Effect of Lanthanum Carbonate on Serum Phosphate, Oxidative Stress, and Vascular Dysfunction in Chronic Kidney Disease.

BACKGROUND: Vascular endothelial dysfunction and arterial stiffness are common in chronic kidney disease (CKD) and independently predict cardiovascular disease (CVD). Elevated serum phosphorus, even within the normal range, associates with CVD and mortality in CKD. Excess phosphorus may increase oxidative stress leading to vascular dysfunction. METHODS: Randomized double-blind trial in which we compared lanthanum carbonate, a non-calcium phosphate binder, with placebo on vascular function and endothelial and circulating measures of oxidative stress and inflammation in 54 participants with CKD 3b-4 and normal phosphorus levels. The primary endpoints were change in brachial artery flow-mediated dilation (FMDBA) and carotid-to-femoral pulse-wave velocity (cfPWV) at 12 weeks. Mechanistic endpoints were changes from baseline in FMDBA after ascorbic acid infusion and circulating and endothelial markers of oxidative stress and inflammation. RESULTS: Age was 65±8 years and eGFR 38±14 mL/min/1.73m2. At 12 weeks serum phosphorus did not change with lanthanum (3.44±0.47 mg/dL vs. 3.44±0.52 mg/dL; p=0.94) but tended to increase with placebo (3.42±0.80 mg/dL vs. 3.74±1.26 mg/dL; p=0.09). FMDBA and cfPWV did not change from baseline in either group. FMDBA lanthanum 3.13%±2.87% to 2.73%±2.48% vs. placebo 3.74%±2.86% to 3.09%±2.49%; p=0.67. cfPWV lanthanum 1214±394 cm/sec to 1216±322 cm/sec vs. placebo 993±289 cm/sec to 977±254 cm/sec; p=0.77. Ascorbic acid infusion to inhibit oxidative stress did not differentially affect FMDBA. Circulating and endothelial markers of oxidative stress and inflammation did not differ between groups. CONCLUSIONS: Lanthanum carbonate did not discernibly affect vascular endothelial function, arterial stiffness, or markers of endothelial oxidative stress among participants with CKD 3b-4 and normophosphatemia.

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AIMS: The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. METHODS: One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OUTCOMES: The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. CONCLUSION: This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing. REGISTRATION: This study is registered on Clinicaltrials.gov # NCT03273413.

Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.

Vascular Dysfunction, Oxidative Stress, and Inflammation in Chronic Kidney Disease.

BACKGROUND: Increased arterial stiffness and vascular endothelial dysfunction are important nontraditional cardiovascular risk factors evident in patients with CKD. Vascular oxidative stress and inflammation may contribute to vascular dysfunction in CKD, but direct evidence is lacking. METHODS: We assessed carotid-femoral pulse-wave velocity (arterial stiffness) and brachial artery flow-mediated dilation (vascular endothelial function) in participants with moderate-to-severe CKD (eGFR 15-59 ml/min per 1.73 m2) and in healthy controls. Change in brachial artery flow-mediated dilation after an acute infusion of ascorbic acid to inhibit vascular oxidative stress (versus saline) was also measured. Protein expression of vascular endothelial cells collected from a peripheral vein and ELISAs to assess circulating markers were also performed. RESULTS: A total of 64 participants with CKD (mean±SD, 65±8 years) and 17 healthy controls (60±5 years) were included. Carotid-femoral pulse-wave velocity was greater in participants with CKD compared with healthy controls (1071±336 versus 732±128 cm/s; P<0.001). Brachial artery flow-mediated dilation was lower in participants with CKD compared with healthy controls (3.5%±2.8% versus 5.5%±3.2%; P=0.02). Circulating inflammation markers (C-reactive protein and IL-6) were elevated in the CKD group (P≤0.02). Endothelial cell protein expression of NADPH (intensity versus human umbilical vein endothelial cell control, 1.48±0.28 versus 1.25±0.31; P=0.05) was greater in participants with CKD. However, ascorbic acid significantly improved brachial artery flow-mediated dilation in control participants (saline, 5.5±3.2; ascorbic acid, 6.8±3.6); as compared with participants with CKD (saline, 3.5±2.8; ascorbic acid, 3.6±3.2) (group×condition interaction P=0.04), suggesting vascular oxidative stress could not be overcome with ascorbic acid in participants with CKD. CONCLUSIONS: Vascular oxidative stress is present in CKD, which cannot be overcome with acute infusion of ascorbic acid.

Automatic measurement of physical mobility in Get-Up-and-Go Test using Kinect sensor.

Get-Up-and-Go Test is commonly used for assessing the physical mobility of the elderly by physicians. This paper presents a method for automatic analysis and classification of human gait in the Get-Up-and-Go Test using a Microsoft Kinect sensor. Two types of features are automatically extracted from the human skeleton data provided by the Kinect sensor. The first type of feature is related to the human gait (e.g., number of steps, step duration, and turning duration); whereas the other one describes the anatomical configuration (e.g., knee angles, leg angle, and distance between elbows). These features characterize the degree of human physical mobility. State-of-the-art machine learning algorithms (i.e. Bag of Words and Support Vector Machines) are used to classify the severity of gaits in 12 subjects with ages ranging between 65 and 90 enrolled in a pilot study. Our experimental results show that these features can discriminate between patients who have a high risk for falling and patients with a lower fall risk.