Sodium Bicarbonate Treatment and Vascular Function in CKD: A Randomized, Double-Blind, Placebo-Controlled Trial.

SIGNIFICANCE STATEMENT: Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. In this randomized, controlled trial, treatment with sodium bicarbonate (NaHCO 3 ) did not improve vascular endothelial function or reduce arterial stiffness in participants with CKD stage 3b-4 with normal serum bicarbonate levels. In addition, NaHCO 3 treatment did not reduce left ventricular mass index. NaHCO 3 did increase plasma bicarbonate levels and urinary citrate excretion and reduce urinary ammonium excretion, indicating that the intervention was indeed effective. NaHCO 3 therapy was safe with no significant changes in BP, weight, or edema. These results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD. BACKGROUND: Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. Prospective interventional trials with sodium bicarbonate (NaHCO 3 ) are lacking. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of NaHCO 3 on vascular function in 109 patients with CKD stage 3b-4 (eGFR 15-44 ml/min per 1.73 m 2 ) with normal serum bicarbonate levels (22-27 mEq/L). Participants were randomized 1:1 to NaHCO 3 or placebo at a dose of 0.5 mEq/lean body weight-kg per day for 12 months. The coprimary end points were change in brachial artery flow-mediated dilation (FMD) and change in aortic pulse wave velocity over 12 months. RESULTS: Ninety patients completed this study. After 12 months, plasma bicarbonate levels increased significantly in the NaHCO 3 group compared with placebo (mean [SD] difference between groups 1.35±2.1, P = 0.003). NaHCO 3 treatment did not result in a significant improvement in aortic pulse wave velocity from baseline. NaHCO 3 did result in a significant increase in flow-mediated dilation after 1 month; however, this effect disappeared at 6 and 12 months. NaHCO 3 resulted in a significant increase in 24-hour urine citrate and pH and a significant decrease in 24-hour urine ammonia. There was no significant change in left ventricular mass index, ejection fraction, or eGFR with NaHCO 3 . NaHCO 3 treatment was safe and well-tolerated with no significant changes in BP, antihypertensive medication, weight, plasma calcium, or potassium levels. CONCLUSION: Our results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD and normal serum bicarbonate levels.

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.

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.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. RESULTS: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. CONCLUSIONS: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.

Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants.

Although often considered to be a disease of adults, complications of autosomal dominant polycystic kidney disease (ADPKD) begin in childhood. While the hallmark of ADPKD is the development and continued growth of multiple renal cysts that ultimately result in loss of kidney function, cardiovascular complications are the leading cause of death among affected patients. Vascular dysfunction (endothelial dysfunction and large elastic artery stiffness) is evident very early in the course of the disease and appears to involve increased oxidative stress and inflammation. Treatment options to prevent cardiovascular disease in adults with ADPKD are limited, thus childhood may represent a key therapeutic window. Curcumin is a safe, naturally occurring polyphenol found in the Indian spice turmeric. This spice has a unique ability to activate transcription of key antioxidants, suppress inflammation, and reduce proliferation. Here we describe our ongoing randomized, placebo-controlled, double-blind clinical trial to assess the effect of curcumin therapy on vascular function and kidney growth in 68 children and young adults age 6-25 years with ADPKD. Baseline demographic, vascular, and kidney volume data are provided. This study has the potential to establish a novel, safe, and facile therapy for the treatment of arterial dysfunction, and possibly renal cystic disease, in an understudied population of children and young adults with ADPKD.

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.

Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD. STUDY DESIGN: Prospective, randomized, controlled, double-blind, clinical trial. SETTING & PARTICIPANTS: 61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor. INTERVENTION: Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks. OUTCOMES: Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point. RESULTS: 60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress. LIMITATIONS: Low level of baseline vascular dysfunction; lack of aldosterone measurements. CONCLUSIONS: 24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD. FUNDING: NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01853553.

Vascular Dysfunction, Oxidative Stress, and Inflammation in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: Both increased arterial stiffness and vascular endothelial dysfunction are evident in patients with autosomal dominant polycystic kidney disease, even early in the course of the disease when kidney function in preserved. Vascular dysfunction in autosomal dominant polycystic kidney disease is thought to be related to vascular oxidative stress and inflammation, but direct evidence is lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed carotid-femoral pulse-wave velocity (arterial stiffness) and brachial artery flow-mediated dilation (vascular endothelial function) in participants with early-stage autosomal dominant polycystic kidney disease (eGFR≥60 ml/min per 1.73 m2) and a history of controlled hypertension and in healthy controls. Brachial artery flow-mediated dilation was also assessed after infusion of ascorbic acid to inhibit vascular oxidative stress compared with saline. Vascular endothelial cells were collected from a peripheral vein to measure expression of proteins, and circulating markers were also assessed by ELISA or liquid chromatography-tandem mass spectrometry. RESULTS: In total, 61 participants with autosomal dominant polycystic kidney disease (34±9 years old [mean±SD]) and 19 healthy controls (30±5 years old) were studied. Carotid-femoral pulse-wave velocity was higher in participants with autosomal dominant polycystic kidney disease compared with healthy controls (650±131 versus 562±81 cm/s; P=0.007). Brachial artery flow-mediated dilation was 8.2%±5.8% in participants with autosomal dominant polycystic kidney disease and 10.8%±4.7% in controls (P=0.08). Among participants with autosomal dominant polycystic kidney disease, flow-mediated dilation increased from 7.7%±4.5% to 9.4%±5.2% with ascorbic acid, a difference of 1.72 (95% confidence interval, 0.80 to 2.63), whereas in control participants, flow-mediated dilation decreased nonsignificantly from 10.8%±4.7% to 10.6%±5.4%, a difference of -0.20 (95% confidence interval, -1.24 to 0.84; P interaction =0.02). Endothelial cell protein expression of NF-κB was greater in participants with autosomal dominant polycystic kidney disease (0.48±0.12 versus 0.41±0.10 [intensity versus human umbilical vein endothelial cell control]; P=0.03). However, circulating oxidative stress markers and bioactive lipid mediators did not significantly differ according to the autosomal dominant polycystic kidney disease diagnosis. CONCLUSIONS: These results provide support for the hypothesis that vascular oxidative stress and inflammation develop with autosomal dominant polycystic kidney disease. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_18_CJASNPodcast_18_10_.mp3.

Cholecalciferol, Calcitriol, and Vascular Function in CKD: A Randomized, Double-Blind Trial.

BACKGROUND AND OBJECTIVES: High circulating vitamin D levels are associated with lower cardiovascular mortality in CKD, possibly by modifying endothelial function. We examined the effect of calcitriol versus cholecalciferol supplementation on vascular endothelial function in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a prospective, double-blind, randomized trial of 128 adult patients with eGFR=15-44 ml/min per 1.73 m2and serum 25-hydroxyvitamin D level <30 ng/ml at the University of Colorado. Participants were randomly assigned to oral cholecalciferol (2000 IU daily) or calcitriol (0.5 µg) daily for 6 months. The primary end point was change in brachial artery flow-mediated dilation. Secondary end points included changes in circulating markers of mineral metabolism and circulating and cellular markers of inflammation. RESULTS: One hundred and fifteen patients completed the study. The mean (SD) age and eGFR of participants were 58±12 years old and 33.0±10.2 ml/min per 1.73 m2, respectively. There were no significant differences between groups at baseline. After 6 months, neither calcitriol nor cholecalciferol treatment resulted in a significant improvement in flow-mediated dilation (mean±SD percentage flow-mediated dilation; calcitriol: baseline 4.8±3.1%, end of study 5.1±3.6%; cholecalciferol: baseline 5.2±5.2%, end of study 4.7±3.6%); 25-hydroxyvitamin D levels increased significantly in the cholecalciferol group compared with the calcitriol group (cholecalciferol: 11.0±9.5 ng/ml; calcitriol: -0.8±4.8 ng/ml; P<0.001). Parathyroid hormone levels decreased significantly in the calcitriol group compared with the cholecalciferol group (median [interquartile range]; calcitriol: -22.1 [-48.7-3.5] pg/ml; cholecalciferol: -0.3 [-22.6-16.9] pg/ml; P=0.004). CONCLUSIONS: Six months of therapy with calcitriol or cholecalciferol did not improve vascular endothelial function or improve inflammation in patients with CKD.

Interleukin-1 inhibition, chronic kidney disease-mineral and bone disorder, and physical function
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OBJECTIVE: Epidemiologic studies have suggested a link between chronic systemic inflammation and chronic kidney disease-mineral and bone disorder (CKD-MBD). Additionally, declining renal function is associated with worsening physical and cognitive function, which may potentially be explained by systemic inflammation, CKD-MBD, or both. We hypothesized that inhibiting inflammation with an interleukin-1 (IL-1) trap would improve markers of CKD-MBD as well as physical/cognitive function in patients with moderate-to-severe CKD. METHODS: In a two-site, double-blind trial, 39 patients with stage 3 - 4 CKD completed a randomized trial receiving either the IL-1 trap rilonacept (160 mg/week) or placebo for 12 weeks. The following CKD-MBD markers were assessed in serum before and after the intervention: calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF23). A battery of tests was also administered in a subgroup (n = 23) to assess multiple domains of physical function (endurance, locomotion, dexterity, balance, strength, and fatigue) and cognitive function. RESULTS: Participants were 65 ± 10 years of age, 23% female, and had a mean estimated glomerular filtration rate of 38 ± 13 mL/min/1.73m2. There were no changes in serum calcium, phosphorus, any vitamin D metabolite, iPTH, or FGF23 levels (p ≥ 0.28) with IL-1 inhibition. Similarly, rilonacept did not alter locomotion, dexterity, balance, strength, fatigue, or cognitive function (p ≥ 0.13). However, endurance (400-m walk time) tended to improve in the rilonacept (-31 s) vs. placebo group (-2 s; p = 0.07). CONCLUSIONS: In conclusion, 12 weeks of IL-1 inhibition did not improve markers of CKD-MBD or physical function.
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IL-1 Inhibition and Vascular Function in CKD.

Vascular endothelial dysfunction and increased arterial stiffness contribute to increased cardiovascular risk in patients with CKD who exhibit chronic systemic inflammation. Because chronic inflammation contributes to vascular dysfunction, blocking inflammation may reduce cardiovascular risk in patients with CKD. In a two-site, double-blind trial, we randomized 42 adult patients with stage 3-4 CKD who were already receiving optimal background therapy to receive either IL-1 trap rilonacept or placebo for 12 weeks. Coprimary end points included change in brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV) after 4, 8, and 12 weeks. Exploratory end points included change in high-sensitivity C-reactive protein (hsCRP), FMDBA after acute ascorbic acid infusion, and vascular endothelial cell protein expression of NADPH oxidase. Participants were 63±11 (mean±SD) years of age and 24% were women; mean eGFR was 38±13 ml/min per 1.73 m2 Compared with placebo, rilonacept improved FMDBA (baseline: 3.36%±2.06% [mean±SD], 12 weeks: 2.45%±2.29% with placebo and baseline: 3.75%±3.12%, 12 weeks: 4.86%±3.20% with rilonacept; P<0.01), without changing aPWV (P=0.56). Rilonacept also reduced hsCRP levels (median [interquartile range]) (baseline: 4.60 [1.90-8.22] mg/L, 12 weeks: 2.16 [0.92-7.38] mg/L; P<0.01) and endothelial cell NADPH oxidase expression (P<0.05). Acute infusion of ascorbic acid to inhibit superoxide production associated with a nonsignificant trend toward increased FMDBA in the placebo group (P=0.07) but not the rilonacept group (P=0.56). Rilonacept was well tolerated (five adverse events versus two with placebo). In conclusion, treatment with an IL-1 trap improved FMDBA without changing aPWV and reduced systemic inflammation in patients with CKD.