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Determining the optimal cholecalciferol dosing regimen in children with CKD: a randomized controlled trial.
Iyengar, A, Kamath, N, Reddy, HV, Sharma, J, Singhal, J, Uthup, S, Ekambaram, S, Selvam, S, Rahn, A, Fischer, DC, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2022;(2):326-334
Abstract
BACKGROUND The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2-4. METHODS An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment. RESULTS Ninety children were randomized to daily (n = 30), weekly (n = 29) or monthly (n = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity. CONCLUSION Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease.
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Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.
Bhandari, S, Kalra, PA, Berkowitz, M, Belo, D, Thomsen, LL, Wolf, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2021;(1):111-120
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Abstract
BACKGROUND The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. METHODS In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). RESULTS A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. CONCLUSIONS Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.
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Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial.
Sarraju, A, Li, J, Cannon, CP, Chang, TI, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Heerspink, HJL, et al
American heart journal. 2021;:141-148
Abstract
We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.
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Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease.
Agarwal, R, Sinha, AD, Cramer, AE, Balmes-Fenwick, M, Dickinson, JH, Ouyang, F, Tu, W
The New England journal of medicine. 2021;(27):2507-2519
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Abstract
BACKGROUND Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease. METHODS We randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed. RESULTS A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m2 of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mm Hg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group. CONCLUSIONS Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.).
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The effect of dietary nitrate on exercise capacity in chronic kidney disease: a randomized controlled pilot study.
Ramick, MG, Kirkman, DL, Stock, JM, Muth, BJ, Farquhar, WB, Chirinos, JA, Doulias, PT, Ischiropoulos, H, Edwards, DG
Nitric oxide : biology and chemistry. 2021;:17-23
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BACKGROUND Chronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients. METHODS AND RESULTS In this randomized, double-blinded crossover study, 12 Stage 3-4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m2) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 μM vs. 28.4 ± 6.6 μM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO2peak (p = 0.35). CONCLUSIONS Our findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies.
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A Randomized Trial of Short-term Treatment with Folic Acid to Reduce the Oxidative Stress of Patients with Chronic Kidney Disease.
Matsumoto, AK, Michelin, AP, Semeão, LO, Sepúlveda-Loyola, W, de Lima Pedrão, JV, Porto, GM, Arceni, BS, Moreira, EG, Delfino, VDA, Barbosa, DS
Current drug metabolism. 2021;(14):1139-1150
Abstract
BACKGROUND Increased generation of reactive oxygen and nitrogen species in chronic kidney disease (CKD) patients leads to increased oxidative stress. The antioxidant capacity of folic acid has been shown to scavenge radicals efficiently. OBJECTIVE The current study was carried out to examine the effects of folic acid treatment on biochemical and oxidative stress biomarkers in patients in different stages of CKD. METHODS This was a randomized, non-blinded, clinical trial that assessed the effects of 3 months of treatment with 5 mg of folic acid daily or no treatment in 113 outpatients within CKD stages 3a and 3b. At the end of the intervention, we analyzed the data of 66 patients treated with folic acid and 47 in the control group. Serum homocysteine levels and biochemical and oxidative/nitrosative stress biomarkers were analyzed in all patients. RESULTS In most patients, folic acid treatment normalized homocysteine levels and increased antioxidant enzyme activity (paraoxonase 1) and decreased sulfhydryl (SH) groups. In addition, oxidative biomarkers (products of nitric oxide and lipid hydroperoxide) were significantly lower post-treatment compared to baseline in the active intervention group. In the no active intervention group, no statistically significant effects were found on the oxidative and biochemical biomarkers. CONCLUSION Folic acid treatment in stages 3a-4 CKD patients effectively ameliorated their hyperhomocysteinemia and increased the activity of antioxidant enzymes, as well as decreased the levels of pro-oxidant biomarkers in stage G3a and G3b CKD patients. Folic acid treatment attenuated oxidative/nitrosative stress and may be considered as a possible strategy to improve redox status and diminish the damages associated with oxidative/nitrosative stress in CKD patients. Further studies are needed to confirm these findings. Clinical Trials Registration No.: This study is registered in the Brazilian Record of Clinical Trials (ReBEC), under reference RBR-2bfthr.
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Tailoring Health-promoting Programs for Patients with Chronic Kidney Disease: Randomized Controlled Trial.
Teng, HL, Yen, M, Fetzer, S, Sung, JM, Hung, SY
Western journal of nursing research. 2021;(2):138-150
Abstract
Research on dietary and lifestyle modifications to decrease cardiovascular risk and slow disease progression has been limited to patients in the later stages of chronic kidney disease (CKD). Studies on the effectiveness of stage-of-change-tailored interventions on lifestyle modifications for individuals with early stage CKD are limited. Using random assignment, 60 patients with early stage CKD who received up to six tailored intervention visits over 30 months were compared to 60 usual care patients on physical indicators, lifestyle behaviors, and quality of life. Tailored interventions were consistent with the trans-theoretical Model of Change. Waist circumference, nutrition, and stress management improved over time in the intervention group. There was no difference or change in quality of life. To promote a healthier lifestyle, findings suggest that clinicians working with patients with CKD should consider patients' readiness to change their behaviors as well as implementation strategies tailored for different processes of change.
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An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients.
Cosola, C, Rocchetti, MT, di Bari, I, Acquaviva, PM, Maranzano, V, Corciulo, S, Di Ciaula, A, Di Palo, DM, La Forgia, FM, Fontana, S, et al
Toxins. 2021;(5)
Abstract
Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability and constipation are typical features accompanying CKD progression and triggering chronic inflammation. In order to verify the efficacy of the innovative synbiotic formulation NATUREN G® in modulating the levels of circulating UTs, intestinal permeability and gastrointestinal symptoms, we set up a randomized, single-blind, placebo-controlled, pilot trial in stage IIIb-IV CKD patients and in healthy controls. Two-month administration of the synbiotic resulted in a decrease of free IS, as compared with the placebo-treated arm, only in the CKD group. The other UTs did not significantly change, although different trends in time (increase in the placebo arm and decrease in the synbiotic arm) were observed. Moreover, after supplementation, reduction of small intestinal permeability and amelioration of abdominal pain and constipation syndromes were observed only in the CKD group. The obtained results suggest the specificity of action of NATUREN G® in CKD and justify further validation in a wider study population.
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Randomized Trial on the Effects of Dietary Potassium on Blood Pressure and Serum Potassium Levels in Adults with Chronic Kidney Disease.
Turban, S, Juraschek, SP, Miller, ER, Anderson, CAM, White, K, Charleston, J, Appel, LJ
Nutrients. 2021;(8)
Abstract
In the general population, an increased potassium (K) intake lowers blood pressure (BP). The effects of K have not been well-studied in individuals with chronic kidney disease (CKD). This randomized feeding trial with a 2-period crossover design compared the effects of diets containing 100 and 40 mmol K/day on BP in 29 adults with stage 3 CKD and treated or untreated systolic BP (SBP) 120-159 mmHg and diastolic BP (DBP) <100 mmHg. The primary outcome was 24 h ambulatory systolic BP. The higher-versus lower-K diet had no significant effect on 24 h SBP (-2.12 mm Hg; p = 0.16) and DBP (-0.70 mm Hg; p = 0.44). Corresponding differences in clinic BP were -4.21 mm Hg for SBP (p = 0.054) and -0.08 mm Hg for DBP (p = 0.94). On the higher-K diet, mean serum K increased by 0.21 mmol/L (p = 0.003) compared to the lower-K diet; two participants had confirmed hyperkalemia (serum K ≥ 5.5 mmol/L). In conclusion, a higher dietary intake of K did not lower 24 h SBP, while clinic SBP reduction was of borderline statistical significance. Additional trials are warranted to understand the health effects of increased K intake in individuals with CKD.
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Prostacyclin analog beraprost sodium efficacy in primary glomerular disease or nephrosclerosis: Analysis of the Japanese subgroup in CASSIOPEIR study.
Kurumatani, H, Okada, K, Origasa, H, Fujita, T, Isono, M, Nakamoto, H
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):551-564
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We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 μg and 240 μg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 μg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 μg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 μg vs. placebo for baseline SCr < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m2 (P = 0.0339, HR0.67), respectively. No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 μg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m2 .