeared less responsive compared to non-Hispanic white subjects for both green tea and high cocoa treatments, and female subjects appeared less responsive than males for the high cocoa treatment. The present results suggest that a short-term flavanol intervention does not generally reduce fasting TMAO levels in subjects with elevated circulating TMAO.

Inulin Supplementation Does Not Reduce Plasma Trimethylamine N-Oxide Concentrations in Individuals at Risk for Type 2 Diabetes.

Trimethylamine N-oxide (TMAO) is associated with type 2 diabetes (T2DM) and increased risk of adverse cardiovascular events. Prebiotic supplementation has been purported to reduce TMAO production, but whether prebiotics reduce fasting or postprandial TMAO levels is unclear. Sedentary, overweight/obese adults at risk for T2DM (n = 18) were randomized to consume a standardized diet (55% carbohydrate, 30% fat) with 10 g/day of either an inulin supplement or maltodextrin placebo for 6 weeks. Blood samples were obtained in the fasting state and hourly during a 4-h high-fat challenge meal (820 kcal; 25% carbohydrate, 63% fat; 317.4 mg choline, 62.5 mg betaine, 8.1 mg l-carnitine) before and after the diet. Plasma TMAO and trimethylamine (TMA) moieties (choline, l-carnitine, betaine, and γ-butyrobetaine) were measured using isocratic ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). There were no differences in fasting or postprandial TMAO or TMA moieties between the inulin and placebo groups at baseline (all p > 0.05). There were no significant changes in fasting or postprandial plasma TMAO or TMA moiety concentrations following inulin or placebo. These findings suggest that inulin supplementation for 6 weeks did not reduce fasting or postprandial TMAO in individuals at risk for T2DM. Future studies are needed to identify efficacious interventions that reduce plasma TMAO concentrations.