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1.
Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease.
Koomen, JV, Stevens, J, Bakris, G, Correa-Rotter, R, Hou, FF, Kitzman, DW, Kohan, DE, Makino, H, McMurray, JJV, Parving, HH, et al
Clinical pharmacology and therapeutics. 2021;(6):1631-1638
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Abstract
Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.
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A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations.
Reutens, AT, Jandeleit-Dahm, K, Thomas, M, Salim, A, De Livera, AM, Bach, LA, Colman, PG, Davis, TME, Ekinci, EI, Fulcher, G, et al
Contemporary clinical trials. 2020;:105892
Abstract
PURPOSE Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DESIGN This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. PRIMARY OUTCOME MEASURES Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. CONCLUSION This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.
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Fenofibrate decreased microalbuminuria in the type 2 diabetes patients with hypertriglyceridemia.
Sun, X, Liu, J, Wang, G
Lipids in health and disease. 2020;(1):103
Abstract
BACKGROUND This study was to research the efficacy of fenofibrate in the treatment of microalbuminuria in the patients with type 2 diabetes mellitus (T2DM) and hypertriglyceridemia. METHODS Type 2 diabetic patients (56) with microalbuminuria and hypertriglyceridemia aged 30 to 75 were randomly divided into the fenofibrate treatment group(n = 28) and the control group (n = 28) for 180 days. Urinary microalbumin /creatinine ratio (UACR) and other metabolic parameters were compared at baseline, during treatment and after treatment. RESULTS After 180 days, the reduction of level of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) between two groups showed no difference. In the treatment group, uric acid (UA) (296.42 ± 56.41 vs 372.46 ± 72.78), triglyceride (TG) [1.51(1.17, 2.06) vs 3.04(2.21, 3.29)], and UACR [36.45 (15.78,102.41) vs 129.00 (53.00, 226.25)] were significantly decreased compared with the baseline. The high-density lipoprotein cholesterol (HDL-C) levels were significantly increased (1.22 ± 0.26 vs 1.09 ± 0.24) compared with the baseline. The decrease in UACR [- 44.05(- 179.47, - 12.16) vs - 8.15(- 59.69, 41.94)]in treatment group was significantly higher compared with the control group. The decrease in UACR was positively associated with the decreases in TG (r = 0.447, P = 0.042) and UA (r = 0.478, P = 0.024) after fenofibrate treatment. CONCLUSION In the patients with hypertriglyceridemia and type 2 diabetes mellitus, fenofibrate can improve microalbuminuria and do not increase the deterioration of glomerular filtration rate. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02314533, 2014.12.9.
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Evaluation of the efficacy and safety of TWHF in diabetic nephropathy patients with overt proteinuria and normal eGFR.
Xiong, C, Li, L, Bo, W, Chen, H, XiaoWei, L, Hongbao, L, Peng, Z
Journal of the Formosan Medical Association = Taiwan yi zhi. 2020;(3):685-692
Abstract
BACKGROUND/PURPOSE The aim of this study was to evaluate the efficacy and safety of Tripterygium Wilfordii Hook F (TWHF) in DN patients with overt proteinuria and normal eGFR. METHODS 124 eligible DN patients were randomly assigned into two groups to receive either valsartan 160 mg/d treatment (control group) or TWHF 60 mg/d plus valsartan 160 mg/d treatments (TWHF group) for 24 weeks. The changes of clinical, biochemical data and adverse events during observation period were all analyzed. The primary endpoint was a reduction in 24-h urine protein excretion between baseline and the end of study, the secondary endpoint was to observe the change in estimated glomerular filtration rate (eGFR) between two groups. RESULTS After treatment, there was a more significant decrease in proteinuria in patients who received TWHF treatment (from 4.95 ± 1.27 g/24 h to 3.36 ± 0.83 g/24 h) compared to valsartan monotherapy (from 5.21 ± 1.59 g/24 h to 4.52 ± 1.06 g/24 h). The percentage change in urine protein excretion was -32.12% in TWHF group and -13.24% in valsartan group. Patients' plasma albumin in TWHF group (from 32.53 ± 5.24 g/L to 36.91 ± 4.42 g/L) was higher than that in control group (from 33.18 ± 4.87 g/L to 34.67 ± 4.75 g/L). No significant change in blood pressure, blood glucose, eGFR, and serum potassium was observed. But the adverse events in TWHF group were higher than those in control group. CONCLUSION TWHF is more effective than valsartan monotherapy in reduction of proteinuria in DN patients with overt proteinuria and normal eGFR, but with more adverse effects.
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Curative Effects of Valsartan Alone or Combined with Alpha-lipoic Acid on Inflammatory Cytokines and Renal Function in Early-stage Diabetic Kidney Disease.
Jiang, Z, Tan, Z, Meng, F, Li, X
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2019;(10):1009-1011
Abstract
The aim of this study was to compare curative effects of valsartan alone or combined with alpha-lipoic acid (ALA) on inflammatory cytokine indices including hypersensitive C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and renal function indices including urinary albumin excretion rate (UAER), β2-microglobulin (β2-MG) and cystatin C (Cys C) of patients with early-stage diabetic kidney disease (DKD). One hundred and two patients with early-stage DKD were randomly divided into group A and group B, with 51 patients in each group. Group A was administered with valsartan alone, while group B was administered with valsartan combined with ALA. Research showed that 14 days after treatment, group B had significantly lowered hs-CRP, TNF-α, UAER, β2-MG and Cys C when compared with group A (all p<0.001). Compared to valsartan alone, valsartan combined with ALA can reduce level of inflammatory cytokines in serum and improve renal function.
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Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
Gerstein, HC, Colhoun, HM, Dagenais, GR, Diaz, R, Lakshmanan, M, Pais, P, Probstfield, J, Botros, FT, Riddle, MC, Rydén, L, et al
Lancet (London, England). 2019;(10193):131-138
Abstract
BACKGROUND Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING Eli Lilly and Company.
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High-Resistant Starch, Low-Protein Flour Intervention on Patients With Early Type 2 Diabetic Nephropathy: A Randomized Trial.
Meng, Y, Bai, H, Yu, Q, Yan, J, Zhao, L, Wang, S, Li, Z, Wang, Q, Chen, L
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2019;(5):386-393
Abstract
OBJECTIVE The objective of this study is to explore the effect of high-resistant starch (RS), low-protein flour as a source of RS on patients with early type 2 diabetic nephropathy (DN) through the clinical intervention trial. DESIGN This was a single center, randomized, comparative, open-label trial. Seventy-five patients with early DN, aged 18 to 80 y, were recruited and randomly assigned to two groups. During the 12-week intervention, the control group patients (38 cases) followed protein-restriction diet daily with a common staple. The intervention group (37 cases) received 50 g of high-RS, low-protein flour instead of a common staple of equal quality at lunch and dinner each day. The blood glucose, blood lipids, nutritional parameters, indicators of renal function, oxidative stress, and inflammatory markers were measured. RESULTS Compared with the control group, high-RS, low-protein flour intake led to a significant reduction in fasting blood glucose, HbA1c, total cholesterol, and triglycerides levels (P < .05 for all). The changes in serum uric acid (UA) and β2-microglobulin (β2-MG) level were observed after high-RS, low-protein flour intervention (uric acid [mean ± standard deviation]: -24.7 ± 38.5 μmol/L, P = .001; β2-MG: 0.5 ± 0.9 mg/L, P = 0.018). In addition, high-RS, low-protein flour intake increased serum superoxide dismutase level by 10.1 ± 27.7 U/mL (P < .05); however, it did not change the interleukin-6 and Tumor Necrosis Factor α (TNF-α) concentration. CONCLUSIONS Twelve-week intervention with high-RS, low-protein flour improved the blood glucose and blood lipid levels, decreased the serum uric acid (UA) and urine β2-MG, and enhanced the ability to prevent antioxidative stress in patients with early DN.
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Impact of Moderate Sodium Restriction and Hydrochlorothiazide on Iodine Excretion in Diabetic Kidney Disease: Data from a Randomized Cross-Over Trial.
Binnenmars, SH, Corpeleijn, E, Kwakernaak, AJ, Touw, DJ, Kema, IP, Laverman, GD, Bakker, SJL, Navis, G
Nutrients. 2019;(9)
Abstract
Sodium restriction may potentially reduce iodine intake. This study aimed to determine the effect of sodium restriction (dietary counseling) on 24-h urinary iodine excretion. Diuretics provide an alternative to sodium restriction and are frequently added to sodium restriction, so the effects of hydrochlorothiazide (50 mg daily) and combined therapy were also studied. We performed a post-hoc analysis of a Dutch multi-center, randomized cross-over trial in 45 patients with diabetic kidney disease with a mean age of 65 ± 9 years, mean eGFR of 65 ± 27 mL/min/1.73 m2, median albuminuria of 648 [230-2008] mg/24 h and 84% were male. During regular sodium intake with placebo, mean 24 h urinary sodium and iodine excretion were 224 ± 76 mmol/24 h and 252 ± 94 ug/24 h, respectively (r = 0.52, p < 0.001). Mean iodine excretion did not change significantly if sodium restriction and hydrochlorothiazide were applied separately; mean difference -8 ug/day (95% CI -38, 22; p = 0.6) and 14 ug/day (95% CI -24, 52; p = 0.5), respectively. Combined therapy induced a significant decrease in mean iodine excretion (-37 ug/day; 95% CI -67, -7; p = 0.02), yet this was not seen to a clinically meaningful level. The number of patients with an estimated intake below recommended daily allowances did not differ significantly between the four treatment periods (p = 0.3). These findings show that sodium restriction is not a risk factor for iodine deficiency.
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Effects of High-dose Vitamin E Supplementation on Markers of Cardiometabolic Risk and Oxidative Stress in Patients with Diabetic Nephropathy: a Randomized Double-blinded Controlled Trial.
Aghadavod, E, Soleimani, A, Hamidi, G, Keneshlou, F, Heidari, A, Asemi, Z
Iranian journal of kidney diseases. 2018;(3):156-162
Abstract
INTRODUCTION Patients with diabetic nephropathy (DN) may benefit from vitamin E's antilipid and antioxidant activities. This study aimed to evaluate the effects of high-dose vitamin E supplementation on markers of cardiometabolic risk and oxidative stress in patients with DN. MATERIALS AND METHODS This randomized controlled trial was carried out on 54 patients with DN that were randomly divided into 2 groups to receive vitamin E supplement (800 IU/d) or placebo for 12 weeks. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine markers of cardiometabolic risk and oxidative stress. RESULTS Vitamin E supplementation, compared with the placebo, resulted in a significant reduction in serum total cholesterol (-14.3 ± 29.9 mg/dL versus -0.8 ± 13.1 mg/L, P = .03), low-density lipoprotein cholesterol (-16.4 ± 28.5 mg/dL versus 0.1 ± 17.2 mg/L, P = .01), and ratio of total cholesterol to high-density lipoprotein cholesterol ratio (-0.5 ± 0.7 versus 0.1 ± 0.5, P = .001), and a significant elevation in vitamin E levels (39.7 ± 12.4 nmol/mL versus -0.5 ± 1.3 nmol/mL, P < .001) and high-density lipoprotein cholesterol levels (1.4 ± 3.7 versus -2.1 ± 5.1 mg/L, P = .006). It also resulted in a significant elevation in plasma glutathione levels. CONCLUSIONS Our study demonstrated that high-dose vitamin E supplementation for 12 weeks had favorable effects on lipid profile and glutathione levels of patients with DN, except for triglycerides, very low-density lipoprotein cholesterol, nitric oxide, and total antioxidant capacity levels.
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AGE Content of a Protein Load Is Responsible for Renal Performances: A Pilot Study.
Normand, G, Lemoine, S, Villien, M, Le Bars, D, Merida, I, Irace, Z, Troalen, T, Costes, N, Juillard, L
Diabetes care. 2018;(6):1292-1294
Abstract
OBJECTIVE Chronic kidney disease is associated with higher morbidity and mortality in patients with diabetes. A low-protein diet is recommended to slow diabetic nephropathy progression because each protein load leads to renal hemodynamic variations. The aim of our study was to evaluate whether the advanced glycation end products (AGE) content of a protein load is responsible for the protein-induced renal hemodynamic variations in humans. RESEARCH DESIGN AND METHODS Ten healthy subjects were assigned to a high-protein (1 g/kg) low-AGE (3,000 kU AGE) versus high-AGE (30,000 kU AGE) meal. Renal perfusion, oxygen consumption, and oxygen content were measured before and 120 min after each meal. RESULTS Renal perfusion (3.2 ± 0.5 vs. 3.8 ± 0.4 mL/min/g; P = 0.0002) and oxygen consumption (0.3 ± 0.04 vs. 0.4 ± 0.08 min-1; P = 0.005) increased significantly after the high-AGE meal compared with the low-AGE meal. CONCLUSIONS Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content.