scholarly journals Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial

BMJ Open ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. e053019
Author(s):  
David J Leehey ◽  
Kimberly Carlson ◽  
Domenic J Reda ◽  
Ian Craig ◽  
Christina Clise ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Usual Care ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Controlled Trial ◽  
Scientific Journal ◽  
Phosphodiesterase Inhibitor ◽  
Major Adverse Cardiovascular Events ◽  
Diabetic Kidney ◽  
Study Results

IntroductionDiabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD.Methods and analysisVeterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period.Ethics and disseminationThis study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal.Trial registration numberNCT03625648.

scholarly journals The New and the Old: Platform Cross-Validation of Immunoaffinity MASS Spectrometry versus ELISA for PromarkerD, a Predictive Test for Diabetic Kidney Disease

Proteomes ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 31
Author(s):  
Scott Bringans ◽  
Kirsten Peters ◽  
Tammy Casey ◽  
Jason Ito ◽  
Richard Lipscombe
Keyword(s):  
Mass Spectrometry ◽  
Kidney Disease ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Clinical Laboratory ◽  
Predictive Test ◽  
Protein Biomarkers ◽  
Diabetic Kidney ◽  
Technology Platforms ◽  
Mass Spectrometry Assay

PromarkerD is a proteomics derived test for predicting diabetic kidney disease that measures the concentrations of three plasma protein biomarkers, APOA4, CD5L and IBP3. Antibodies against these proteins were developed and applied to a multiplexed immunoaffinity capture mass spectrometry assay. In parallel, and facilitating current clinical laboratory workflows, a standard ELISA was also developed to measure each protein. The performance characteristics of the two technology platforms were compared using a cohort of 100 samples, with PromarkerD test scores demonstrating a high correlation (R = 0.97). These technologies illustrate the potential for large scale, high throughput clinical applications of proteomics now and into the future.

scholarly journals Mitochondrial DNA: A New Predictor of Diabetic Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yajing Huang ◽  
Jingwei Chi ◽  
Fanxiang Wei ◽  
Yue Zhou ◽  
Yihai Cao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Endothelial Damage ◽  
Inflammatory Factors ◽  
Mtdna Copy Number ◽  
Diabetic Kidney ◽  
Patients With Diabetes ◽  
Stage Renal Disease

Diabetic kidney disease (DKD) is a common cause of end-stage renal disease, and diagnosis and treatment in time can help delay its progress. At present, there are more and more studies on the pathogenesis of DKD; mitochondrial dysfunction plays an important role in DKD. The occurrence and development of DKD is closely related to epigenetic changes and the interaction between mtDNA, ROS, inflammatory factors, and endothelial damage, which continuously aggravates kidney. The change of mtDNA is both the cause of DKD and the result of DKD. It is of great significance to incorporate the change of mtDNA into the monitoring of patients with diabetes. Existing evidence indicates that changes in mtDNA copy number in blood and urine reflect mitochondrial dysfunction and the severity of DKD. However, large-scale, long-term follow-up clinical trials are still needed to determine the threshold range. By the time, mitochondrial-targeted antioxidants will become a new method for the treatment of DKD and other diabetic complications; mtDNA also can be a therapeutic target for them.

scholarly journals Metabolomics in Diabetic Kidney Disease: Unraveling the Biochemistry of a Silent Killer

2016 ◽  
Vol 44 (2) ◽  
pp. 92-103 ◽  
Author(s):  
Manjula Darshi ◽  
Benjamin Van Espen ◽  
Kumar Sharma
Keyword(s):  
Kidney Disease ◽  
Small Molecules ◽  
Animal Studies ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Acid Oxidation ◽  
Treatment Interventions ◽  
Diabetic Kidney ◽  
Bioinformatic Tools ◽  
Large Scale Analysis

The development of new therapies for chronic diseases, such as diabetic kidney disease (DKD), will continue to be hampered by lack of sufficient biomarkers that will provide insights and will be responsive to treatment interventions. The recent application of metabolomic technologies, such as nuclear magnetic resonance and mass spectroscopy, has allowed large-scale analysis of small molecules to be interrogated in a targeted or untargeted manner. Recent advances from both human and animal studies that have arisen from metabolomic analysis have recognized that mitochondrial function and fatty acid oxidation play key roles in the development and progression of DKD. Although many challenges in the technology for clinical chronic kidney disease (CKD) are yet to be validated, there will very likely be ongoing major contributions of metabolomics to develop new biochemical understanding for diabetic and CKD. The clinical application of metabolomics and accompanying bioinformatic tools will likely be a cornerstone of personalized medicine triumphs for CKD.

Effects of the chymase inhibitor fulacimstat in diabetic kidney disease—results from the CADA DIA trial

2020 ◽  
Author(s):  
Peter Rossing ◽  
Jorma Strand ◽  
Angelo Avogaro ◽  
Michael Becka ◽  
Friederike Kanefendt ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Enzyme Inhibitor ◽  
Controlled Trial ◽  
Least Square ◽  
Analysis Of Covariance ◽  
Ang Ii ◽  
Tissue Remodelling ◽  
Diabetic Kidney ◽  
Chymase Inhibitor

Abstract Background The protease chymase generates multiple factors involved in tissue remodelling including angiotensin II (Ang II) and has been implicated in the pathophysiology of diabetic kidney disease (DKD). This study investigated the effects of the chymase inhibitor fulacimstat on albuminuria in patients with Type II diabetes mellitus and a clinical diagnosis of DKD. Methods In this double-blind, randomized, placebo-controlled trial, patients were on the maximum tolerated dose of either an Ang II receptor blocker or an Ang-converting enzyme inhibitor since at least 3 months before the screening visit. Eligible patients were randomized in a 2:1 ratio to treatment with either 25 mg fulacimstat (n = 99) or placebo (n = 48) twice daily on top of standard of care. Results The randomized patients had a mean urine albumin–creatinine ratio (UACR) of 131 mg/g (range: 29–2429 mg) and a mean (standard deviation) estimated glomerular filtration rate of 60.8 ± 16.9 mL/min/1.73 m2 before treatment start. Fulacimstat was safe and well tolerated, and achieved mean total trough concentrations that were ∼9-fold higher than those predicted to be required for minimal therapeutic activity. UACR increased by 27.4% [coefficient of variation (CV) 86%] and 3% (CV 88.9%) after 24 weeks of treatment with placebo or fulacimstat, respectively. Analysis of covariance revealed a least square mean UACR ratio (fulacimstat/placebo) of 0.804 (90% CI 0.627–1.030, P = 0.1477), indicating a statistically non-significant UACR reduction of 19.6% after fulacimstat treatment compared with placebo. Conclusions Fulacimstat was safe and well tolerated but did not reduce albuminuria in patients with DKD. These findings do not support a therapeutic role for chymase inhibition in DKD.

scholarly journals Diabetic kidney disease: update on clinical management and non-glycaemic effects of newer medications for type 2 diabetes

2021 ◽  
Vol 12 ◽  
pp. 204201882110206
Author(s):  
Áine M. de Bhailís ◽  
Shazli Azmi ◽  
Philip A. Kalra
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Major Adverse Cardiovascular Events ◽  
Diabetic Kidney ◽  
Renal Outcomes ◽  
First Choice ◽  
Treatment Of Diabetes

Type 2 diabetes is a leading cause of chronic kidney disease worldwide and continues to increase in prevalence. This in turn has significant implications for healthcare provision and the economy. In recent years there have been multiple advances in the glucose-lowering agents available for the treatment of diabetes, which not only modify the disease itself but also have important benefits in terms of the associated cardiovascular outcomes. The cardiovascular outcome trials of agents such as glucagon-like peptide-1 receptor agonists (GLP-RAs) and sodium glucose cotransporter 2 inhibitors (SGLT-2) have demonstrated significant benefits in reducing major adverse cardiovascular events, admissions for heart failure and in some cases mortality. Secondary analysis of these trials has also indicated significant renoprotective benefit. Canagliflozin and Renal Outcomes in Type 2 Diabetes Mellitus and Nephropathy (CREDENCE) a renal-specific trial, has shown major benefits with canagliflozin for renal outcomes in diabetic kidney disease, and similar trials with other SGLT-2 inhibitors are either underway or awaiting analysis. In this article we review current goals of treatment of diabetes and the implications of advancing renal impairment on choice of treatments. Areas discussed include the diagnosis of diabetic kidney disease and current treatment strategies for diabetic kidney disease ranging from lifestyle modifications to glycaemic control. This review focuses on the role of GLP-RAs and SGLT-2 inhibitors in treating those with diabetes and chronic kidney disease with some illustrative cases. It is clear that these agents should now be considered first choice in combination with metformin in those with diabetes and increased cardiovascular risk and/or reduced renal function, and in preference to other classes such as dipeptidyl peptidase-4 (DPP-4) inhibitors or sulphonylureas.

scholarly journals A Multidisciplinary Approach for Improving Quality of Life and Self-Management in Diabetic Kidney Disease: A Crossover Study

2020 ◽  
Vol 9 (7) ◽  
pp. 2160
Author(s):  
Nancy Helou ◽  
Dominique Talhouedec ◽  
Maya Zumstein-Shaha ◽  
Anne Zanchi
Keyword(s):  
Quality Of Life ◽  
Renal Function ◽  
Kidney Disease ◽  
Glycemic Control ◽  
Usual Care ◽  
Diabetic Kidney Disease ◽  
Self Management ◽  
Diabetic Kidney ◽  
Diet Habits

Individuals with diabetic kidney disease are at high risk of complications and challenged to self-manage. Previous research suggested that multidisciplinary approaches would improve health outcomes. This study investigated the effect of a multidisciplinary self-management approach of diabetic kidney disease on quality of life, and self-management, glycemic control, and renal function. A uniform balanced crossover design was used because it attains a high level of statistical power with a lower sample size. A total of 32 participants (aged 67.8 ± 10.8) were randomized into four study arms. In differing sequences, each participant was treated twice with three months of usual care alternated with three months of multidisciplinary management. The intervention improved the present dimension of quality of life demonstrating higher mean rank as compared to usual care (52.49 vs. 41.01; p = 0.026, 95% CI) and three self-care activities, general diet habits, diabetes diet habits, and blood sugar testing (respectively: 55.43 vs. 38.31; p = 0.002, 56.84 vs. 37.02; p = 0.000, 53.84 vs. 39.77; p = 0.008; 95% CI). Antihypertensive medication engagement was high across the study period (Mean = 95.38%, Min = 69%, Max = 100%). Glycemic control and renal function indicators were similar for the intervention and the usual care. Studies are needed to determine how the new recommended therapies for diabetic kidney disease such as SGLT2 inhibitors and GLP-1 receptor agonists impact on self-management and quality of life.

scholarly journals Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julie Klein ◽  
Cécile Caubet ◽  
Mylène Camus ◽  
Manousos Makridakis ◽  
Colette Denis ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Enzyme Inhibitor ◽  
Oral Treatment ◽  
Drug Repurposing ◽  
Water Soluble ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Connectivity Mapping

Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

scholarly journals Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons

2019 ◽  
Vol 8 (3) ◽  
pp. 287 ◽  
Author(s):  
Javier Donate-Correa ◽  
Víctor G. Tagua ◽  
Carla Ferri ◽  
Ernesto Martín-Núñez ◽  
Carolina Hernández-Carballo ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Positive Impact ◽  
Drug Repositioning ◽  
Phosphodiesterase Inhibitor ◽  
Western World ◽  
Renal Protection ◽  
Diabetic Kidney ◽  
Definitive Evidence

Diabetic kidney disease is one of the most relevant complications in diabetes mellitus patients, which constitutes the main cause of end-stage renal disease in the western world. Delaying the progression of this pathology requires new strategies that, in addition to the control of traditional risk factors (glycemia and blood pressure), specifically target the primary pathogenic mechanisms. Nowadays, inflammation is recognized as a critical novel pathogenic factor in the development and progression of renal injury in diabetes mellitus. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic properties clinically used for more than 30 years in the treatment of peripheral vascular disease. In addition, this compound also exerts anti-inflammatory actions. In the context of diabetic kidney disease, pentoxifylline has shown significant antiproteinuric effects and a delay in the loss of estimated glomerular filtration rate, although at the present time there is no definitive evidence regarding renal outcomes. Moreover, recent studies have reported that this drug can be associated with a positive impact on new factors related to kidney health, such as Klotho. The use of pentoxifylline as renoprotective therapy for patients with diabetic kidney disease represents a new example of drug repositioning.

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